Colorectal Cancer Diagnosis through Breath Test Using a Portable Breath Analyzer-Preliminary Data.

Screening methods available for colorectal cancer (CRC) to date are burdened by poor reliability and low patient adherence and compliance. An altered pattern of volatile organic compounds (VOCs) in exhaled breath has been proposed as a non-invasive potential diagnostic tool for distinguishing CRC patients from healthy controls (HC). The aim of this study was to evaluate the reliability of an innovative portable device containing a micro-gas chromatograph in enabling rapid, on-site CRC diagnosis through analysis of patients' exhaled breath. In this prospective trial, breath samples were collected in a tertiary referral center of colorectal surgery, and analysis of the chromatograms was performed by the Biomedical Engineering Department. The breath of patients with CRC and HC was collected into Tedlar bags through a Nafion filter and mouthpiece with a one-way valve. The breath samples were analyzed by an automated portable gas chromatography device. Relevant volatile biomarkers and discriminant chromatographic peaks were identified through machine learning, linear discriminant analysis and principal component analysis. A total of 68 subjects, 36 patients affected by histologically proven CRC with no evidence of metastases and 32 HC with negative colonoscopies, were enrolled. After testing a training set (18 CRC and 18 HC) and a testing set (18 CRC and 14 HC), an overall specificity of 87.5%, sensitivity of 94.4% and accuracy of 91.2% in identifying CRC patients was found based on three VOCs. Breath biopsy may represent a promising non-invasive method of discriminating CRC patients from HC.

Quality of life meta-analysis following coloanal anastomosis versus abdominoperineal resection for low rectal cancer.

AIM: In low rectal cancers without sphincter involvement a permanent stoma can be avoided without compromising oncological safety. Functional outcomes following coloanal anastomosis (CAA) compared to abdominoperineal excision (APR) may be significantly different. This study examines all available comparative quality of life (QoL) data for patients undergoing CAA versus APR for low rectal cancer. METHODS: Published studies with comparative data on QoL outcomes following CAA versus APR for low rectal cancer were extracted from electronic databases. The study was registered with PROSPERO and adhered to PRISMA (Preferred Reporting Items in Systematic Reviews and Meta-analyses) guidelines. Data was combined using random-effects models. RESULTS: Seven comparative series examined QoL in 527 patients. There was no difference in the numbers receiving neoadjuvant radiotherapy in the APR and CAA groups (OR: 1.19, 95% CI: 0.78-1.81, p = 0.43). CAA was associated with higher mean scores for physical functioning(std mean diff -7.08, 95% CI: -11.92 to -2.25, p = 0.004) and body image (std. mean diff 11.11, 95% CI: 6.04-16.18, p < 0.0001). Male sexual problems were significantly increased in patients who had undergone APR compared to CAA (std. mean diff -16.20, 95% CI: -25.76 to -6.64, p = 0.0009). Patients who had an APR reported more fatigue, dyspnoea and appetite loss. Those who had a CAA reported higher scores for both constipation and diarrhoea. DISCUSSION: It is reasonable to offer a CAA to motivated patients where oncological outcomes will not be threatened. QoL outcomes appear to be superior when intestinal continuity is maintained, and permanent stoma avoided.

Effects of Curative Colorectal Cancer Surgery on Exhaled Volatile Organic Compounds and Potential Implications in Clinical Follow-up.

OBJECTIVE: The aim of this study was to determine whether the volatile organic compounds (VOCs) pattern in colorectal cancer (CRC) patients is modified by curative surgery for a potential application in the oncologic follow-up. BACKGROUND: CRC has been proved to induce metabolic derangements detectable by high through-output techniques in exhaled breath showing a specific pattern of VOCs. METHODS: Forty-eight CRC patients and 55 healthy controls (HC) entered the study. Thirty-two patients (M/F: 1.4; mean age 63 years) attended the oncologic follow-up (mean 24 months) and were found disease-free. Breath samples were collected under similar environmental conditions into a Tedlar bags and processed offline by thermal-desorption gas chromatography-mass spectrometry (TD-GC-MS). VOCs were selected by U test to build a Probabilistic Neural Network (PNN) model to set-up a training phase, which was cross-validated using the leave-one out method. RESULTS: A total of 11 VOCs were finally selected for their excellent discriminant performance in identifying disease-free patients in follow-up from CRC patients before surgery, (sensitivity 100%, specificity 97.92%, accuracy 98.75%, and AUC: 1). The same VOCs pattern discriminated follow-up patients from HC, with a sensitivity of 100%, specificity of 90.91%, accuracy of 94.25%, and AUC 0.959. CONCLUSIONS: Exhaled VOCs pattern from CRC patients is modified by cancer removal confirming the tight relationship between tumor metabolism and exhaled VOCs. PNN analysis provides a high discriminatory tool to identify patients disease-free after curative surgery suggesting potential implications in CRC screening and secondary prevention.

The inulin hydrogen breath test predicts the quality of colonic preparation.

BACKGROUND: Successful bowel preparation is essential to an adequate performance of colonoscopy. Polyethylene glycol (PEG) with electrolyte solutions induces diarrhea with depletion of substrates fermentable by hydrogen (H2)-producing colonic microbiota. Inulin has recently been suggested as a prebiotic substrate for the H2 breath test because it is resistant to intestinal hydrolysis and is fermented mostly by the colonic bacteria. This study aimed to assess time-dependent changes in H2 breath levels in order to predict the colonic preparation of patients scheduled for colonoscopy with or without oral supplementation of inulin. METHODS: In this prospective nonrandomized trial, 127 subjects drank 4 l of PEG 280-mg solution as bowel preparation for colonoscopy. A subgroup of 31 patients also ingested inulin (10 g in 200 ml of water) at breakfast as an additional substrate to increase colonic H2 production. Measurements of H2 breath levels were performed immediately before and after colonic preparation. As the main outcome measure, the quality of the colonic preparation was scored as excellent to fair (i.e., clean bowel allowing successful pan-colonoscopy, including the terminal ileum) or poor (incomplete colonoscopy due to fecal debris). RESULTS: The H2 breath levels decreased from 11.0 ± 1.8 ppm before PEG to 1.8 ± 0.3 ppm after PEG (n = 18; P < 0.001). The H2 concentrations after PEG ingestion were significantly lower (P < 0.001) in the patients with excellent-to-fair preparation than in the 19 patients with poor preparation. Ingestion of inulin induced an overall increase in H2 breath levels and improved discrimination between the patients with excellent-to-fair colonic preparation and those with poor preparation, leading to the sensitivity and specificity of such a test reaching 100 %. CONCLUSIONS: The H2 breath test with inulin ingestion can be a simple, noninvasive, reliable method for predicting successful colonic preparation that leads to cost savings and less patient discomfort/stress or need to repeat colonoscopy.

Thrombosed external hemorrhoids during pregnancy: surgery versus conservative treatment.

The management of thrombosed external hemorrhoids (TEH) during pregnancy is still under debate because of the fear of potential adverse effects on the fetus. This study aims to compare efficacy and safety of conservative versus surgical treatment of acute TEH in pregnant women. Furthermore, the outcome of two different surgical approaches was evaluated. This is a prospective observational study including a sub-analysis on two randomized groups of pregnant women affected by TEH. The primary outcome measured was the impact of conservative and surgical treatment defined in terms of VAS, clinical patient grading assessment scale (CPGAS) and the SF-12 questionnaire. In a randomized sub-analysis of the surgical treatment, the outcome of local excision (LE) versus thrombectomy (TE) was compared. Fifty-three patients entered the study. Twenty-six patients had conservative treatment and 22 underwent surgery. Within the surgical group, 8 were randomized for TE and 14 for LE. VAS, SF-12 and CPGAS improved in both groups after 3 and 10 days from the treatment. However, physical (PCS) and mental health (MCS) domains of the SF-12 and CPGAS showed a significant difference in favor of surgery on the 10th day (PCS: p < 0.002 and MCS: p = 0.03; CPGAS: p = 0.002). The surgical group showed an earlier significant reduction of pain on the 3rd day (p = 0.0004). In the surgical group, randomization was halted due to ethical concerns arising from a notable difference in the primary end point between subgroups during interim analysis. Specifically, the re-thrombosis rate was 38% (3/8) after TE and 7% (1/14) after LE. No complications occurred for either mothers or fetuses. Both surgical and conservative treatments are safe and effective. However, surgery allows a faster relief of anal pain. Thrombectomy is associated with higher risk of re-thrombosis when compared to local excision (clinicaltrials.gov ID number NCT04588467).

Coloanal anastomosis or abdominoperineal resection for very low rectal cancer: what will benefit, the surgeon's pride or the patient's quality of life?

PURPOSES: Sphincter-saving operation with coloanal anastomosis (CAA) has become an established option for very low rectal cancer, but few studies have compared its functional results and quality of life (QoL) with abdominoperineal resection (APR) showing controversial results. PATIENTS AND METHODS: Patients treated for low rectal cancer with APR or CAA, disease-free after a median follow-up period of 26.5 (8-84) and 52.5 (12-156) months, respectively, were retrospectively reviewed. General and disease-specific changes in QoL and severity of disease were evaluated by Karnofsky scale, EORTC-C30, EORTC-CR38, SF-36, PGWBI, FIQL, PAC-QoL, ICIQ-SF, Stoma-QoL, AMS, Wexner's score and obstructed defecation syndrome (ODS) score. RESULTS: Twenty-six APR patients and 34 CAA patients entered the study. Karnofsky score did not show significant differences. The median Stoma-QoL was 58.2 (45-76.6), indicating a good stoma function in 95% of patients. EORTC-C30, CR38, PGWBI and SF-36 questionnaires did not show significant differences between the two groups except for sexual function (better after CAA, p = 0.01). Eleven patients after APR and eight after CAA had urinary incontinence, and its severity did not differ significantly. Eighteen of 21 CAA patients complained of faecal incontinence [AMS, 80 (15-120); Wexner, 13 (2-19)] with an impact on their QoL [FIQL: lifestyle, 1.75 (0-4); coping/behaviour, 1.3 (0-3.5); depression, 2.1 (0-5.2); embarrassment, 2 (0-4.6)] and 11 complained of obstructed defecation [7.5 (3-16)] with significant consequences on QoL [PAC-QoL, 30.4 (19.2-80.3)]. CONCLUSIONS: QoL in patients with permanent stoma and in those after CAA did not differ significantly. APR patients had worse sexual function, while most CAA patients had faecal incontinence and sometime obstructed defecation, with important impact on their QoL.

Undeserved authorship in surgical research: an underestimated bias with potential side effects on academic careers.

The incidence of courtesy authorship in research over time has probably increased due to the enormous pressure to publish to increase the bibliometric indexes necessary to achieve an academic role. The aim of this survey was to quantify and characterize this research malpractice among a very selected group of surgeons from different surgical specialties belonging to the European Association of Surgery (ESA). E-mail addresses for the invitation to take part to the survey were collected by the Twenty-eighth Annual Meeting final program. Five-item were designed and developed by the authors using an online platform. Eighty-six members from 21 countries completed the survey (female/male ratio: 0.09). In the last 10 years, almost half of the responders (41, 47.7%, 37 academics) have included colleagues for courtesy authorship. The most common reason of courtesy authorships was to support the academic career of another researcher (62.5%). Other reasons were fear of retaliation (12.5%), reciprocal authorship (12.5%) or support for a partner (10%). This survey showed that undeserved authorship is sadly confirmed to be a common research misconduct across any countries and medical specialties, even among a very selected group of surgeons with international reputation irrespective of the academic position.

Identification of a characteristic VOCs pattern in the exhaled breath of post-COVID subjects: are metabolic alterations induced by the infection still detectable?

SARS-CoV-2 is expected to cause metabolic alterations due to viral replication and the host immune response resulting in increase of cytokine secretion and cytolytic activity. The present prospective observational study is addressed at exploring the potentialities of breath analysis in discrimination between patients with a documented previous history of symptomatic SARS-CoV-2 infection and, at the moment of the enrollment, exhibiting a negative nasopharyngeal swab and acquired immunity (post-COVID) and healthy subjects with no evidence of previous SARS-CoV-2 infection (no-COVID). The main purpose is to understand if traces of metabolic alterations induced during the acute phase of the infection are still detectable after negativization, in the form of a characteristic volatile organic compound (VOC) pattern. An overall number of 60 volunteers aged between 25 and 70 years were enrolled in the study (post-COVID: n.30; no-COVID: n. 30), according to well-determined criteria. Breath and ambient air samples were collected by means of an automated sampling system (Mistral) and analyzed by thermal desorption-gas chromatography-mass spectrometry (TD-GC/MS). Statistical tests (Wilcoxon/Kruskal-Wallis test) and multivariate data analysis (principal component analysis (PCA), linear discriminant analysis) were performed on data sets. Among all compounds detected (76 VOCs in 90% of breath samples), 5 VOCs (1-propanol, isopropanol, 2-(2-butoxyethoxy)ethanol, propanal and 4-(1,1-dimethylpropyl)phenol) showed abundances in breath samples collected from post-COVID subjects significantly different with respect to those collected from no-COVID group (Wilcoxon/Kruskal-Wallis test,p-values <0.05). Although not completely satisfactory separation between the groups was obtained, variables showing significant differences between the two groups and higher loadings for PCA are recognized biomarkers of COVID-19, according to previous studies in literature. Therefore, based on the outcomes obtained, traces of metabolic alterations induced by SARS-CoV-2 infection are still detectable after negativization. This evidence raises questions about the eligibility of post-COVID subjects in observational studies addressed at the detection of COVID-19. (Ethical Committee Registration number: 120/AG/11).

Functional outcome of sacral nerve stimulation in patients with severe constipation.

BACKGROUND: Sacral nerve stimulation has been reported as an effective treatment for constipation. OBJECTIVE: This study aimed to evaluate the therapeutic efficacy of permanent sacral nerve stimulation on the treatment of idiopathic constipation resistant to medical and behavioral management over a median follow-up period of 25.6 (range, 6-96) months. DESIGN: A retrospective review of a prospectively maintained institutional review board-approved database was performed. SETTING: The study was performed at 2 tertiary-care European institutions with expertise in sacral nerve stimulation. PATIENTS: Patients were considered eligible if they had had symptoms for at least 1 year and if conservative treatment had failed. INTERVENTION: Patients were tested by percutaneous nerve evaluation before the procedure. If this evaluation was successful, patients underwent sacral nerve therapy with an implanted device. MAIN OUTCOME MEASURE: Patients were evaluated by means of a bowel function diary and the Wexner constipation score. RESULTS: A total of 48 consecutive patients (39 females, median age 50.0 years (range, 17-79 years) entered the study. Twenty-three patients were implanted with a permanent stimulator. On an intention-to-treat basis, only 14 of 48 patients (29.2%) met the definition of a successful outcome at the latest follow-up period (median, 25.6 (range, 6-96) months). The mean Wexner score decreased from 20.2 (SD 3.6) at baseline to 5.8 (SD 4.1) at the latest follow-up examination (p < 0.001). However, 6 of 14 patients (42.8%) were still using laxatives and/or enemas at the last follow-up. LIMITATIONS: The study was limited by the pragmatic approach necessary to evaluate the results in routine clinical practice. CONCLUSIONS: This study shows that sacral nerve stimulation has limited efficacy on an intention-to-treat basis as a routinely recommended therapy for intractable idiopathic constipation.

Cutting-Edge Research Trends in Colorectal Disease.

The scientific effort in improving colorectal disease treatment and outcomes has allowed for a continuous shift of burdens that were previously thought to be unassailable [...].

Management and Treatment of External Hemorrhoidal Thrombosis.

Background: External hemorrhoidal thrombosis (EHT) is a common complication of hemorrhoidal disease. This condition causes extreme pain, likely resulting from internal anal sphincter hypertonicity, which traps the hemorrhoids below the dentate line thus leading to congestion and swelling. The choice of treatment remains controversial and both conservative and surgical options have been proposed in the last decades. Methods: This mini-review focuses on the most relevant studies found in literature evaluating conservative and surgical management of EHT. Special conditions such as pregnancy and EHT in elderly patients have been considered. Results: Traditionally, symptoms duration represents the discriminant in the choice between medical and surgical treatment. Several Coloproctological Societies considered conservative treatment as the first-line approach to EHT and a variety of options have been proposed: wait and see, mixture of flavonoids, mix of lidocaine and nifedipine, botulinum toxin injection and topical application of 0.2% glyceryl trinitrate. Meanwhile, different surgical treatments are recommended when EHT fails to respond to conservative management or when symptoms onset falls within the last 48-72 h: drainage with radial incision, conventional excision, excision under local anesthesia and stapled technique. Conclusion: The management and treatment of EHT is still controversial since no specific guidelines have been published. Both medical and surgical treatment have been proven effective but randomized clinical trials and structured consensus-based guidelines are warranted.

No rectopexy versus rectopexy following rectal mobilization for full-thickness rectal prolapse: a randomized controlled trial.

BACKGROUND: No randomized controlled trial has compared no rectopexy with rectopexy for external full-thickness rectal prolapse. OBJECTIVE: This study was performed to test the hypothesis that recurrence rates following no rectopexy are not inferior to those following rectopexy for full-thickness rectal prolapse. DESIGN: This was a multicenter randomized controlled trial. Eligible patients were randomly assigned to no rectopexy or rectopexy. The end point was recurrence rates defined as the presence of external full-thickness rectal prolapse after surgery. A prerandomized controlled trial meta-analysis suggested a sample size of 251 patients based on a 15% expected difference in the 5-year cumulative recurrence rate. Recurrence-free curves were generated and compared using the Kaplan-Meier method and log-rank test, respectively. Data were presented as median (range). SETTING: This study was conducted in 41 tertiary centers in 21 countries. PATIENTS: Patients with prior surgery for rectal prolapse or pelvic floor descent were not included. INTERVENTIONS: The no-rectopexy arm was defined as abdominal surgery with rectal mobilization only. The rectopexy arm was defined as abdominal surgery with mobilization and rectopexy. Sigmoid resection was not randomized and was added in the presence of constipation. MAIN OUTCOME MEASURES: Two hundred fifty-two patients with external full-thickness rectal prolapse were randomly assigned to undergo no rectopexy or rectopexy in 41 centers. All patients but one underwent the allocated intervention. One hundred sixteen no-rectopexy patients were comparable to 136 rectopexy patients for age (P = .21), body mass index (P = .61), ASA grade (P = .29), and previous abdominal surgery (P = .935), but not for sex (P = .013) and external full-thickness rectal prolapse length (8 (1-25) cm vs 5 (1-20) cm, P = .026). Sigmoid resection was performed more frequently in the no-rectopexy arm (P < .001). There was no significant difference in complication rates (11% vs 17.9%; P = .139). The mortality rate was 0.8%. The loss of patients to 5-year follow-up was 10.3%. Actuarial analysis demonstrated a significant difference in 5-year recurrence rates between study arms (8.6% vs 1.5%) (log-rank, P = .003). LIMITATIONS: Limitations were the high proportion of male patients, randomization timing, the lack of standardization for rectopexy technique, and the 10% loss to follow-up. CONCLUSIONS: Recurrence rates following no rectopexy are inferior to those following rectopexy for external full-thickness rectal prolapse.

Solitary schwannoma of the rectum mimicking rectal cancer. Report of a case and review of the literature.

A case of a submucosal tumor bulging into the rectum in an old female patient is reported. It proved to be a very rare case of rectal schwannoma, whose differential diagnosis is difficult to obtain preoperatively and optimal treatment and prognosis still uncertain. The mass was removed by means of an ultrasound device after an open anterior rectotomy. The operation was uneventful and the patient is disease free 18 months after.

Classifications and Clinical Assessment of Haemorrhoids: The Proctologist's Corner.

BACKGROUND: Haemorrhoidal disease (HD) is a benign condition affecting a considerable part of adult population. HD can be considered a social and economic burden with high impact on patients' lifestyle. Several new techniques and devices have been proposed for HD treatment; however, preoperative assessment is essential and the use of classification system is recommended. METHODS: In the last two decades many studies described the preoperative assessment and several attempts of classification for HD. This review focuses on the most relevant studies found in literature where classification systems and clinical evaluation with differential diagnosis have been evaluated. RESULTS: The knowledge of classification systems and differential diagnosis for HD has been shown to play a central role in the clinical assessment and the best treatment choice. Although there are new challenging techniques and devices for HD treatment, a preoperative assessment is always mandatory. CONCLUSION: Preoperative clinical evaluation is essential for HD patient treatment and outcome. Classification systems are useful for the therapeutic choice and researches on new medical or surgical treatments. In fact, the international guidelines advise several therapeutic options depending on the severity of the HD.

Systematic review with meta-analysis: volatile organic compound analysis to improve faecal immunochemical testing in the detection of colorectal cancer.

BACKGROUND: Faecal immunochemical test (FIT) is emerging as a valid test to rule-out the presence of colorectal cancer (CRC). However, the accuracy of FIT is dependent on the cut-off applied. An additional low-cost test could improve further detection of CRC. AIMS: To evaluate the efficacy of combined FIT and volatile organic compounds (VOC) in the detection of CRC within symptomatic populations. METHODS: Systematic reviews on the diagnostic accuracy of FIT and VOC, for the detection of CRC, were updated. Meta-analyses were performed adopting a bivariate model for sensitivity and specificity. Clinical utility of combined FIT and VOC was estimated using Fagan's nomogram. Post-test probability of FIT negatives was used as a pre-test probability for VOC. RESULTS: The pooled sensitivity and specificity of FIT at 10 µg/g faeces, for the detection of CRC, were 0.914 (95% confidence interval [CI] = 0.894-0.936) and 0.783 (CI = 0.850-0.696), respectively. For VOC, the sensitivity was 0.837 (CI = 0.781-0.881) and the specificity was 0.803 (CI = 0.870-0.712). The area under the curve for FIT and VOC were 0.926 and 0.885, respectively. In a population with 5% CRC prevalence, the estimated probability of having CRC following a negative FIT was 0.5% and following both negative FIT and VOC was 0.1%. CONCLUSIONS: In a FIT-negative symptomatic population, VOC can be a good test to rule-out the presence of CRC. The estimated probability reduction by 0.4% when both tests being negative offers adequate safety netting in primary care for the exclusion of CRC. The number needed to colonoscope to identify one CRC is eight if either FIT or VOC positive. Cost-effectiveness and clinical accuracy of this approach will need further evaluation.

Trop-2 induces ADAM10-mediated cleavage of E-cadherin and drives EMT-less metastasis in colon cancer.

We recently reported that activation of Trop-2 through its cleavage at R87-T88 by ADAM10 underlies Trop-2-driven progression of colon cancer. However, the mechanism of action and pathological impact of Trop-2 in metastatic diffusion remain unexplored. Through searches for molecular determinants of cancer metastasis, we identified TROP2 as unique in its up-regulation across independent colon cancer metastasis models. Overexpression of wild-type Trop-2 in KM12SM human colon cancer cells increased liver metastasis rates in vivo in immunosuppressed mice. Metastatic growth was further enhanced by a tail-less, activated ΔcytoTrop-2 mutant, indicating the Trop-2 tail as a pivotal inhibitory signaling element. In primary tumors and metastases, transcriptome analysis showed no down-regulation of CDH1 by transcription factors for epithelial-to-mesenchymal transition, thus suggesting that the pro-metastatic activity of Trop-2 is through alternative mechanisms. Trop-2 can tightly interact with ADAM10. Here, Trop-2 bound E-cadherin and stimulated ADAM10-mediated proteolytic cleavage of E-cadherin intracellular domain. This induced detachment of E-cadherin from ß-actin, and loss of cell-cell adhesion, acquisition of invasive capability, and membrane-driven activation of ß-catenin signaling, which were further enhanced by the ΔcytoTrop-2 mutant. This Trop-2/E-cadherin/ß-catenin program led to anti-apoptotic signaling, increased cell migration, and enhanced cancer-cell survival. In patients with colon cancer, activation of this Trop-2-centered program led to significantly reduced relapse-free and overall survival, indicating a major impact on progression to metastatic disease. Recently, the anti-Trop-2 mAb Sacituzumab govitecan-hziy was shown to be active against metastatic breast cancer. Our findings define the key relevance of Trop-2 as a target in metastatic colon cancer.