Treatment options and outcomes for older AML patients.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"213",leadTitle:null,fullTitle:"Environmental Management in Practice",title:"Environmental Management in Practice",subtitle:null,reviewType:"peer-reviewed",abstract:"In recent years the topic of environmental management has become very common. 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Acute myeloid leukaemia (AML) is a heterogeneous group of malignant haematological diseases. It is predominantly a disease of older adults, with a median age at diagnosis of 68 years [1]. Indeed, 75% of the AML patients are older than 60 years (Figure 1). Besides a higher incidence of AML at older age, AML in older adults differs biologically and clinically from AML in younger adults [2]. AML in older adults is characterised by a markedly reduced long-term survival resulting from the combination of poor chemotherapeutic tolerance and inherent chemotherapy resistance compared with younger AML patients [3]. AML in older adults has a lower frequency of favourable core-binding chromosomal abnormalities and a higher incidence of complex aberrant karyotypes [4, 5]. These differences in clinical and cellular behaviour of AML in older adults suggest activation of different target genes by oncogenic events in aged stem or progenitor cells compared with younger stem or progenitor cells. Indeed a distinct gene-expression profile noted for older compared to younger adults with AML supports a molecular basis for disparities in outcome related to age [2, 5, 6]. In addition, more frequent comorbid conditions, the decreased immune competence of older patients and psychosocial factors influence treatment outcome of AML in older adults. The effects of age on both disease- and patient-related factors result in a lower rate of disease remission, a higher incidence of early death during chemotherapy, and a reduced probability of long-term survival [2, 3]. In light of this, population based studies report a treatment percentage of only 30% in AML patients aged 65 and older [7, 8]. Indeed, regardless of treatment, outcomes for older AML patients are unsatisfactory, with median overall survival (OS) of 5–10 months and 5-year survival of about 10% [9, 10, 11]. In contrast with the progress made for younger adults with AML, the treatment in older adults has not improved significantly in recent decades, despite numerous efforts to find effective and tolerable treatments [12].
AML incidence rates by age at diagnosis (2013–2017).
The optimal treatment of older adults with AML in daily clinical practice remains challenging, and is dependent on patient characteristics (age, performance, comorbidities), disease characteristics (cytogenetic and molecular abnormalities, white blood cell count) and the preference of the patient [3]. Regular treatment options include: best supportive care (BSC), low-dose chemotherapy (e.g. low dose cytarabine (LDAC)), hypomethylating agents (HMA), and intensive chemotherapy (IC) (Table 1).
Response: CR/CRi (%) | Median OS (months) | 2-year OS (%) | 5-year OS (%) | |
---|---|---|---|---|
41–70 36–78 | 10–20 7–34 | 12–42 53 | 10–30 36 | |
18 | 4 | — | — | |
15–47 | 8–13 (25) | 20–50 | Not curative, unless consolidated with HCT | |
+ HMA [19] + LDAC [60] + IC [65] + LDAC [66] | — —66 48 30–40 78 —40 17 53–67 | — —14.7 8.4 11–13 —14.7 8.8 15 | — — — — —45.6 | — |
Treatment options and outcomes for older AML patients.
Population data from the Swedish Acute Leukaemia Registry suggest the majority of older patients should be considered candidate for antileukemic therapy [13]. However, only few prospective randomised studies in older AML patients are available to guide treatment decisions. A pivotal clinical trial, although with a limited number of patients (n = 60), showed that standard IC decreases early death rates and improves long-term survival compared with BSC [14]. Also LDAC and gemtuzumab ozogamicin (GO) have been reported to result in superior survival compared with BSC; although neither had an effect in patients with adverse cytogenetics [15, 16].
In addition to IC and LDAC, the armamentarium for the treatment of AML has been expanded in recent years with two cytosine analogues with DNA hypomethylating properties: azacitidine and decitabine. The hypomethylating agents (HMAs) azacitidine and decitabine have relatively mild side effects and are particularly feasible for the treatment of AML in older patients and patients with comorbidities. Importantly, both azacitidine and decitabine have proven efficacy in patients with adverse cytogenetic abnormalities. Although not in their primary analyses, recent phase III trials have shown the superiority of azacitidine and decitabine treatment compared with conventional care for older AML patients [17, 18].
New combinations of HMAs with targeted drugs are being explored. Recently, the results of a phase 3 study of azacitidine in combination with venetoclax versus azacitidine alone in treatment-naïve adults with AML, who were ineligible for standard induction therapy, have been reported (VIALE-A trial; NCT02993523). This study confirmed the additive value of venetoclax to azacitidine treatment by an increase in remission rate from 28–66% and an increase in median OS from 9.6 months to 14.7 months [19]. The high remission rate which was achieved by adding venetoclax to azacitidine treatment is striking. Studies are ongoing to explore the added value of IDH1 or IDH2 inhibitors (ivosidenib or enasidenib) in combination with azacitidine and azacitidine plus venetoclax, for those older AML patients with mutated
Optimal treatment selection for older patients also requires consideration of treatment tolerance and life expectancy, derived from the evaluation of comorbidities, physical function and cognition [2]. Charlson comorbidity index >1 and haematopoietic cell transplantation comorbidity index (HCT-CI) >2 have been reported to be associated with lower remission rates, increased early mortality and decreased survival in patients treated with IC [20, 21, 22]. In a study on 177 patients aged ≥65 years who received IC the early death rates were 3% if the HCT-CI score was 0, 11% if the HCT-CI score was 1 to 2, and 29% if the HCT-CI score was ≥3 [20]. In addition, performance status, scored according to ECOG or WHO guidelines, has shown to be associated with survival in several studies [10, 23, 24].
To adequately assess fitness in older patients, beyond performance status and comorbidities, geriatric assessment (GA) is attracting more attention. GA is an approach to the evaluation of multiple patient characteristics (i.e. physical function, comorbid disease(s), cognitive function, psychological state, social support, polypharmacy, nutritional status) to help characterise individual patient complexity and discriminate among fit, vulnerable and frail patients. GA in older AML patients has been associated with treatment outcomes. In a single-institution prospective study conducted with AML patients ≥60 years of age treated with IC, geriatric assessment performed at diagnosis was associated with survival. In this study (n = 74, median age 68 years), impaired physical performance (measured as short physical performance battery (SPPB) score < 9) and impaired cognition (measured as modified mini-mental state (3MS) exam score < 77) were independently associated with OS, after accounting for other disease and patient characteristics [25]. In a study of 107 non-intensively treated AML patients, the scores for independence in activities of daily living and the Karnofsky score for performance status were associated with survival in multivariate analysis [21]. Although randomised data of comprehensive assessment of older AML patients are lacking, the above mentioned studies support the use of pre-treatment performance and comorbidity assessment in the setting of AML therapy.
Various studies have been undertaken with the aim to create prediction models for treatment effectiveness and to provide support for an educated treatment choice in the setting of AML. These algorithms include patient-specific factors (e.g. performance, comorbidity, body temperature, age) and disease-specific factors (e.g. cytogenetics, white blood cell counts, blast counts, primary or secondary leukaemia, haemoglobin level, platelet count, fibrinogen level, serum concentration of lactate dehydrogenase (LDH)) [23, 24, 26, 27]. However, most prediction models have not been successfully validated in independent cohorts of older patients. In addition, the data used to create most of these algorithms come from a patient population selected to receive intensive chemotherapy and therefore likely do not reflect the real world of older patients with AML. Although prediction models might be useful in identifying patients who are ‘fit’ for intensive chemotherapy, this does not automatically imply for AML patients with specific disease characteristics (or combinations) associated with poor outcome. This includes the high-risk AML subtypes with mutant
The combination of anthracycline and cytarabine (‘3 + 7’) has been the standard of care for patients with AML for the last four decades [28]. However, the use of this regimen in older patients with AML does not yield similar results to those reported for younger patients, even in carefully selected patients. Although 50–60% of patients will attain a complete remission (CR), this does not translate into a similar survival benefit as for younger patients, with a 2-year survival of only 15–20% [3, 29]. To improve the outcome for older AML patients receiving intensive chemotherapy (IC) many studies have evaluated modifications of the traditional ‘3 + 7’ combination. Strategies have included dose attenuation [9, 30], addition of gemtuzumab ozogamicin (GO) [31, 32], addition of midostaurin [33], addition of lenalidomide [34], and other attempts (e.g. growth factors, modulation of multidrug resistance).
The HOVON43 study assessed the effect of an escalated daunorubicin dose (90 mg/m2 vs. 45 mg/m2) in older AML patients (> 60 years) receiving conventional ‘3 + 7’ chemotherapy [9]. Median age was 67 years and 24% of patients had an unfavourable or very unfavourable cytogenetic risk. Although the CR rate was higher in the escalated-treatment group (64% vs. 54% [P = 0.002]), this did not translate into a survival benefit (2-year OS 31% vs. 26% [P = 0.16]). However, an unplanned post-hoc analysis showed that patients in the escalated-treatment group who were 60 to 65 years of age had higher CR rates and increased survival compared to patients aged 60 to 65 years in the conventional dose group (CR rates 73% vs. 51% and 2-year OS 38% vs. 23%, respectively). These data suggest the survival benefit of an escalated dose of daunorubicin was limited to the younger part of older patients. The MRC-AML-14 study randomised patients four times to a higher (50 mg/m2) or lower (35 mg/m2) dose of daunorubin, a higher (400 mg/m2) or lower (200 mg/m2) dose of cytarabine, allocation to receive the multidrug resistance modulator PSC-833 or not, and to receive three or four courses of treatment [30]. The CR rate was 54% and 5-year OS 12% for all patients, and no benefits were observed in either dose escalation groups, or from a fourth course of treatment.
Several studies investigated the addition of GO to standard chemotherapy to improve outcome in older AML patients. The MRC-AML-16-I study (addition of 3 mg/m2 GO on day 1 of course 1) found 3-year relapse incidence and survival was significantly better in the GO arm (relapse 68% vs. 76%; survival 25% vs. 20%), although there was no difference in CR rate between both arms [31]. There was no difference in 30- or 60-day mortality and no major increase in toxicity with GO. The French ALFA-0701 trial investigated addition of fractionated doses of GO (3 mg/m2 on day 1, 4, and 7) to standard chemotherapy and found similar results in patients aged 50–70 years. The CR rate did not differ between both arms (81% in GO-arm vs. 75% in no GO-arm), but survival was increased in the GO-arm (median 34 vs. 19 months; 2-year OS 53.2% vs. 41.9%) [35]. However, in the EORTC-GIMEMA-AML17 trial, randomising patients to a course of GO (6 mg/m2 on day 1 and 15) followed by IC or IC alone, a trend for inferior survival in the GO-arm was observed (median OS 7.1 vs. 10 months) [32]. Patients aged ≥70 years did significantly worse with GO due to the combined effect of increased induction mortality and poorer OS among those not achieving CR. This study incorporated a higher dose of GO (6 mg/m2 vs. 3 mg/m2). GO, especially in higher doses, has been associated with increased toxicity and after initial FDA approval in 2000 was voluntarily withdrawn in 2010 after safety concerns. Since then fractionated doses have been proved safe and efficacious in a large meta-analysis of five randomised controlled trials, leading to re-approval in 2017 [36].
There is ongoing discussion whether older AML patients benefit from treatment with intensive chemotherapy. Retrospective analysis of the outcomes 446 older AML patients (≥70 years) treated with intensive chemotherapy between 1990 and 2008 showed that despite a reasonable CR rate of 45%, the median OS was only 4.6 months and 1-year survival 28% [37]. The surprisingly low median OS was due to high 4-week and 8-week mortality rates of 26% and 36%, and the authors concluded that intensive chemotherapy may not be beneficial to most older patients with AML, although some subgroups (e.g. CBF AML and good risk status) might benefit. In response to this, a Swedish group published updated outcomes of 998 unselected older AML patients, of who 55% received intensive chemotherapy between 1997 and 2006 and concluded that older patients do benefit from intensive treatment with a median OS in
For patients not eligible for intensive chemotherapy treatment a choice can be made between best supportive care (BSC), low dose chemotherapy (LDAC) or hypomethylating agents (HMAs). Several studies have shown the efficacy of the HMAs azacitidine and decitabine. In addition, HMAs are well-tolerated and have low extra-medullary toxicity. Therefore HMAs are very suitable for the treatment of older patients with AML.
Azacitidine was first studied in the context of high-risk myelodysplastic syndromes (MDS). A phase III trial conducted in intermediate-2 and high-risk MDS patients included a subset of patients with 20–30% blasts, who were reclassified to AML according to redefined WHO criteria [38, 39]. The relative efficacy and safety of azacitidine versus conventional care regimens (CCR; comprising prespecified allocation to BSC, LDAC, or IC) was thus compared in this subgroup of patients (n = 113) and showed an increased median OS (24.5 vs. 16.0 months, P = 0.005) and increased 2-year survival (50% vs. 16%, P = 0.001) for azacitidine-treated patients compared with CCR patients [40]. In addition, a phase III study on the efficacy of azacitidine versus CCR (standard IC, LDAC or BSC) in newly diagnosed AML patients with >30% blasts was conducted [17]. The median OS was longer in the azacitidine group compared to the CCR group (10.4 vs. 6.5 months), although in multivariate analysis significance was lost (HR 0.85 [95% CI 0.69–1.03], P = 0.101). However, in a pre-planned sensitivity analysis censoring for subsequent AML therapy, the median OS was 12.1 months versus 6.9 months in the azacitidine-arm and CCR-arm respectively, with a stratified HR 0.76 (95% CI 0.60–0.96, P = 0.019). Azacitidine was well tolerated as more than half of the patients received six or more treatment cycles. The difference in median OS between the two reported studies (24.5 months vs. 12.1 months) could be explained by the lower blast count in the first study and thereby selection of more indolent disease. Unfortunately both studies were not powered to detect direct differences between azacitidine treatment and intensive chemotherapy.
Decitabine is another hypomethylating agent registered for treatment of AML. Two decitabine schedules are currently in use in clinical practice: the 5-day schedule and the 10-day schedule. A randomised phase III trial compared the efficacy and safety of 5-day decitabine (20 mg/m2) (n = 242) with treatment choice of BSC (n = 28) or LDAC (n = 215) in older patients(≥ 65 years) with newly diagnosed AML and poor- or intermediate-risk cytogenetics [18]. The CR rate in the decitabine group was 15.7%. Although the planned primary analysis after 396 deaths did not show a significant improvement of OS with decitabine versus treatment choice (median OS 7.7 months vs. 5.0 months), an unplanned analysis after 446 deaths showed a significant benefit for decitabine (HR 0.82 [95% CI 0.68–0.99], P = 0.037). A small but pivotal phase II trial in 53 patients evaluated the effect of a longer 10-day decitabine schedule and found an increased CR rate of 47% and overall response of 64% with a median OS of 13 months [41]. The beneficial effects of the 10-day decitabine schedule were confirmed in two large single-centre retrospective studies that found response rates and median OS of 40% and 11 months, and 35% and 11 months, respectively [42, 43]. Recently, the result of a phase II trial directly comparing 5-day versus 10-day decitabine treatment was reported. The researchers concluded both schedules have similar efficacy (CR rates 29% vs. 30% [P = 0.88], median OS 5.5 vs. 6.0 months [P = 0.47]), although there was an uncorrected imbalance in disease characteristics favouring the 5-day schedule and the randomisation allocation was skewed towards the 10-day schedule [44]. Therefore caution has to be taken when interpreting the results. However, these data show that decitabine, both in 5-day and 10-day schedules, is efficient and suggest that decitabine as a single agent might provide a framework upon which to build future combination studies to improve outcomes for older AML patients.
Guadecitabine is a next generation HMA given subcutaneously which provides prolonged in vivo exposure to its active metabolite decitabine, thus offering potential clinical advantages over current HMAs. In a large randomised trial 815 untreated AML patients not eligible for IC were randomised to either guadecitabine (5 days 60 mg/m2 every 4 weeks) or a preselected treatment of azacitidine, decitabine, or LDAC (ASTRAL-1 trial, NCT02920008). Although this trial showed that guadecitabine is an effective drug, the trial did not achieve its primary endpoints of statistically significant superiority of guadecitabine vs. preselected treatment for CR or OS [45].
ASTX727 is a next generation HMA with a unique fixed-dose combination of the hypomethylating agent decitabine and the novel cytidine deaminase inhibitor, E7727 (cedazuridine). ASTX727 was designed to deliver decitabine by oral administration. By inhibiting cytidine deaminase, cedazuridine inhibits the major mechanism by which decitabine is degraded in the gastrointestinal tract and liver, and the combination therefore permits the efficient delivery of decitabine orally. It has shown promising effects in a phase II trial conducted in intermediate- and high-risk myelodysplastic syndromes and chronic myelomonocytic leukaemia patients [46]. This trial is now expanding to include AML patients (NCT04093570).
An important question is whether intensive chemotherapy is superior to hypomethylating agents in older AML patients. The results of the above reported clinical trials cannot be directly compared due to differences in patient population studied. The MD Anderson Cancer Center reported the results of a retrospective cohort study of 671 patients, including 114 patients treated with HMAs (either azacitidine or decitabine) and 557 patients treated with IC [47]. Both groups were balanced according to cytogenetics and performance status and were older than 65 years. Patients who had received IC had a higher CR rate compared to patients who had received HMAs (42% vs. 28% [P = 0.001], respectively). However, the median OS was comparable in the 2 groups (6.7 vs. 6.5 months, P = 0.41). Multivariate analysis confirmed that type of AML therapy (IC or HMAs) was not an independent prognostic factor for survival. Interestingly, this study revealed that decitabine was associated with improved median OS compared with azacitidine (8.8 vs. 5.5 months, respectively, P = .03), also in multivariate analysis. No published prospective randomised trials have compared the efficacy of azacitidine with decitabine nor the efficacy of intensive chemotherapy (‘3 + 7’) with hypomethylating agents. The results of the EORTC-1301 phase III trial, comparing upfront treatment with intensive chemotherapy or decitabine, are eagerly awaited (NCT02172872).
Low-dose cytarabine (LDAC) (20 mg twice daily for 10 days) has been used in the treatment of AML for several years. Treatment with LDAC has low toxicity and a higher CR rate than best supportive care (18% vs. 1%) [15]. Although the OS for the LDAC-treated group has been demonstrated to be statistically significantly better, it is worth noting that in absolute terms, the therapeutic advantage is marginal, with a prolongation of OS of only a few months. Additionally, the benefit is restricted to the small fraction of patients who achieve a response (median survival 19 months vs. 2 months in responders vs. non-responders respectively) [15]. Patients with adverse cytogenetics do not seem to benefit from LDAC. Combinations of LDAC with other agents have been tested in clinical trials and although some additions resulted in higher CR rates survival was not improved [48, 49, 50, 51, 52, 53]. Thus, the OS in patients receiving LDAC is still highly unsatisfactory (median 5 months) [3]. Recently, the results of the VIALE-C trial have been reported, demonstrating an increased efficacy by adding venetoclax to LDAC (see 7.1).
Since 2017 the FDA has approved 8 new drugs for the treatment of AML [54]. New developments to treat AML, especially in older patients, include 1) drugs targeting specific signalling pathways (like the hedgehog pathway or apoptosis); 2) drugs specifically targeting mutations in AML (e.g. targeting the epigenetic modifiers IDH1/IDH2 and mutated cytokine receptor FLT3) and 3) an alternative formulation of classic chemotherapeutic drugs (CPX-315).
Venetoclax (ABT-199/GDC-0199), an orally available inhibitor of the anti-apoptotic molecule Bcl-2, has shown great efficacy in chronic lymphocytic leukaemia [55, 56, 57]. After observing single-agent activity in AML cell lines [58], venetoclax has been tested as monotherapy in relapsed and refractory AML patients showing activity with a CR/CRi rate of 19% [59]. Promising results have been reported for combinatorial studies with venetoclax in AML. In the randomised phase 3 trial VIALE-C (LDAC +/− venetoclax) 211 patients were randomised 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus LDAC on days 1 to 10 [60]. The primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs. LDAC alone, although not statistically significant (hazard ratio [HR], 0.75; P = .11), and a median OS of 7.2 vs. 4.1 months, respectively. An unplanned analysis with additional 6-month follow-up did demonstrate a significant benefit with a median OS of 8.4 months for venetoclax added to LDAC (HR, 0.70; P = .04).
In addition, the results of a phase 3 study of venetoclax in combination with azacitidine versus azacitidine alone in treatment-naïve older AML patients, who were ineligible for standard induction therapy, have recently been reported (VIALE-A trial; NCT02993523). This study confirms the additive value of venetoclax to azacitidine by a significant increase in CR/CRi rate from 28–66% and an increase in median OS from 9.6 months to 14.7 months [19]. The high remission rate which can be achieved by adding venetoclax to azacitidine treatment is striking. The impressive results of this study will likely make the combination of an hypomethylating agent with venetoclax the new standard for the treatment of older unfit AML patients.
The
Glasdegib is small molecule inhibitor of the hedgehog receptor smoothened. The hedgehog pathway is important during embryogenesis but repressed after birth. However, aberrant hedgehog signalling has been identified in AML, particularly in leukaemic stem cells, and has been associated with chemoresistance [64]. Inhibition of hedgehog signalling with glasdegib has shown promising results. A phase II study evaluating the combination of glasdegib and intensive chemotherapy in patients over 55 years of age with newly diagnosed AML reported a CR rate of 40% and median OS of 14.7 months [65]. Glasdegib was also evaluated in combination with LDAC in older patients unfit for intensive chemotherapy. Patients receiving glasdegib + LDAC had increased CR rates, 17.0% vs. 2.3%, and improved median OS 8.8 vs. 4.9 months, compared to patients receiving LDAC alone [66]. Based on these results, the FDA has approved glasdegib in combination with LDAC for AML patients ≥75 years or patients ineligible for intensive chemotherapy. In addition, glasdegib is being evaluated in combination with hypomethylating agents and a phase III trial of glasdegib in combination with intensive chemotherapy is ongoing (BRIGHT AML1019, NCT03416179).
CPX-315 is a liposomal formulation that delivers a 5:1 fixed-molar ratio of cytarabine and daunorubicine. With the liposomal encapsulation both drugs can be delivered in a fixed ratio with the highest proportion of synergy to enhance treatment efficacy [67]. CPX-351 preferentially targets leukaemic cells to a greater degree than non-leukaemic cells in the bone marrow, leading to decreased cytotoxicity against normal haematopoietic cells [68]. A small study of CPX-351 as first-line therapy in 30 newly-diagnosed AML patients ≥65 years showed a promising remission rate of 53.2% with a median OS 14.5 months [68]. In a randomised phase II trial in older adults with untreated AML comparing CPX-351 and conventional ‘3 + 7’ treatment a trend towards increased response rates was observed in the CPX-351 group, 66.7% vs. 51.2%. Survival was comparable between both treatment groups (14.7 vs. 12.9 for the CPX-351 and ‘3 + 7’ group respectively). However, CPX-351 treatment was superior in the subset of secondary AML patients with a median OS of 12.1 months vs. 6.1 months in the ‘3 + 7’ group [67]. Superiority of CPX-351 to conventional ‘3 + 7’ chemotherapy in secondary AML, also including AML with MDS related changes, was confirmed in a phase III trial including 309 older AML patients. The observed remission rates were 47.7% vs. 33.3% and median OS was 9.6 vs. 6.0 months in favour of CPX-351 [69]. The safety profile of CPX-351 was similar to that of conventional chemotherapy.
Allogeneic haematopoietic cell transplantation (HCT), as post-remission treatment, offers the highest potential for long-term survival and cure for patients with AML. For younger patients, the choice for consolidation with an allogeneic transplant is nuanced, as particular younger patients with high-risk disease, entailing high-risk mutations and presence of measurable residual disease after treatment, benefit post-remission treatment with an allogeneic HCT. As older patients generally have low chance for long-term survival, also if they have “good-risk” cytogenetic abnormalities, allogeneic HCT should be considered in older (fit) AML patients [10, 70, 71]. Nevertheless, only a minority of older patients actually receives an allogeneic HCT [72, 73]. Allogeneic HCT in older patients is limited by concerns related to treatment-related mortality (TRM) (e.g. TRM is >40% in patients with a HCT-comorbidity score ≥ 3) [74]. However, the development of less toxic conditioning regimens (reduced intensity conditioning (RIC) and non-myeloablative (NMA)), has been an important conceptual change that has created the opportunity for older patients with AML to receive an allogeneic HCT. These conditioning regimen are less dependent on cytotoxic effects of the conditioning regimen and more dependent on the graft-versus-leukaemia effect.
Several studies evaluating allogeneic HCT after RIC in older AML patients have shown promising results. A phase II study of 114 older patients receiving an allogeneic HCT after RIC with fludarabine and busalfan reported a 2-year OS of 48% with a non-relapse mortality (NRM) of 15%. However, cumulative incidence of relapse was 44% at 2 years [75]. A large retrospective study analysing the outcomes of 1080 AML patients who underwent allogeneic HCT after RIC found a 2-year OS of 36% in patients age ≥ 65 years, a NRM of 34%, and 2-year relapse probability of 33% [76]. This analysis included several age groups ranging from 40 to above 65 years and found no significant impact of age on NRM, relapse, disease-free survival, or OS. In addition, studies comparing allogeneic HCT after RIC to conventional post-remission treatments have reported favourable outcomes with allogeneic HCT after RIC. A study comparing allogeneic HCT after RIC (n = 97), chemotherapy (n = 44), autologous transplantation (n = 23), and no further treatment (n = 336) as post-remission therapy reported a 5-year OS of 35% for patients receiving allogeneic HCT after RIC compared to 26% and 21% for chemotherapy/autologous transplantation and no treatment, respectively [77]. Multivariate analysis confirmed the beneficial effect allogeneic HCT after RIC on 5-year survival. A comparison between allogeneic HCT after RIC and chemotherapy in patients age 60–70 years showed that allogeneic HCT after RIC was associated with a lower risk of relapse at 3 years (32 vs. 81%) although NRM was increased (36% vs. 4%), leading to an OS of 37% vs. 25% at 3 years [78]. These studies underscore the delicate balance between sufficient antileukemic effect and treatment toxicity, which is challenging in post-remission treatment of older AML patients.
The efficacy and safety of NMA conditioning consisting of low-dose total body irradiation alone or combine with fludarabine (90 mg/m2) in older patients was evaluated in a prospective cohort of 372 patients aged 60 to 75 years. The OS at 5 years post-transplantation was 35% with an NRM of 27%. Relapse rate was 41% at 5 years indicating the need for further improvement [73]. Nevertheless, these data compare very favourably with historical data on long-term survival of about 10% after treatment of older AML patients with intensive chemotherapy without post-remission treatment with allogeneic HCT.
Treatment of relapsed or refractory (R/R) AML, in general, has presented challenges for haematologists for decades. Despite numerous clinical studies, outcomes are consistently disappointing with 5-year OS rates of ∼10%. Allogeneic HCT at the time of second complete remission remains the only reliable option with curative potential. For older patients, treatment of R/R AML is even more difficult and outcomes poorer. However, the availability of new drugs, like venetoclax, gilteritinib, ivosidenib and enasidenib offer reasonable chances of temporally disease control with acceptable side effects. This implies the importance of detailed molecular analysis, also in the R/R setting, as the R/R disease might contain different (targetable) mutations. Phase 1 studies are generally an option for those patients with a strong wish to receive treatment. Finally, only best supportive care with antibiotics and transfusions can be a preferable option.
Since the publications of Park and Eisenhammer in the 1960s to 1970s, we have gained better understanding on the pathogenesis of cryptoglandular infection leading to perianal abscesses and eventually fistula in ano. With this knowledge, we have moved in strides in producing numerous classifications and treatment options, ranging from minimally invasive techniques to surgical procedures that produces significant disruption to the anorectal anatomy.
Anorectal fistulous abscesses and chronic fistula-in-ano are the same disease. This view has been shared by both Parks and Eisenhammer [1, 2]. We tend to separate both topics and discuss the management separately. However, recent views suggest we should treat it as a same disease, both at different spectrum.
We have yet to achieve a gold standard as recurrence rates and success rates still varies widely across continent. I believe the reasons are:
Lack of comprehensive classification of fistula-in-ano due to a lack of understanding of the natural pattern and progression of the disease.
Lack of unified surgical approach to address different types of fistula-in-ano. Understanding and practices of surgical techniques varies according to institutions and regions.
Chapter Outline:
Revisiting the pathogenesis of cryptoglandular infection.
Relevant updates in anorectal anatomy.
Understanding the natural patterns of cryptoglandular abscesses and fistulas.
Review of practicality of classifications for fistula in ano.
Using natural patterns to classify anorectal abscess and fistula.
Definitive surgical treatment in acute abscess stage.
Emerging concepts in managing cryptoglandular anal fistulas.
In 1961, Park reported his study of 44 specimens of normal anorectal anatomy, and 30 resected specimens from fistula-in-ano surgery. Anal glands were racemose structure of widely ramifying ducts, opening internally via the anal crypts (at dentate line), and extended deep into internal sphincters or ends in the longitudinal layer. They never extend into external sphincter muscles. He concluded that, anal glands provided free channels for infection to pass from the anal lumen deep into the internal sphincter muscles [1]. This observation was echoed by Eisenhammer in 1966, who added that main concentration of large crypts was situated posteriorly, followed by the anterior commissure and last, laterally. Internal orifice of a fistula was always found at the crypt entrance in the pectinate line, at approximately the midlevel of the anal canal [2]. Another study in 1994 by Seow found that 1% of anal glands in fact do penetrate the external sphincter [3]. However, infection arising from external sphincter was never reported.
The term fistulous abscess was used by Eisenhammer; the acute stage represents the abscess, and the chronic stage represents the fistula [2]. Acute abscess progress to a recurrent acute abscess or a chronic infection within the anal glands [1]. Fistula is a granulation tissue tract, develops after abscesses spontaneously rupture or are surgically drainage, where it continues to discharge materials from infected anal gland/ducts. It is kept open by chronic granulomatous inflammation [1, 2].
Pyogenic infections constituting 90% of all cases [1, 2]. Parks noted that 73% of infections occurred at either anterior or posterior midline [1]. Eisenhammer postulated that this intermuscular infection is due to obstructive suppurative adenitis, where causative organism were intestinal bacilli, streptococcus or anaerobes [2].
The cryptoglandular infection pathogenesis remains relevant till present day. From the evidence of early studies, we can conclude that:
Anorectal abscess and fistula are essentially the same disease, both at different end of a spectrum, and therefore should always be treated as a single disease entity.
Origin of infection lies in deep to the internal anal sphincter and longitudinal layer, but not in the external sphincter based on clinical assessments. In the present-day practice, we understand this anatomical region as the intersphincteric space [4].
Majority of the origin of infection lies in either anterior or posterior aspect of anal canal.
Location of the internal opening should be predictable.
90% are pyogenic infection, which can be dealt with appropriate surgery and antibiotics.
Why does complex fistula occur?
Of course, secondary causes of complex fistula-in-ano are not uncommon. It can be due to tuberculosis, Crohn’s disease, perforated colonic diverticular disease or any form of pelvic sepsis [5, 6]. These are beyond the scope of this chapter.
Eisenhammer believes both spectrums of this disease have a pre-determined pattern and is predictable. He wrote: ‘When faulty surgery is performed, natural anatomic barriers become disrupted, new planes of infections opened, leading to complex and complicated conditions’ [6]. Recently, this concept is highlighted again. The pattern of spread should be predictable. Infection of the anorectal region should track in between the anogenital muscular and fascia layers rather than penetrating them, forming abscesses in various anorectal spaces. Anorectal musculature, fascias and spaces are constant. Therefore, the natural patterns of anal fistula should also follow a constant pattern [7].
To understand how cryptoglandular disease manifest as simple or complex disease, we should first discuss the natural patterns of cryptoglandular anorectal abscesses and fistulas.
Quoting Kurihara et al. in 2006, ‘To be able to successfully treat cryptoglandular anorectal abscesses and fistulas, we need to understand the exact anatomy and extension course’ [8]. Secondly, as mentioned before, we need to understand that infection will spread along the least resistant plane, along the planes of anorectal muscles and fascia to reach the respective anorectal spaces [7].
Important anatomical structures are depicted in Figure 1a and b. The internal sphincter and the longitudinal muscle are continuation of the circular and longitudinal smooth muscles of rectum respectively in the anal canal. There are 3 components of external sphincters, subcutaneous, superficial and deep external sphincters, whereas puborectalis is a component of the levator ani [1, 2]. Recent publications suggest that puborectalis is also known to be the same entity as deep external sphincter [7, 9]. Perianal space and Ishio-rectal fossa were described by Parks as the 2 most common spaces for abscess formation [1]. However, his postulation that the source of infection was between internal sphincter and longitudinal muscle was later updated [1].
Coronal view of the anorectal anatomy. Potential space for abscess to form; ISA: ischioanal space, IFL: Infralevator space, SL: Supralevator space, DPA: deep postanal space, PDS: posterior deep space (intersphincteric), IS: intersphincteric space, PRA: perianal space, SP: Superficial perineal space. SIF: septum of ischioanal fossa, TF: transversalis fascia, DPM: deep perineal membrane, ACL: anococcygeal ligament, IAS: internal anal sphincters. EAS: external anal sphincters, components: deep, sup (superficial) and sub (subcutaneous). Deep EAS is interchangeably termed puborectalis muscle. Sagittal view shows significant difference between anterior and posterior perineum. Deep perineal space lies above deep perineal membrane (DPM). Yellow lined arrows show postulated paths for intersphincteric sepsis to traverse the sphincter complex into respective anorectal spaces. Detailed explanation in segment 4.
Internal sphincter circular muscles and longitudinal muscle layer are fused together, and the intersphincteric plane is a potential space between the longitudinal layer and the fascia of striated muscle external sphincters [4, 7] (see Figure 1a and b).
Deep external sphincter overlaps with puborectalis (part of levator ani), and superficial external sphincter overlaps with deep external sphincter, implicating that the external sphincter is not a continuous sheet of striated muscles. The author made a clear distinction between puborectalis and deep external anal sphincter as 2 separate entities, with weak connective tissue between each group [8].
However, other view states that the vertical portion of the levator ani’s striated muscles around the anorectal ring is the puborectalis muscle, interchangeably known as the deep external sphincter [7]. This is supported by previous study by Shafik in 1975 confirming that puborectalis muscle and deep external sphincter are actually fused and functions as a single loop termed the top loop [9].
Both authors stipulate that there is a potential point of weakness between the vertical group and the horizontal group of striated muscles at the level of anorectal ring, allowing infection in the intersphincteric space to spread into the Infralevator space [7, 8].
The emerging terms of deep postanal space, posterior deep space and septum of ischiorectal fossa which will be explained next (refer to segments 4.2 & 4.5) [7, 8, 10, 11].
The anatomy of anterior perineum, especially superficial and deep perineal space are equally important to explain anterior patterns of abscesses and fistulas. Anterior perineum lacks puborectalis/deep external sphincter component. Posteriorly, there is a complex interconnection between intersphincteric space, supralevator space, posterior deep space and deep postanal space. (Shown in Figure 1b) Deep postanal space communicates with both ischioanal space and Infralevator space laterally and deep perineal space anteriorly (refer to segment 4.2) [7].
The 2 most common fistulas described by Park in 1976 were intersphincteric fistula and transphincteric fistula, which accounts for 75% of his series. Eisenhammer in 1966 also reported that 80% in his series were low intermuscular type. Infection arising from anal gland forms suppuration in the intersphincteric space, forming an intersphincteric abscess. Alternatively, it can track along the potential intersphincteric space caudally to the intersphincteric groove or along the subcutaneous external sphincter fibers/septaes to form a perianal abscess. This forms an intersphincteric fistula once it ruptures outwards. However, if it spreads between subcutaneous and superficial external sphincter, it forms a low transphincteric fistula and results in a perianal or ischiorectal abscess. These 2 patterns are the most common findings reported and can occur anteriorly or posteriorly [1, 5, 6, 7, 12].
Posterior perineum divided into 2 compartments, infra-levator space and the clinical ischioanal space by a septum [8]. Abscess in the intra-levator space presents similarly as a clinical supralevator abscess and may not be apparent from external inspection. It can tract anteriorly to the deep perineal space. Infection/abscesses in the clinical ischioanal space is easily diagnosed by clinical examination externally due to inflamed, indurated or fluctuant ischioanal fossa.
There are 3 levels of soft tissue compartments [7].
The lowest level consists of bulbus spongiosus and subcutaneous external sphincter, separated from the mid-level by transversalis fascia. Infection spreads radially in a linear fashion.
The mid-level is termed superficial perineal space containing superficial transverse perineii muscles at the same level as the superficial external sphincter, separated from the deep level by perineal membrane. In males, infection in this space can extend to the scrotal area.
The upper level is the deep perineal space, between the perineal membrane and the levator ani. It communicates posteriorly with the infra-levator space [7]. One should remember that in the deep perineal space, deep external sphincter or puborectalis is absent. Infection can spread between deep perineal space (anterior) and infra-levator space (laterally).
Low or high? This represents the level where infection extends through external sphincter into ischiorectal space. In clinical practice, we define low transphincteric fistula as those involving <1/3 of external sphincter, and high transphincteric fistula if >1/3 involved [12, 13]. Intersphincteric infection can pass through the external sphincter [1, 2, 8, 11], at junctions of each external sphincter portions [8]. If the infection passes through junction between levator ani and deep external sphincter, abscess may present as a Infralevator abscess, and the resulting fistula is a Suprasphincteric type as described by Park [5]. This typically occurs posteriorly and leads to horseshoe pattern (described in 2.2.5). On the other hand, if infection spread at the junction between superficial and deep external sphincter, it will cause ischioanal abscess and a high transphincteric fistula. A low transphincteric fistula results from infection spreading between the junction of superficial and subcutaneous external sphincter.
Infection originating from anterior glands or posterior glands will results in typical patterns. Various authors reported internal openings found mainly at the anterior or posterior anal canal, which corresponds well with infected anal gland/crypt [1, 6].
Anterior gland infection that spreads via transphincteric route have predictable patterns. A low transphincteric pattern will tract along the subcutaneous tissue and below transversalis fascia in a linear fashion. A high transphincteric pattern will tract along the perineal space, in male, it extends into the scrotum. In female, it may result in ano-vaginal fistula or opens around the labia majora or causes perineal abscesses. Anterior horseshoe pattern has also been reported. It extends into the ischioanal space at 11 and 1 o’clock position [2, 6, 7].
Posterior gland infections are as described in 4.3 and 4.5.
Hanley described the horseshoe pattern in detail; Infected anal glands originated from posterior midline of the anal canal, spreading along the longitudinal muscle cranially, passing superior or inferior to deep external sphincter (transphincteric extension) into the space known as deep postanal space. Deep postanal space communicates with both ischiorectal spaces above the surface of the superficial external sphincter. Pus will extend through the plane of least resistance into one or both ischiorectal spaces [10, 11].
In 2006, Kurihara made further anatomical discovery regarding posterior horseshoe pattern. Ischiorectal space is divided into 2 compartments by the septum of ischiorectal space, which starts at the Alcock’s canal to border between puborectalis (part of levator ani) and deep external anal sphincter. This septum is important as the inferior rectal vessels and nerve runs along this fascia layer to penetrate the upper anal canal wall at the deep external sphincter level. At the point where inferior rectal vessels and nerve enters the external sphincter, tissue is loose. Infection spreads upwards along the intersphincteric plane, forms a nidus at the level of deep external sphincter within the intersphincteric space, which is termed as posterior deep space. It can extend via the weak points into either above or below the septum of ischiorectal space, spread either unilaterally or bilaterally to form horseshoe abscesses/fistulas [8]. Both authors however agreed that the internal opening is usually situated at the mid-anal canal posteriorly [8, 10]. Rojanasakul reports that the posterior high transphincteric fistula can occurs at 5 and 7 o’clock position of the anal canal [7].
In rare cases, intersphincteric sepsis tracks cranially, reaching the supralevator space via intersphincteric plane, limited only by the fascia of levator ani (extension of pelvic fascia) [2, 5]. It is unlikely that these collections spread across the levator ani. However, it is possible for the collection to enter the deep postanal space (posteriorly) or infra-levator space via a high transphincteric path or a suprasphincteric path as described above, forming an infra-levator abscess. These 2 are difficult to differentiate clinically, and erroneous drainage of these abscesses may lead to more complex iatrogenic fistulas such as extra-sphincteric fistula or a translevator fistula. Therefore, MRI imaging is advocated if such pattern is suspected [14, 15].
There are numerous classifications of fistula in ano published over the last 4 decades. This chapter will focus on some of the most commonly used classifications to discuss the practicality in clinical scenario.
Park’s classification of fistula-in ano remains popular as the standard terminology used by surgeons. It was published in 1976, based on operative findings of 400 patients over a span of 15 years [5]. The 4 main types are commonly used and reproduced in literatures. However, minimal attention was actually paid to the 14 sub-types in his original report (refer to Figure 2). Park’s classification relied on intra-operative findings as it presented, and focused on the position or configuration of the fistula tract in relation to the external sphincter [5]. There were several disadvantages of this classification.
It does not stratify the complexity of each type of fistula, e.g. low or high fistula, single or multiple tracts.
It does not guide clinicians in locating the source of intersphincteric sepsis and in selecting appropriate surgical treatment.
His clinical findings are recently disputed by several studies using modern imaging, especially the suprasphincteric and extrasphincteric type [8, 14, 16]. Even in 1976, Park described that some cases had difficult anatomy due to fibrosis (recurrence and previous surgery), thus exact anatomy was not entirely ascertained. There was no imaging to guide the findings back then.
Park’s Classification in 1976. 4 main types with its sub-types (diagrams obtained from Park et al, 1976. A classification of fistula-in-ano. Br J Surg. 1976;63[1]:1–12). [
Eisenhammer published his final evaluation (refer to Table 4) based on low or high fistula, location of infection and pattern of spread. It was a useful guide for surgeons to predict the location of internal opening (intersphincteric infection) and course of fistula tract [6]. Eisenhammer stated that his series was mainly from private practice where all the patients presented to him were new cases, thus reporting the actual natural progression and patterns [6]. It is by far the most complete set of classification and focused on patterns of fistula, while stratifying each type by complexity. However, it did not gain popularity due to its’ complex terminologies.
In year 2000, St James University Hospital improved Park’s classification using Magnetic Resonant Imaging (MRI) studies. They analyzed 300 cases and classified fistula to five grades [16]. Essentially an anatomical classification, this classification refined the findings of Parks based on MRI (as shown in Table 1), splitting each of Park’s type I (intersphincteric fistulas) & II (transphincteric fistulas) in two further grades (grade I into I & II and grade II into III & IV) and fused grade III & IV into one grade (grade V) [16]. This classification attempts to stratify fistula into simple or complex, allowing clinicians to judge the use of simple fistulotomy or more complex strategies/expert referrals. However, like Park’s classification, it does not guide clinicians on the location of intersphincteric sepsis nor if the fistula is low or high. Furthermore, recent publications showed that not all intersphincteric fistulas are simple, and not all transphincteric fistulas are complex [7, 12].
St James’s Classification | Description | Park’s Classification |
---|---|---|
Grade 1 | Simple Linear Intersphincteric Fistula | Type 1 – Intersphincteric |
Grade 2 | Intersphincteric Fistula with intersphincteric abscess and secondary fistulous tract | |
Grade 3 | Trans-sphincteric Fistula | Type 2 - Transphincteric |
Grade 4 | Trans-sphincteric Fistula with abscess or secondary track within the ischioanal or ischiorectal fossa | |
Grade 5 | Supralevator & Translevator Disease | Type 3 – Suprasphincteric |
Type 4 - Extrasphincteric |
Comparison of St James Classification and Park’s Classification. The former recognizes the need to stratify Park’s Type 1 and 2 into simple and complex (information extracted from Morris et al, 2000. MR imaging classification of perianal fistulas and its implications for patient management, Radiographics 20 [2000] 623-635 discussion 635-7) [16].
A practical and simple solution was created by Standard Practice Task Force in 2005, classified fistula-in-ano in just two categories-simple and complex [17]. The treatment of complex fistulas posed a high risk to anal continence and in simple fistulas, fistulotomy could be done safely without any risk of incontinence. The latter usually involved less than one-third of sphincter complex. Fistulotomy is not recommended in complex fistulas.
However, a study in 2017 showed that 32.1% (93/290) of complex fistulas were amenable to fistulotomy [12]. Simple and complex classification was shown to overestimate complexity of fistula. Furthermore, it was not particularly useful for clinicians in differentiating different types or patterns of complexity and determining the specific management.
The most recent classification was introduced in 2017 and validated in 2020 with over 848 patients using combination of MRI study and intra-operative findings [12, 18]. This classification provided comprehensive and detailed grouping of anal fistula into 5 grades, from simple to complex grading (Table 2). In general, complexity was determined by low or high fistula, presence of multiple secondary tracts or collections. Intersphincteric and transphincteric fistulas were both recognized as simple if the fistula is low and safe for fistulotomy. This classification allows stratification of fistula-in-ano in a practical manner to guide their management strategies. Grade 1 and 2 fistulas were reported as safe to be treated with fistulotomy, whereas grade 3 to 5 requires more complex surgical strategy or expert referral (refer to Table 2) [12]. This method of stratification was validated to be safe. Following the Garg’s new classification, patients underwent fistulotomy did not show significant changes in continence score post operatively [18]. However, this grading method relies heavily on MRI, which is not readily available in all institutions. Furthermore, there are many subclassifications to remember and challenging complex type such as suprasphincteric, supralevator and extrasphincteric types, were group into a single category even though each have unique patterns.
Grade 1 | Low* Fistula with single branch | SIMPLE ¥ |
Intersphincteric or Transphincteric | ||
Grade 2 | Low* Fistula with multiple tracts, abscess or horseshoe. | |
Intersphincteric or Transphincteric | ||
Grade 3 | High* Transphincteric with single branch | |
Anterior fistula in female | ||
May have: Impaired continence, Crohn’s disease or Previous radiation | ||
Grade 4 | High* Transphincteric with | |
Multiple tracts, Abscess, Horseshoe. | ||
Grade 5 | High* Transphincteric with Supralevator tract | |
Or Suprasphincteric | ||
Or Extrasphincteric |
Garg’s New Classification of Anal Fistulas (information extracted from Garg [18]).
Low transphincteric: <1/3 of external sphincter involved. High transphincteric: > 1/3 of external sphincter involved.
Grade 1: Fistulotomy should be possible in almost all these fistulas (>95%). Grade 2: Fistulotomy should be possible in majority of these fistulas (>90%).
A useful classification allows clinicians:
To categorize various subsets or presentations of a disease for better understanding.
Stratification of a disease according to severity or complexity.
To guide clinicians in treatment strategy and prognostication.
In general, most of the classifications above do not fulfill all 3 criteria above. Garg’s classification was a significant improvement in categorizing, stratification and suggested treatment options for each grade. However, when faced with complex fistulas, there is still a general lack of understanding of its pathogenesis and optimal surgical treatment. This author believes, the step forward is to provide a more comprehensive treatment algorithm/guideline based on knowledge of natural patterns and progressions. To achieve this, the author believes classification based on natural patterns of cryptoglandular abscess and fistula will provide further insight.
The new idea. Most classifications focus on anatomical configurations of fistula. It is possible to classify anorectal abscesses and fistula-in-ano based on natural patterns. This type of classification is beneficial as:
It helps clinician to understand the pathogenesis better, leading to a better understanding of different types and patterns of complex fistulas.
It helps clinician to predict the source of infected anal glands and intersphincteric sepsis, and the same time identify secondary extensions and external tracts.
This author postulate that it may reduce clinicians’ reliance on imaging modalities.
Eisenhammer produced a classification method and later modified it in 1978 on his final evaluation of 800 patients over a span of 25 years. In general, the basis of his classification lied on low or high fistula/abscess, the position of the infected anal crypt (anterior or posterior), confined to intermuscular space (intersphincteric space) or spread to ischiorectal space [6]. However, it was not commonly utilized over the next few decades.
Rojanasakul proposed to classify the Natural Pattern of Anal Abscess and Fistula. It is effectively summarized into 5 main patterns and each pattern predicts the location of internal opening (refer to Table 3). This is paramount for surgeons to locate the offending anal gland/crypt for optimal treatment. Almost all patterns can be summarized by a simple classification of 5 patterns (refer to Figure 3) [7].
Pattern | Internal opening (& Intersphincteric tract) | Proportion |
---|---|---|
1. Intersphincteric pattern | Internal opening: any direction | 3.8% |
2. Low transphincteric pattern | Internal opening: any direction, most common anterior and posterior | 26.9% |
3. Anterior high transphincteric pattern | Internal opening: anterior. 11, 12 or 1 o’clock position | 27.9% |
4. Posterior high transphincteric pattern | Internal opening: posterior Common: posterior midline Less common: 5 and 7 o’clock position | 31.7% |
5. High intersphincteric pattern | Internal opening: posterior Common to occur concurrently with posterior high transphincteric fistula (horseshoe fistula) | 9.6% |
Summary of natural patterns of anorectal abscesses and fistulas with predicted internal opening, intersphincteric tract and proportion (information extracted with permission from Rojanasakul & Tsang, 2021. Emerging Concepts in Classification of Anal Fistulae. Pelvic Floor Disorders, Springer) [7].
Diagrammatic illustration of 5 types of natural patterns. SLA: Supralevator abscess. DPA: Deep post-anal abscess. Red dotted line represents the course of horseshoe pattern due to connection between deep post-anal space and ischioanal space/Infralevator space.
Type 4 and 5 can occur in combination. This is often complex and confusing to clinicians as it may present with a supralevator abscess concurrently with bilateral horseshoe or ischioanal abscesses (Shown in Figure 3). The key to managing this combination type is to address both the high intersphincteric tract and the high transphincteric tract with combination of surgical techniques (will be described in segment 8). When we compare both Eisenhammer’s finding to this new classification of natural patterns, we find that all of the previously described types can be simplified into these 5 main patterns (refer to Table 4). Clinicians should be mindful that it is possible for 2 patterns to occur concurrently [7].
Comparing current classification of natural patterns with Eisenhammer’s updated description and classification in 1978 [6, 7].
Infection occurs in the clinical ischiorectal space.
Infection occurs in the infra-levator space.
Ω π μAnterior high transphincteric pattern can present as bilateral horseshoe, anovulvar tract or unilateral horseshoe. Bilateral anterior horseshoe pattern tends to have a lower internal opening compared to unilateral anterior horseshoe pattern [2, 6]. However, no other studies reported similar findings.
Park attributes extrasphincteric fistula to the following causes: secondary to a transphincteric fistula, trauma, specific anorectal disease and pelvic inflammation [5]. Eisenhammer’s stated in both his initial series and final evaluation that extrasphincteric fistula was due to either iatrogenic probing or secondary causes such as pelvic sepsis, colonic diverticular diseases or inflammatory bowel disease [2, 6]. Garg’s evaluation of more than 400 patients with anal fistula using MRI reported that there were no cases of extrasphincteric fistula in his series [12]. The most probable cause of extrasphincteric fistula: It is a combination of posterior high transphincteric fistula and high intersphincteric fistula situated posteriorly, resulting in both supra-levator collection and Infralevator collection. Incorrect drainage or probing of either can lead to a communication between the two collections across the levator ani [7]. Therefore, it is reasonable to conclude that extrasphincteric fistula does not fit into the natural pattern of cryptoglandular infection. Its finding should alert surgeons of possibility of previous erroneous surgery or secondary sepsis originating from pelvis/abdomen [6].
Understanding the pathogenesis and natural pattern helps in management of fistula-in-ano. Lessons from early publications showed that successful treatment of fistula-in-ano lies on the ability of surgeons to eradicate the source of infection, which is the infected anal crypt/gland and the intersphincteric abscess/tract [1, 2, 10, 19]. Recent publications further emphasized on eradicating secondary tracts or abscesses to prevent recurrences [15, 20, 21]. Therefore, objective clinical assessment should assist clinicians to:
Identify the internal opening & intersphincteric tract/abscess.
Identify the location of anorectal space involved.
Identify the external tract and secondary branches.
Ascertain the level of sphincter involved.
In the author’s view, using the knowledge and classification of the Natural Patterns of Anal Abscess and Fistula [7], the above information can be actively sought after using a combination of clinical assessment and imaging modalities.
In cases of acute abscess, clinical examination generally elicits tenderness and fluctuation around perianal or ischioanal fossa. However, detailed assessment is usually informative with sedation, local or regional anesthesia. In high intersphincteric abscesses or Infralevator abscesses, tenderness is elicited on digital rectal examination at the anorectal ring. Examination under anesthesia may reveal pus discharge from internal opening upon insertion of anoscope. Perianal abscess is typical of type 1 (Intersphincteric) and type 2 (Low Transphincteric) patterns, and internal opening usually corresponds with the location of abscess. Ischioanal fossa abscess is the usual presentation of type 3 and 4 (high transphincteric) patterns. However, it should also be remembered that type 4 pattern produces Infralevator abscess, where internal opening is almost always posterior. Type 5 pattern produces high intersphincteric abscess and internal opening is usually posterior [6, 7].
In cases of chronic fistula, location of external opening and course of fistula tract should direct clinicians to the possible patterns. Low fistulas are clinically palpable as thickened fibrous cord extending from the external opening towards the infected anal crypt (internal opening). In high fistulas, tracts are usually not palpable subcutaneously. Digital examination may reveal chronic induration over the anorectal ring adjacent to lateral wall of rectum. External tracts usually runs deep and parallel with the anal canal on probing [6].
In cases where internal opening is not apparent, there are several techniques described to facilitate the identification of internal openings [6, 15].
Hard, board like changes to the deep surface of the internal sphincter usually represents the location of infected anal crypt.
Offending anal crypt retracts into a funnel on pulling the external tract.
Palpation of cord-like fibrous tract.
Internal opening probing: using hook or right-angled blunt tip forceps.
Gentle probing from external sinus: using small sized urethral catheter. Lacrimal probe is not advisable as it may cause false tracts.
Injection of dye (methylene blue solution) or water via external sinus.
Sensitivity of clinical examination in detecting the primary fistula tract is 68.7%, followed by 62.1% for secondary extension, and 59.7% for localizing internal opening [22]. Therefore, imaging is required as adjunct.
Magnetic resonant imaging (MRI) and Endoanal ultrasound (EAUS) are the 2 most reliable imaging modality to delineate anorectal abscess and fistula. Conventionally, both modalities are equally sensitive in detecting anal fistula, but MRI has slightly superior specificity compared to EAUS [23]. MRI is not readily available in all institutions, whereas EAUS is operator dependant and requires significant learning curve.
Kim et al. in 2009 reported that 3 dimensional endoanal ultrasound is the preferred method, and use of hydrogen peroxide contrast may increase the detection rate of anal fistula. Sensitivity in detecting primary fistula tract is 84.4%, 81.8% for secondary extension and 84.2% for localizing the internal opening [22].
Recently, the interest in MRI has surged, in line with renewed efforts from various institutions to produce new classifications [16, 18]. With the availability of MRI scan, the fistula could be assessed in all three dimensions (axial, coronal and sagittal) [14]. The sensitivity and specificity of MRI in diagnosing fistula tracts were 98.8 and 99.7%, and in identifying internal opening were 97.7 and 98.6% respectively [14]. In addition, MRI is able to reclassify simple fistula based on clinical assessment to complex fistula, as it has the extra benefit of detecting additional secondary tracts, horseshoe tracts and supralevator extensions [18].
Clinical assessment and imaging adjunct helps clinicians to identify internal opening and intersphincteric tract/abscess, location of abscess, external tracts and secondary tracts. It also helps to define low and high fistula. This information will assist clinicians to recognize the type of anal fistula/abscess, thus allowing stratification and planning for appropriate surgical treatment. Surgical treatment will be discussed in the next segments.
Eisenhammer wrote: ‘
Major guidelines recommend that immediate fistulotomy should be undertaken only by experienced surgeons, and a more conservative practice of simple abscess drainage in most circumstances is safest. Fistulotomy should only be done in low or simple fistulas [13, 25, 26]. This approach is known to be beneficial for 2 reasons: 1) Simple incision and drainage procedure, especially as an office procedure, allows quick return of function and daily living, thus avoiding prolong wound healing and hospital stay [2, 27]. 2) Less experienced surgeons may be confused with the exact anatomy of the fistula, or may cause iatrogenic injury and incorrect fistulotomy [6].
However, in the author’s view, definitive surgery during the acute abscess stage has its advantage. Sharing Eisenhammer’s view, the ideal management should be during the acute abscess stage [6]. Treating the fistula during acute abscess stage will reduce the number of chronic fistula formation [19]. A meta-analysis showed that definitive treatment leads to a risk reduction of 83% in recurrent fistula [24]. Furthermore, this is cost effective for health care facilities in general as the burden of treating chronic fistula is greatly reduced by reducing the need for re-operations.
Conventionally, several techniques were described in treating fistula during acute abscess stage. For perianal and ischioanal abscesses with identifiable fistula tract, fistulotomy, fistulectomy and cutting seton were used [19, 24, 25, 26]. Internal sphincterotomy was reported for intersphincteric abscess [6, 13]. Oliver reports performing immediate fistulotomy only for low transphincteric, intersphincteric and subcutaneous type, with recurrence rate of 5% [28].
A meta-analysis in 2006 analyzed 5 studies with a total of 405 patients showed that internal opening is not found in 10–17% of cases [24]. Inability to locate internal opening leads to higher recurrence rate as the source of infected anal crypt is not dealt with. Recurrence rate increased from 5–29% when internal opening was not found [28]. Imaging modalities are not readily available in cases of acute abscess.
The same meta-analysis reported that sphincter-cutting procedures like fistulotomy and cutting seton during acute abscess is associated with 2-fold increase of risk of fecal incontinence to flatus and soiling. Severe incontinence rate was reported up ranging from 0 to 40%, although sample sizes for most studies were small [24].
The principles of treating acute fistulous abscess were laid down by McElwain:
Identification and excision of offending anal crypt [19] – position of infected gland and internal opening
Laying open the intermuscular abscess cavity [19] – drainage of intersphincteric space
Create a superficial external drainage for abscess beyond the external sphincter [19] – drainage of extrasphincteric abscesses
This author adds another 2 important principles:
Keeping wound open for drainage and to allow secondary healing.
Preservation of continence as best as possible.
In line with sphincter preservation as an important principle, a recent prospective study showed promising results utilizing sphincter preserving techniques for drainage and definitive treatment of fistulous anorectal abscess [29]. 86 patients with anorectal abscesses were operated by a single surgeon with intention of definitive single stage surgery and preservation of sphincter muscles. Using Rojanasakul’s Natural Patterns of Anorectal Abscess and Fistula classification as guide, this study proposes 2 important steps: 1) Drainage of the perianal abscess at its most bulging point, 2) Exploration of the intersphincteric space to locate internal opening and intersphincteric tract/abscess. Internal opening was found in 95% of cases and intersphincteric tract was found in 77% of cases. Intersphincteric tract is treated with ligation as per LIFT procedure [4], whereas intersphincteric abscess were drained with suture closure of internal opening. Intersphincteric exploration wound is loosely closed with tube drains to promote drainage and secondary healing. This method reported overall healing rate of 83%, where the best results is obtained if intersphincteric tract is well formed. There were no cases of post-op incontinence. The remaining 17% non-healing group went on to elective surgery for definitive surgery of chronic fistula [29].
It is well known that in patients with anorectal abscesses undergoing simple drainage, 2/3 will progress to chronic fistula [27]. Definitive treatment of fistula may reduce the incidence of chronic fistula to an estimated below 30% based on recent evidence [28, 29]. With emerging sphincter preserving approaches, guided by our understanding of patterns of infection spread and imaging modalities, we are better equipped to approach acute fistulous abscesses with intention of single stage surgery.
Principle of surgical treatment of chronic fistula-in-ano should include the following:
Identification and removal of the source of sepsis in the intersphincteric space [1, 4, 6, 30].
Eradication of external and secondary tracts or abscesses [15, 20].
Maintaining the intersphincteric space open to heal by secondary intention [15].
Preservation of continence as best as possible [13, 25, 26].
An ideal surgical procedure should fulfill all 4 criteria above. Various surgical techniques have been described in literatures, ranging from sphincter cutting procedures to minimally disruptive biomaterials or novel techniques. In this segment, the author attempts to classify various surgical procedures into categories, thereby assessing its suitability for specific fistula types and adherence to the above principles.
Fistulotomy is the oldest, simplest, and most widely used procedure for anal fistulae. Most major guidelines recommend fistulotomy as a suitable and safe procedure for simple or low fistula [13, 25, 26]. This procedure involves laying open the entire fistula tract, together with the sphincter muscles it traverses, with adequate curettage to remove all granulation tissue tract [13, 31]. Marsupialization of the edges appears to speed up wound healing and reduces post-op pain and bleeding, but reported benefits were not significant [13]. Success rate is more than 90%, but incontinence rate is reported as high as 28% in elective setting [31]. According to Garg et al. in 2020, fistulotomy performed on low intersphincteric and low transphincteric fistulas (Garg’s Classification grade 1 & 2) is safe. Post-operative mean continence score increased from 0.044 to 0.135, without reaching statistical significance. Low fistula is defined as involvement of less than 1/3 of external sphincter [18]. Failure of treatment or recurrence is associated with inappropriate selection of patients with high fistula or multiple tracts [31].
Internal sphincterotomy was first reported by Eisenhammer in 1966 to treat low intermuscular fistula (low intersphincteric type) which accounted for majority of cases in his series [2]. The principle is similar to fistulotomy, where the only difference is only lower half of internal sphincter muscles were laid open to eradicate intersphincteric sepsis. This technique gradually became synonymous with fistulotomy in various literatures as later studies showed that low intersphincteric type is far less common than low transphincteric type [7, 12]. In recent decade, ASCRS Practice Parameters introduced it as a treatment for intersphincteric fistulous abscess [13]. This technique is suitable for low intersphincteric type and does not cause incontinence [6].
Surgeons generally try to avoid sphincter cutting techniques. Ligation of Intersphincteric Tract (LIFT) procedure avoids sphincter cutting, using a small incision to explore the intersphincteric space to ligate and excise the intersphincteric tract [4] or to drain intersphincteric abscess [29]. Additional procedure in combination with LIFT such as closure of internal opening, excision of external tract and bioprosthetic mesh have been reported to improve outcomes [32]. A recent report from the original birthplace of LIFT procedure reported 10 year overall primary healing rate of 87.65%, and overall healing rate after re-operation was 99.2%. True recurrences were due to recanalization as a result of incorrect identification of intersphincteric tract. However, majority of recurrences were due to infection in the intersphincteric wound, leading to intersphincteric fistula which was easily treated by fistulotomy [20]. Other reports cited Crohn’s disease, complex multiple fistulas and horseshoe pattern as a common cause of recurrences [33], stressing the importance of identification of secondary tracts and abscesses. In the author’s view, LIFT procedure is best combined with additional curettage, drainage or excision of external fistula tracts/abscess. Recently, the original author reported slight modification where LIFT incision was loosely approximated and tube drain inserted to reduce intersphincteric space infection and promote secondary healing [29]. A recent meta-analysis and systematic review reported overall pooled success rate of 76.5% and incontinence rate of 1.4% [21].
Excision of fistula with immediate sphincter reconstruction is an alternative to reduce the risk of incontinence, at the same time completely eradicate intersphincteric and secondary tracts. It is suitable for both low and high transphincteric fistula. Procedure is similar as described in 8.1, with additional sphincter repair to restore continuity. Term as Fistulotomy or fistulectomy with primary sphincteroplasty (FIPS), Ratto reports 93.2% overall success rate, with a low morbidity rate [33]. Overall postoperative worsening continence rate was 12.4% mainly post-defecation soiling, without significant changes in anorectal manometry parameters [33]. In general, this technique produces higher success rate compared to LIFT procedure, albeit variations of techniques and terms used across institutions [34]. Incontinence is still a major concern, despite being much lower than fistulotomy alone. It is recommended in the German’s S3 guideline but not in other major guidelines [26]. In the author’s recent experience, this procedure produces excellent outcome in both low and high transphincteric chronic fistula, and extrasphincteric secondary (branching) tracts can be excised or curetted concurrently. However, in acute abscess stage, initial seton drainage is preferred prior to FIPS to reduce the risk of breakdown of sphincter repair [34].
Loose draining seton allows initial control of sepsis prior to definitive surgery to improves success rate. German S3 guideline used the term fibrosing seton [26]. It allows drainage of abscess and forms a thick fibrous fistula tract, which can be dealt with easily on the next elective surgery. Draining seton before LIFT shows no added benefits [32]. However, seton before fistulotomy and sphincter reconstruction showed benefits in downstaging high transphincteric to low transphincteric type [34]. From personal experiences, seton drainage can also be utilized to drain ischioanal/Infralevator collections with multiple external openings after debridement or curettage to prevent extensive wounds in the perineum.
Many sphincter saving biomaterials and novel techniques surfaced in the last 4 decades to deal with complex fistula with wide variation of success rates across continents. Among those are anal fistula plug [35, 36], fibrin glue [26], laser procedures [37], Video Assisted Anal Fistula Tract Treatment (VAAFT) [38] and endoscopic clips (OTSC) [39]. Across the board, none of these procedures have reported very high success rate. This is likely due to the fact that most procedures, in their attempt to avoid cutting sphincters, only focus on the closure of internal opening and/or the fistula tract, but do not eradicate the intersphincteric sepsis and its secondary tracts. The author’s opinion is that these procedures are highly specialized and are often based on selected specialized institutions. Therefore, usage of these techniques should be reserved to experts of the respective fields.
Garg described an improved procedure in 2017 for high fistulas termed Transanal Opening of the Intersphincteric Space (TROPIS) [30]. High intersphincteric tracts and abscesses are typically difficult to reach via intersphincteric approach or conventional probing from external opening, and usually branching. TROPIS procedure allows lay open and drainage of these tracts into the anal canal, thus eradicating septic nidus at the high intersphincteric plane, which is usually posterior and was termed as the posterior deep space in the previous segment 4.5. This is done through the internal opening and external sphincter is not cut. The external branching tracts in the ischiorectal fossa were curetted. The space is left open for secondary healing. In the initial prospective cohort of 61 patients, success rate was 84.6% with no significant changes in continence score. The series consist of a mixture of high transphincteric type (anterior and posterior) and high intersphincteric type [30]. Incision on the internal sphincter is shown to be safe without worsening incontinence [2, 30, 40]. In author’s personal experience, TROPIS procedure is an excellent approach for high intersphincteric type and posterior high transphincteric type, especially if transphincteric fistula is located at the puborectalis level. However, like LIFT procedure, combination with drainage, curettage or excision of external tracts is necessary to reduce recurrences.
To achieve good outcomes for anal fistula surgery, the author concludes that; 1) Understanding of type and natural patterns of fistula is extremely important, 2) The 4 principles of surgical treatment should be adhered to as closely as possible, and 3) No one surgical technique is suitable for all types of fistula. Therefore, selecting the appropriate procedure is important and to our best knowledge, no guidelines or classifications so far outlines a complete treatment algorithm especially on complex fistulas. Based on this review of evidence and best clinical judgment of the author, Table 5 below attempts to summarize reasonable treatment options available for different fistula types to guide surgeons, where combination of procedures, additional procedures or modification of procedures is preferred over single modality (refer to Table 5).
Type of pattern | Suitable procedure | Intersphincteric sepsis eradication | Eradication of external and secondary tracts/abscesses | Healing by secondary intention | Preservation of continence |
---|---|---|---|---|---|
1. Low Intersphincteric | Fistulotomy or Internal Sphincterotomy | Yes | NA | Yes | Yes |
FIPS | Yes | NA | NA | Yes | |
2. Low Transphincteric | Fistulotomy | Yes | Yes | Yes | Unpredictable |
FIPS | Yes | Yes | NA | Yes | |
LIFT | Yes | Yes | Yes | ||
3. Anterior High Transphincteric | FIPS* | Yes | Yes | NA | Yes |
LIFT | Yes | Yes | |||
4. Posterior High Transphincteric | FIPS | Yes | Yes | NA | Yes |
LIFT | Yes | Yes | |||
TROPIS | Yes | Yes | Yes | ||
5. High Intersphincteric | TROPIS | Yes | Yes | Yes | Yes |
6. Combination type 4 & 5 | Combination: TROPIS + | Yes | Yes | Yes | |
Staged approach. TROPIS, draining seton and delayed LIFT or FIPS | Yes | Yes | Yes | Yes |
Summary of appropriate surgical treatment for different types of fistula pattern based on the principles of surgical treatment. No single procedure is 100% successful, therefore our clinical judgment is important in deciding on additional procedures, combination, staged approaches or modification to achieve our goal.
Caution in performing FIPS in anterior transphincteric fistula, especially in female patients where external sphincter is thin, lack of support anteriorly and risk injuring perineal body.
CED: Short for closure of external sphincter defect. After lay open of intersphincteric tracts and abscesses, an attempt is made to close the defect where transphincteric tract traverses the external sphincter. This can be done transanally or via external opening wound.
Mod: Modification by loosely approximate incision with tube drains to allow drainage and secondary healing of intersphincteric wound [29].
Add: Additional procedures includes drainage of ischioanal/Infralevator abscess, curettage or excision of external tracts, insertion of drains to the ischiorectal space [15, 29, 30].
Seton: Use of loose draining seton for drainage, induce fibrosis to form thickened tract and allows downgrading of high to low transphincteric fistula [34].
NA: Not applicable.
Revisiting the anatomy and pathogenesis facilitates us to understand the natural patterns of anorectal abscess and fistula. With this new idea, we are able to classify and stratify this disease according to level of complexity and sphincter involvement, thus selecting the appropriate tool to manage it. Definitive treatment in acute abscess stage is feasible if the principles are followed. Surgical options and strategies should be carefully selected to suite each pattern, while adhering to the principles of surgical treatment. Challenges in managing cryptoglandular fistula-in-ano are summarized in Appendix (Table 6). The proposed solution is carefully selected from the current review of evidence and the experience of a high-volume tertiary centre.
The author would like to acknowledge Dr. Khairul Mustaqim Mazlan, Hospital Universiti Sains Malaysia (Kota Bharu) for contributing the graphics and figures in this paper, and Dr. Ng Hui Been, Hospital Raja Pemaisuri Bainun (Ipoh) for her contribution in prove reading and language editing.
The author declares no conflict of interest.
Challenges | Complications | Proposed solution |
---|---|---|
i. Confusion in classification | • Wrong diagnosis | Adapting classifications that allows clear delineation of patterns, stratification of severity and guides management [7, 12] |
• Wrong stratification into simple or complex | ||
ii. Incorrect delineation of pattern | • Wrong procedure | Combination of clinical assessment and imaging modalities: MRI, EAUS |
• Risk of recurrence and incontinence | ||
iii. Acute abscess | • Develop chronic fistula | McElwain’s principle [19] |
Consider intersphincteric exploration [29] | ||
iv. High fistula | • Difficult to delineate | Role of MRI [15] |
• High risk of incontinence if treated with sphincter cutting surgery | TROPIS procedure [30] | |
v. Multiple secondary tracts and abscesses | • Risk of recurrence if not completely treated | Role of MRI and natural patterns classification [7, 14] |
• Technically more demanding | Additional procedures: drainage, curettage, excision. | |
vi. Internal opening not found | • Risk of recurrence | Combination of clinical assessment and imaging modalities: MRI, EAUS |
Attempt closure of internal opening at its predicted site [29]. |
Challenges in managing fistula-in-ano, with summary of its complications and proposed solutions.
Special gratitude to my beloved wife, Dr. Ingrid Ting for her unwavering support in the process of completing this writing.
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The Open Access publishing movement started in the early 2000s when academic leaders from around the world participated in the formation of the Budapest Initiative. They developed recommendations for an Open Access publishing process, “which has worked for the past decade to provide the public with unrestricted, free access to scholarly research—much of which is publicly funded. Making the research publicly available to everyone—free of charge and without most copyright and licensing restrictions—will accelerate scientific research efforts and allow authors to reach a larger number of readers” (reference: http://www.budapestopenaccessinitiative.org)
\n\nIntechOpen’s co-founders, both scientists themselves, created the company while undertaking research in robotics at Vienna University. Their goal was to spread research freely “for scientists, by scientists’ to the rest of the world via the Open Access publishing model. The company soon became a signatory of the Budapest Initiative, which currently has more than 1000 supporting organizations worldwide, ranging from universities to funders.
\n\nAt IntechOpen today, we are still as committed to working with organizations and people who care about scientific discovery, to putting the academic needs of the scientific community first, and to providing an Open Access environment where scientists can maximize their contribution to scientific advancement. By opening up access to the world’s scientific research articles and book chapters, we aim to facilitate greater opportunity for collaboration, scientific discovery and progress. We subscribe wholeheartedly to the Open Access definition:
\n\n“By “open access” to [peer-reviewed research literature], we mean its free availability on the public internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from gaining access to the internet itself. The only constraint on reproduction and distribution, and the only role for copyright in this domain, should be to give authors control over the integrity of their work and the right to be properly acknowledged and cited” (reference: http://www.budapestopenaccessinitiative.org)
\n\nOAI-PMH
\n\nAs a firm believer in the wider dissemination of knowledge, IntechOpen supports the Open Access Initiative Protocol for Metadata Harvesting (OAI-PMH Version 2.0). Read more
\n\nLicense
\n\nBook chapters published in edited volumes are distributed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0). IntechOpen upholds a very flexible Copyright Policy. There is no copyright transfer to the publisher and Authors retain exclusive copyright to their work. All Monographs/Compacts are distributed under the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0). Read more
\n\nPeer Review Policies
\n\nAll scientific works are Peer Reviewed prior to publishing. Read more
\n\nOA Publishing Fees
\n\nThe Open Access publishing model employed by IntechOpen eliminates subscription charges and pay-per-view fees, enabling readers to access research at no cost. In order to sustain operations and keep our publications freely accessible we levy an Open Access Publishing Fee for manuscripts, which helps us cover the costs of editorial work and the production of books. Read more
\n\nDigital Archiving Policy
\n\nIntechOpen is committed to ensuring the long-term preservation and the availability of all scholarly research we publish. We employ a variety of means to enable us to deliver on our commitments to the scientific community. Apart from preservation by the Croatian National Library (for publications prior to April 18, 2018) and the British Library (for publications after April 18, 2018), our entire catalogue is preserved in the CLOCKSS archive.
\n\nOpen Science is transparent and accessible knowledge that is shared and developed through collaborative networks.
\n\nOpen Science is about increased rigour, accountability, and reproducibility for research. It is based on the principles of inclusion, fairness, equity, and sharing, and ultimately seeks to change the way research is done, who is involved and how it is valued. It aims to make research more open to participation, review/refutation, improvement and (re)use for the world to benefit.
\n\nOpen Science refers to doing traditional science with more transparency involved at various stages, for example by openly sharing code and data. It implies a growing set of practices - within different disciplines - aiming at:
\n\nWe aim at improving the quality and availability of scholarly communication by promoting and practicing:
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However, before attributing health benefits to these compounds, absorption, distribution, and metabolism of each phenolic compound in the body are important points that should be considered.",book:{id:"5609",slug:"phenolic-compounds-biological-activity",title:"Phenolic Compounds",fullTitle:"Phenolic Compounds - Biological Activity"},signatures:"Igor Otavio Minatel, Cristine Vanz Borges, Maria Izabela Ferreira,\nHector Alonzo Gomez Gomez, Chung-Yen Oliver Chen and\nGiuseppina Pace Pereira Lima",authors:[{id:"146379",title:"Dr.",name:"Giuseppina",middleName:null,surname:"Lima",slug:"giuseppina-lima",fullName:"Giuseppina Lima"},{id:"194002",title:"MSc.",name:"Cristine",middleName:null,surname:"Vanz Borges",slug:"cristine-vanz-borges",fullName:"Cristine Vanz Borges"},{id:"194003",title:"Prof.",name:"Igor Otavio",middleName:null,surname:"Minatel",slug:"igor-otavio-minatel",fullName:"Igor Otavio Minatel"},{id:"194004",title:"Dr.",name:"Maria Izabela",middleName:null,surname:"Ferreira",slug:"maria-izabela-ferreira",fullName:"Maria Izabela Ferreira"},{id:"194005",title:"Prof.",name:"Hector",middleName:null,surname:"Gomez-Gomez",slug:"hector-gomez-gomez",fullName:"Hector Gomez-Gomez"},{id:"194006",title:"Prof.",name:"Chung-Yen Oliver",middleName:null,surname:"Chen",slug:"chung-yen-oliver-chen",fullName:"Chung-Yen Oliver Chen"}]},{id:"45635",title:"Application of Cellulose and Cellulose Derivatives in Pharmaceutical Industries",slug:"application-of-cellulose-and-cellulose-derivatives-in-pharmaceutical-industries",totalDownloads:10348,totalCrossrefCites:60,totalDimensionsCites:138,abstract:null,book:{id:"3173",slug:"cellulose-medical-pharmaceutical-and-electronic-applications",title:"Cellulose",fullTitle:"Cellulose - Medical, Pharmaceutical and Electronic Applications"},signatures:"Javad Shokri and Khosro Adibkia",authors:[{id:"140056",title:"Prof.",name:"Javad",middleName:null,surname:"Shokri",slug:"javad-shokri",fullName:"Javad Shokri"}]},{id:"57200",title:"Introductory Chapter: Principles of Green Chemistry",slug:"introductory-chapter-principles-of-green-chemistry",totalDownloads:2816,totalCrossrefCites:2,totalDimensionsCites:7,abstract:null,book:{id:"6067",slug:"green-chemistry",title:"Green Chemistry",fullTitle:"Green Chemistry"},signatures:"Hosam El-Din Mostafa Saleh and M. Koller",authors:[{id:"144691",title:"Prof.",name:"Hosam M.",middleName:null,surname:"Saleh",slug:"hosam-m.-saleh",fullName:"Hosam M. Saleh"},{id:"218817",title:"Dr.",name:"Martin",middleName:null,surname:"Koller",slug:"martin-koller",fullName:"Martin Koller"}]},{id:"66517",title:"Microbial Cellulases: An Overview and Applications",slug:"microbial-cellulases-an-overview-and-applications",totalDownloads:3563,totalCrossrefCites:42,totalDimensionsCites:91,abstract:"Cellulases are a complex group of enzymes which are secreted by a broad range of microorganisms including fungi, bacteria, and actinomycetes. In the natural environment, synergistic interactions among cellulolytic microorganisms play an important role in the hydrolysis of lignocellulosic polymer materials. In fact, it is the combined action of three major enzymes which determines the efficiency of this process. They are exoglucanases, endoglucanases, and β-glucosidase. Microorganisms produce these enzymes in a diverse nature which determines their efficiency in cellulose hydrolysis. During the cellulose degradation reaction, the enzyme targets the β-1,4-linkages in its polymeric structure. This is an essential ecological process as it recycles cellulose in the biosphere. The application of this same scenario for industrial purposes is identified as an emerging area of research. Biofuel production, textile polishing and finishing, paper and pulp industry, and lifestyle agriculture are among the key areas where cellulase enzyme shows a broader potential. The objective of this chapter is to discuss the structure, function, possible applications, as well as novel biotechnological trends of cellulase enzymes. Furthermore, possible low-cost, enzymatic pretreatment methods of lignocellulosic material in order to use it as an efficient raw material for biofuel production will be discussed.",book:{id:"7363",slug:"cellulose",title:"Cellulose",fullTitle:"Cellulose"},signatures:"Sandhya Jayasekara and Renuka Ratnayake",authors:null}],onlineFirstChaptersFilter:{topicId:"85",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"65119",title:"Introductory Chapter: Polyaniline - From Synthesis to Practical Applications",slug:"introductory-chapter-polyaniline-from-synthesis-to-practical-applications",totalDownloads:975,totalDimensionsCites:2,doi:"10.5772/intechopen.83397",abstract:null,book:{id:"7503",title:"Polyaniline - From Synthesis to Practical Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7503.jpg"},signatures:"Florin Nastase"}],onlineFirstChaptersTotal:1},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:90,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:107,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:33,numberOfPublishedChapters:330,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:14,numberOfPublishedChapters:145,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:9,numberOfPublishedChapters:139,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:122,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:112,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:21,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:10,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:1,numberOfPublishedChapters:19,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:"2753-6580",doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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