Carcinogenesis of Male Oral Submucous Fibrosis Alters Salivary Microbiomes.

Most oral squamous cell carcinoma (OSCC) tumors arise from oral premalignant lesions. Oral submucous fibrosis (OSF), usually occurring in male chewers of betel quid, is a premalignant stromal disease characterized by a high malignant transformation rate and high prevalence. Although a relationship between the inhabited microbiome and carcinogenesis has been proposed, no detailed information regarding the oral microbiome of patients with OSF exists; the changes of the salivary microbiome during cancer formation remain unclear. This study compared the salivary microbiomes of male patients with OSCC and a predisposing OSF background (OSCC-OSF group) and those with OSF only (OSF group). The results of high-throughput sequencing of the bacterial 16S rRNA gene indicated that OSF-related carcinogenesis and smoking status significantly contributed to phylogenetic composition variations in the salivary microbiome, leading to considerable reductions in species richness and phylogenetic diversity. The microbiome profile of OSF-related malignancy was associated with increased microbial stochastic fluctuation, which dominated the salivary microbiome assembly and caused species co-occurrence network collapse. Artificial intelligence selection algorithms consistently identified 5 key species in the OSCC-OSF group: Porphyromonas catoniae, Prevotella multisaccharivorax, Prevotella sp. HMT-300, Mitsuokella sp. HMT-131, and Treponema sp. HMT-927. Robust accuracy in predicting oral carcinogenesis was obtained with our exploratory and validation data sets. In functional analysis, the microbiome of the OSCC-OSF group had greater potential for S-adenosyl-l-methionine and norspermidine synthesis but lower potential for l-ornithine and pyrimidine deoxyribonucleotide synthesis and formaldehyde metabolism. These findings indicated that the salivary microbiome plays important roles in modulating microbial metabolites during oral carcinogenesis. In conclusion, our results provided new insights into salivary microbiome alterations during the malignant transformation of OSF.

JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

Management of complex anorectal fistulas with seton drainage plus partial fistulotomy and subsequent ligation of intersphincteric fistula tract (LIFT).

BACKGROUND: Ligation of intersphincteric fistula tract (LIFT) is a relatively new technique in the treatment of complex anorectal fistulas. As it spares the anal sphincter, rates of post-operative incontinence may be lower when compared to conventional treatment. To date, there have not been enough reports of long-term fistula recurrence rates. We performed a long-term follow-up study of 75 patients who underwent LIFT following seton drainage and partial fistulotomy. METHODS: Only patients with complex cryptogenic anorectal fistulas were included. After seton insertion and partial fistulotomy, the tract was reviewed at 4 months for the absence of anorectal sepsis. Patients then underwent LIFT in a day surgery setting. Operative time, complications, recurrences and incontinence were evaluated. RESULTS: Between May 2008 and June 2013, 75 patients [51 men, mean age 49.5 years, standard error of the mean (SEM) 1.4 years] were treated with a LIFT protocol. The mean operating time for LIFT was 13.2 min (SEM 1.5 min). Complications included minor bleeding, superficial wound dehiscence and perianal pain. At a mean follow-up of 14.6 months (SEM 1.7 months), there were nine (12 %) recurrences, diagnosed at a mean 9.2 months (SEM 2.7 months). They were treated with seton insertion followed by LIFT with biomesh or anorectal advancement flap, and there were no subsequent recurrences. Review of preoperative and post-operative continence scores revealed only one (1.3 %) patient with minor incontinence following LIFT. Recurrences were significantly related to fistulas with multiple tracts (p < 0.001). CONCLUSIONS: Our results suggest that the protocol of seton insertion and partial fistulotomy followed by LIFT is associated with a low recurrence rate comparing well with published results from studies involving other techniques and protocols for treating anal fistula.

Harmonic scalpel compared with conventional excisional haemorrhoidectomy: a meta-analysis of randomized controlled trials.

BACKGROUND: Haemorrhoidectomy is the most effective and definitive treatment for grade 3 or 4 haemorrhoids despite being associated with considerable pain. The aim of this study was to search the literature, which compares outcomes of harmonic scalpel haemorrhoidectomy and traditional surgical procedures, and conduct a quantitative meta-analysis of the randomized trials. METHODS: Randomized controlled trials (RCTs) were identified from the major electronic databases using the keywords "harmonic scalpel haemorrhoidectomy" and "haemorrhoidectomy" and a quantitative meta-analysis conducted. The eight trials that met the inclusion criteria included 468 patients (233 in the harmonic scalpel group). Pain was the primary outcome measure, and other parameters assessed included duration of operation, length of hospital stay, time to return to work, and complications. RESULTS: Significantly, more patients returned to work in the first post-operative week, and pain scores were an average of one unit lower following harmonic scalpel haemorrhoidectomy. Generally, the incidence of complications in the harmonic scalpel group was less than half that found in conventional haemorrhoidectomy. There was no significant difference between the groups as regards operating time or length of hospital stay. Recurrence was not reported in any of the studies. CONCLUSIONS: The meta-analysis showed that harmonic scalpel haemorrhoidectomy is a safe and effective modality associated with less post-operative pain and a more rapid return to work than traditional surgery for haemorrhoids. Statistical heterogeneity was high; thus, it may be too early to place complete confidence in these results. Further RCTs are required.

Factors influencing circumferential resection margin in rectal cancer.

AIM: Abdominoperineal excision (APR) has been associated with higher circumferential resection margin (CRM) involvement and local recurrence rates than extralevator APR for low rectal cancer. This study aimed to evaluate the CRMs in APR and low anterior resection (LAR) specimens and to identify factors influencing CRM involvement. METHOD: All pathological specimens from consecutive patients with rectal cancer who underwent curative resection at the Cleveland Clinic Florida, from January 2000 to July 2010, were reviewed by two pathologists. Demographics, tumour characteristics, operative data, postoperative pathology and Dworak's tumour regression grade were compared between specimens with positive and negative CRMs. RESULTS: One-hundred and fifty-four patients underwent curative APR (n = 65) or LAR (n = 69). Mean tumour size was 3.6 cm, and mean distance from the dentate line was 5.4 cm. Nine (6.8%) patients had a positive CRM (n = 6 APR, n = 3 LAR), which was associated with tumour size > 5.9 cm (P = 0.002), a distance of ≤ 2.6 cm from the dentate line (P = 0.013), microvascular invasion (P = 0.009), perineural invasion (P < 0.001), number of positive lymph nodes (P = 0.046) and incomplete total mesorectal excision (TME) (P < 0.001). APR specimens were three times more likely than LAR specimens to have an incomplete mesorectum (9.8%vs 2.9%, P = 0.322). CONCLUSIONS: Factors associated with a positive CRM were tumour size > 5.9 cm, a distance of ≤ 2.6 cm from the dentate line, incomplete TME, number of positive nodes and microvascular and perineural invasion. The incidence of a positive CRM was not significantly different between LAR and APR (n = 3 LAR and n = 6 APR).

Biofeedback therapy for symptoms of bowel dysfunction following surgery for colorectal cancer.

BACKGROUND: Following colorectal cancer (CRC) surgery, up to 60% of patients experience post-surgery bowel dysfunction (PSBD). This retrospective review aimed to evaluate biofeedback therapy with regard to patients' symptoms of fecal incontinence (FI) and stool frequency. METHODS: Patients with symptoms including frequency, urgency, FI, incomplete evacuation, failure to respond to dietary, medication or standard pelvic floor exercises (≥ 6 months) underwent biofeedback therapy between 2003 and 2006. Patients attended 3-4 sessions 1 week apart incorporating: anorectal function assessment; Fecal Incontinence Quality of Life (FIQL) and severity questionnaires; suggested coping strategies; dietary advice; bowel, food and exercise diary training; relaxation breathing; evacuation techniques; anal and pelvic floor muscle exercises using computerized visual feedback; and were reassessed at a final session following 4 weeks of home practice. RESULTS: Nineteen CRC PSBD patients [anterior resection (3); ultra-low anterior resection (10); segmental colectomy (2); and proctocolectomy (4)], mean age: 64.1 (95% CI: 47.0-81.3) years, participated. FIQL scales improved significantly for lifestyle, coping and embarrassment but not depression. Incontinence severity and number of bowel motions significantly decreased. Satisfaction with results of therapy was high. Subjective bowel control rating improved. FIQL scores further improved 2 years later. CONCLUSION: The holistic biofeedback protocol for PSBD in CRC patients is successful in the short and medium term.

Laparoscopic right hemicolectomy with intracorporeal anastomosis.

The author presents a technique for performing laparoscopic right hemicolectomy, accompanied by an online video. This method is suitable for a single surgeon working with a single assistant, who is also the cameraman. It starts with a hybrid medial-to-lateral or lateral-to-medial dissection of the right colon and mesentery, adapting to the actual anatomical findings and adhesions encountered in each individual patient. A step-by-step approach is described. Achieving the anatomical goals of each step facilitates the performance of the next step. An intracorporeal technique for anastomosis is demonstrated.

Meta-analysis of survival of patients with stage IV colorectal cancer managed with surgical resection versus chemotherapy alone.

BACKGROUND There is no consensus regarding the appropriate management of asymptomatic and minimally symptomatic patients with stage IV colorectal cancer and irresectable metastases. METHODS A literature search was conducted on Medline and Embase. Outcome measures included: survival; postoperative morbidity and mortality; complications from the primary tumor and the need for surgery to manage complications; the likelihood of curative surgery after initial response to primary therapy; and length of hospital stay. Quantitative meta-analysis was performed where appropriate. RESULTS Eight retrospective studies, including 1,062 patients, met the criteria for inclusion in this study. Meta-analysis has shown an improvement in the survival of patients managed with palliative resection of their primary tumor, with an estimated standardized median difference of 6.0 months (standardized difference, 0.55; 95% confidence interval (CI), 0.29, 0.82; p < 0.001). Patients managed with chemotherapy alone were 7.3 times more likely to have a complication from the primary tumor (95% CI, 1.7, 34.4; p = 0.008). There was no difference in the response rates to chemotherapy, making metastatic disease amendable to curative resection (0.85; 95% CI 0.40, 1.8; p = 0.662). CONCLUSIONS To date, only retrospective data are available, showing that palliative resection of the primary tumor in asymptomatic or minimally symptomatic patients with stage IV colorectal cancer is associated with longer survival. Resection of the primary tumor reduces the likelihood of complications from the primary tumor and avoids the need for emergency procedures.

PTQ anal implants for the treatment of faecal incontinence.

BACKGROUND: In North Queensland demand for conservative faecal incontinence treatments outweighs supply. Injectable bulking agents offer a safe and effective treatment for patients with internal anal sphincter (IAS) dysfunction. METHODS: Information, including age and sex, baseline incontinence score, quality of life, resting and squeeze pressures, was collected for 74 patients (37 men) who received intersphincteric PTQ injections. Postimplant satisfaction was assessed at 6-week review. Incontinence scores and satisfaction ratings were determined annually. RESULTS: At a median follow-up of 28 months, 52 patients (70 per cent) with IAS dysfunction who received PTQ anal implants as a treatment for faecal incontinence were continent and extremely satisfied with the result. The incontinence score in participants who remained incontinent was reduced significantly from 12 of 20 before implant to 3.5 of 20 at follow-up (P < 0.001). Migration rates improved with experience. The poorest results occurred in women with pudendal neuropathy, or patients who had previously received biofeedback treatment. CONCLUSION: Implanted PTQ provides an effective solution to faecal incontinence in the short and mid term for patients with IAS dysfunction.

A new method for CE-EC determination of mercaptopurine (MP) in a PMMA biochip with on-chip gold nano-electrode ensemble (GNEE) working and decouple electrodes.

This paper presents a new method for CE-EC determination of Mercaptopurine (MP), one of the most important medicines for inflammatory bowel disease (IBD) and acute lymphoblastic leukemia (ALL) treatment, in a PMMA-based microfluidic chip. A simple and reliable process for preparing the template of gold nanoelectrode ensemble (GNEE) and fabricating the integrated microfluidic chip is reported in the present study. The use of GNEE electrodes for both electric current decoupling and signal sensing in the proposed CE-EC chip not only enhances the signal response but also decreases the background noise during detection. Results show that a good detection limit of 100 nM for detecting mercaptopurine is achieved with the proposed method. In addition, the measured results also shows a good linear response between the detected CE-EC signals and the concentration of MP within the range of 100 nM-10 mM (R2 = 0.989). The proposed microchip device provides a novel and fast detection method for mercaptopurine analysis.

Updated meta-analysis of randomized controlled trials comparing conventional excisional haemorrhoidectomy with LigaSure for haemorrhoids.

BACKGROUND: To compare the surgical outcome of haemorrhoidectomy performed using LigaSure bipolar diathermy with conventional haemorrhoidectomy. METHODS: Only randomized and alternate allocated studies were included from the major electronic databases using the search terms "ligasure" and "haemorrhoids". Duration of operation, blood loss during operation, postoperative pain score, wound healing, in-hospital stay, time to return to normal activities and complications were assessed. RESULTS: The 11 trials contained a total of 1,046 patients; the largest study was based on 273 patients and two earlier studies were based on 34 patients. No significant gender mismatch between the groups was reported in any of the studies. The patients' ages were similar between groups in the studies, as was disease severity. All 11 studies reported a shorter duration of the operation when using LigaSure compared to the conventional technique (p<0.001). The postoperative pain score (p=0.001) and blood loss during operation (p=0.001) were significantly reduced. After LigaSure haemorrhoidectomy wound healing (p=0.004) and the return to normal activities (p=0.001) were significantly faster than after conventional haemorrhoidectomy. However, the overall incidence of complications reported was not significantly different (p=0.056). CONCLUSIONS: LigaSure is an effective instrument for haemorrhoidectomy which results in less blood loss, quicker wound healing and earlier return to work.

Elective laparoscopic surgical management of recurrent and complicated sigmoid diverticulitis.

BACKGROUND: To review the results of elective laparoscopic anterior resection (LAR) for recurrent and complicated sigmoid diverticulitis, and determine the factors associated with surgical complications. METHODS: Data on patients who had had elective surgery for recurrent and complicated sigmoid diverticulitis were extracted from a prospective computerized database. RESULTS: Review of the database revealed 62 consecutive patients who had undergone LAR. These patients were initially compared with 20 patients who had undergone elective open anterior resection (OAR). There were no significant differences between the groups in relation to age, sex, indication for surgery, Hinchey stage of perforation, extent of adhesions or comorbidities. The intraoperative time for LAR was significantly shorter (mean+/-SEM 110.87+/-4.8 min vs. OAR 134.35+/-8.4; p=0.032) and blood loss was less (88+/-18 ml vs. OAR 134+/-24 ml; p=0.003). Postoperative passage of flatus occurred earlier after LAR (p<0.003). Hospital stay was shorter after LAR (p<0.001). Complications occurred in nine patients (15%) after LAR and in six patients (30%) after OAR (p=NS). Among the LAR patients the risk of complications was higher in those with preexisting comorbidities (p=0.037). Time to postoperative passage of flatus correlated positively with age (p=0.004). CONCLUSIONS: Elective LAR for recurrent and complicated sigmoid diverticulitis could be performed safely and expediently. Bowel function recovered later in older patients. The risk of medical complications was related to preexisting comorbidities.

Reasons for non-disclosure of faecal incontinence: a comparison between two survey methods.

PURPOSE: We explored reasons for discordance in disclosure of faecal incontinence (FI) between 2 measurement instruments: the Self Administered Faecal Incontinence Questionnaire (SAFIQ) and the Cleveland Clinic Florida Fecal Incontinence Score (CCF-FI) METHODS: Patients >or=18 years attending the urogynaecology (n=135) and colorectal (n=148) outpatient clinics at The Townsville Hospital, a referral centre serving regional North Queensland, Australia, were invited to complete the SAFIQ and answer questions from the CCF-FI asked by their treating doctor. Selected patients undertook semistructured interviews. RESULTS: 262 patients completed both questionnaires. The prevalence of FI in this population was 25.6% (SAFIQ) and 29.9% (CCF-FI). 24% disclosed FI on both instruments, 3.1% on SAFIQ only and 6.1% on CCF-FI only. Major reasons for non-disclosure were: FI historical but not current; problem not considered as FI by patient; SAFIQ too long; condition embarrassing; doctor considered too busy; patient wanted to focus on primary reason for consultation; and doctor explained that a one-off bout of uncontrollable diarrhoea was not FI. Interviewees reported they would respond to FI questions initiated by their general practitioner (GP) during regular consultations, or in a generic questionnaire in the GP's surgery. CONCLUSIONS: GPs could identify patients with FI by initiating discussions during routine consultations. Such patients could then be referred to colorectal surgeons for treatment. A more specific definition of FI, which excludes historical data and isolated instances of diarrhoea, is desirable. A measurement instrument suitable for population surveys should contain simple language and acknowledge issues of embarrassment.

Concurrent laparoscopic right hemicolectomy and ultra-low anterior resection with colonic J-pouch anal anastomosis for synchronous carcinoma.

An extensive large bowel resection with a single anastomosis is the accustomed management option for widely spaced synchronous colorectal neoplasms. We report a successful case of concurrent laparoscopic right hemicolectomy and ultra-low anterior resection with colonic J-pouch anal anastomosis in an 85-year-old man with synchronous cancers of the hepatic flexure and lowrectum. This surgical technique is advantageous for elderly patients as it provides the benefits of multiple segmental resection and laparoscopic surgery while potentially reducing mortality, time of procedure, postoperative pain, ileus, length of hospitalization and direct cost of care, and improving independence at discharge. The technique for efficient multiple extractions of specimens and effective reconstitution of pneumoperitoneum for a multistaged procedure is discussed.

Prospective randomized trial comparing stapled hemorrhoidopexy versus closed Ferguson hemorrhoidectomy.

BACKGROUND: Ferguson hemorrhoidectomy is believed to result in less postoperative pain because of a closed wound. Stapled hemorrhoidopexy, without a perianal wound, should thus have lesser pain. We conducted a prospective randomized trial to compare stapled hemorrhoidopexy (SH) with Ferguson hemorrhoidectomy (FH). METHODS: Fifty patients with third-degree or early fourthdegree hemorrhoids who required surgery were recruited. Patients were prospectively randomized to receive either FH or SH. Data collected include operative time, hospital stay, fecal incontinence and pain scores, morbidity and complications. RESULTS: SH patients had less pain in the early postoperative period. There were no significant differences in hospital stay or major complications. One patient after SH required emergency reintervention for thrombosed hemorrhoids distal to the staple line. FH patients had more minor problems of bleeding, wound discharge and pruritus. Fecal incontinence was similar in the 2 groups but two of the three patients with daily incontinence to gas after SH claimed that their lifestyle was affected. CONCLUSIONS: SH is safe to perform and results in less postoperative pain as well as less minor morbidity. Early reintervention and incontinence to gas compromising lifestyle occurred only after SH.

Randomized clinical trial comparing oral nifedipine with lateral anal sphincterotomy and tailored sphincterotomy in the treatment of chronic anal fissure.

BACKGROUND: The conventional treatment of chronic anal fissure is lateral sphincterotomy (LAS). The alternative options of tailored sphincterotomy (TS) and 'chemical sphincterotomy' using medication such as nifedipine have recently become available. METHODS: A prospective randomized trial was conducted to compare LAS with TS and oral nifedipine. The main endpoints were fissure healing, symptom relief, recurrence and continence. RESULTS: One hundred and thirty-two patients were treated and followed up for 4 months. LAS was significantly more effective than TS in providing pain relief (P = 0.004) and better patient satisfaction (P = 0.020) at 4 weeks. Surgery (LAS and TS) was associated with significantly better fissure healing rates (both P < 0.001 at 16 weeks) and less recurrence (both P = 0.003) than nifedipine. There were substantial problems with compliance in the nifedipine group (17 of 41 patients), related to side-effects and slow healing. There were no differences in continence between the three treatment groups. CONCLUSION: LAS was most effective in providing pain relief and allowing rapid fissure healing, with minimal recurrence and no increased risk of incontinence, in patients with good anal sphincter function.

Inflammatory fibroid polyp of the caecum in a patient with neurofibromatosis.

INTRODUCTION: Inflammatory fibroid polyp of the large intestine is uncommon. To our knowledge, this condition has not been reported in a patient with neurofibromatosis. CLINICAL PICTURE: In this report, a 66-year-old woman with neurofibromatosis was found to have a large polyp in the caecum. TREATMENT: Right hemicolectomy was performed because of the size of the polyp. OUTCOME: Pathological examination showed that the polyp was an inflammatory fibroid polyp. CONCLUSION: Clinicians should be aware that inflammatory fibroid polyps could be one of the many manifestations of neurofibromatosis in the gastrointestinal tract.