Investigation of Microbial Translocation, TLR and VDR Gene Polymorphisms, and Recurrence Risk in Stage III Colorectal Cancer Patients.

Gut microbial dysbiosis and microbial passage into the peripheral blood leads to colorectal cancer (CRC) and disease progression. Toll-like (TLR) and vitamin D (VDR) receptors play important role in the immune modulation and polymorphisms that may increase CRC risk and death rates. The aim of the current study was to demonstrate the prognostic value of microbial DNA fragments in the blood of stage III CRC patients and correlate such microbial detection to TLR/VDR polymorphisms. Peripheral blood was collected from 132 patients for the detection of microbial DNA fragments, and TLR/VDR gene polymorphisms. In the detection of various microbial DNA fragments, TLR and VDR polymorphisms was significantly higher compared to healthy group. Homozygous individuals of either TLR or VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. Mutational and MSI status were significantly correlated with TLR9 and VDR polymorphisms. Significantly shorter disease-free survival was associated with patients with BRAF mutated tumors and ApaI polymorphisms, whereas shorter overall survival was associated with the detection of C. albicans. The detection of B. fragilis, as demonstrated by the multivariate analysis, is an independent poor prognostic factor for shorter disease-free survival. TLR/VDR genetic variants were significantly correlated with the detection of microbial fragments in the blood, and this in turn is significantly associated with tumorigenesis and disease progression.

Ventral Prosthesis Rectopexy for obstructed defaecation syndrome: a systematic review and meta-analysis.

Obstructed Defecation Syndrome (ODS) is a rather complex entity concerning mainly females and causing primarily constipation. Surgical treatment in the form of Ventral Prosthesis Rectopexy (VPR) has been proposed and seems to have the best outcomes. However, the selection criteria of patients to undergo this kind of operation are not clear and the reported outcomes are mainly short-term and data on long-term outcomes is scarce. This study assesses new evidence on the efficacy of VPR for the treatment of ODS, specifically focusing on inclusion criteria for surgery and the long-term outcomes. A search was performed of MEDLINE, EMBASE, Ovid and Cochrane databases on all studies reporting on VPR for ODS from 2000 to March 2020. No language restrictions were made. All studies on VPR were reviewed systematically. The main outcomes were intra-operative complications, conversion, procedure duration, short-term mortality and morbidity, length of stay, faecal incontinence and constipation, quality of life (QoL) score and patient satisfaction. Quality assessment and data extraction were performed independently by three observers. Fourteen studies including 963 patients were eligible for analysis. The immediate postoperative morbidity rate was 8.9%. A significant improvement in constipation symptoms was observed in the 12-month postoperative period for ODS (p < 0.0001). Current evidence shows that VPR offers symptomatic relief to the majority of patients with ODS, improving both constipation-like symptoms and faecal incontinence for at least 1-2 years postoperatively. Some studies report on functional results after longer follow-up, showing sustainable improvement, although in a lesser extent.

Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies.

Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy, although considerable progress has resulted from molecular alterations in guiding optimal use of available treatments. CRC recurrence remains a great barrier in the disease management. Hence, the spotlight turns to newly mapped fields concerning recurrence risk factors in patients with resectable CRC with a focus on genetic mutations, microbiota remodeling and liquid biopsies. There is an urgent need for novel biomarkers to address disease recurrence since specific genetic signatures can identify a higher or lower recurrence risk (RR) and, thus, be used both as biomarkers and treatment targets. To a large extent, CRC is mediated by the immune and inflammatory interplay of microbiota, through intestinal dysbiosis. Clarification of these mechanisms will yield new opportunities, leading not only to the appropriate stratification policies, but also to more precise, personalized monitoring and treatment navigation. Under this perspective, early detection of post-operative CRC recurrence is of utmost importance. Ongoing trials, focusing on circulating tumor cells (CTCs) and, even more, circulating tumor DNA (ctDNA), seem to pave the way to a promising, minimally invasive but accurate and life-saving monitoring, not only supporting personalized treatment but favoring patients' quality of life, as well.

Management of the adenocarcinoma of the upper rectum: a reappraisal.

The present review attempts to assess whether upper rectal cancer (URC) should be treated either as colon cancer or as rectal one, namely to be managed with upfront surgery without neo-adjuvant treatment and partial mesorectal excision (PME), or with neo-adjuvant short course radiotherapy (SCRT) or chemoradiotherapy (CRT) as indicated, followed by surgery with total mesorectal excision. Reports from current evidence including studies, reviews and various guidelines are conflicting. Main reasons for inability to reach safe conclusions are (i) the various anatomical definitions of the rectum and its upper part, (ii) the inadequate preoperative local staging,(iii) the heterogeneity of selection criteria for the neo-adjuvant treatment,(iv) the different neo-adjuvant treatment regimens, and(v) the variety in the extent of surgical resection, among the studies. Although not adequately supported, locally advanced URC can be treated with neo-adjuvant CRT provided the lesion is within the radiation field of safety, and a PME if the lower border of the tumour is located above the anterior peritoneal reflection. There is evidence that adjuvant chemotherapy is of benefit in high-risk stage II and stage III lesions.

Hellenic society of medical oncology (HESMO) guidelines for the management of anal cancer.

Despite considerable improvement in the management of anal cancer, there is a great deal of variation in the outcomes among European countries, and in particular among different hospital centres in Greece and Cyprus. The aim was to elaborate a consensus on the multidisciplinary management of anal cancer, based on European guidelines (European Society of Medical Oncologists-ESMO), considering local special characteristics of our healthcare system. Following discussion and online communication among members of an executive team, a consensus was developed. Guidelines are proposed along with algorithms of diagnosis and treatment. The importance of centralisation, care by a multidisciplinary team (MDT) and adherence to guidelines are emphasised.

Intestinal Microbiota in Colorectal Cancer Surgery.

The intestinal microbiota consists of numerous microbial species that collectively interact with the host, playing a crucial role in health and disease. Colorectal cancer is well-known to be related to dysbiotic alterations in intestinal microbiota. It is evident that the microbiota is significantly affected by colorectal surgery in combination with the various perioperative interventions, mainly mechanical bowel preparation and antibiotic prophylaxis. The altered postoperative composition of intestinal microbiota could lead to an enhanced virulence, proliferation of pathogens, and diminishment of beneficial microorganisms resulting in severe complications including anastomotic leakage and surgical site infections. Moreover, the intestinal microbiota could be utilized as a possible biomarker in predicting long-term outcomes after surgical CRC treatment. Understanding the underlying mechanisms of these interactions will further support the establishment of genomic mapping of intestinal microbiota in the management of patients undergoing CRC surgery.

Neo-adjuvant chemotherapy alone for the locally advanced rectal cancer: a systematic review.

Neo-adjuvant chemoradiation (NA-CRT) is the standard of management for the locally advanced rectal cancer (LARC), achieving very low rates of local recurrence (LR). However, NA-CRT fails to control distant recurrence and improve survival, whilst it is associated with increased postoperative morbidity and increased acute and late toxicity. In recent years, neo-adjuvant chemotherapy (NACTx) appears in the literature as an alternative to NA-CRT in patients with LARC. In the present study, the authors review all current evidence on the specific subject. Following a systematic search of the literature, 25 studies were identified reporting on short- or long-term outcomes of NACTx for LARC. Seventeen studies were prospective or retrospective series, and 8 comparative. Of the comparative studies, one was a randomized control trial (RCT) comparing NACTx to NA-CRT and to the combination of NACTx/NA-CRT, and another a non-randomized study comparing NACTx to NA-CRT. Chemotherapeutic regimens were 5-fluoropyrimidine and oxaliplatin based. In some of them, irinotecan or/and bevacizumab was added. A pooled analysis showed that NACTx is associated with a mean anastomotic leak rate of 6.8%. In the RCT, postoperative morbidity and overall toxicity was significantly less in the NACTx group. Mean T downstaging (ypStage 0-I) was 49.6%, mean N downstaging 69.6% and mean pathologic complete response (pCR) 10.7%. The RCT showed an inferior pCR rate after NACTx than after NA-CRT, but similar rates of T downstaging. Mean LR was 8.6% and mean distant recurrence 17.2%. Satisfactory survival rates are reported by several studies. NACTx seems to be an alternative to NA-CRT for patients with LARC, associated with low anastomotic leak, adequate tumour downstaging, low LR and rather high survival rates. Further data deriving from high-quality studies are necessary to assess safety and efficacy of NACTx as a substitute to NA-CRT, for at least a subset of patients with LARC.

The Role of Vitamin D Receptor Gene Polymorphisms in Colorectal Cancer Risk.

Vitamin D deficiency has been associated with increased colorectal cancer (CRC) incidence risk and mortality. Vitamin D mediates its action through the binding of the vitamin D receptor (VDR), and polymorphisms of the VDR might explain these inverse associations. The aim of the study was the investigation of the relevance of rs731236; Thermus aquaticus I (TaqI), rs7975232; Acetobacter pasteurianus sub. pasteurianus I (ApaI), rs2228570; Flavobacterium okeanokoites I (FokI) and rs1544410, Bacillus stearothermophilus I (BsmI) polymorphisms of the VDR gene to colorectal carcinogenesis (CRC) and progression. Peripheral blood was obtained from 397 patients with early operable stage II/III (n = 202) and stage IV (n = 195) CRC. Moreover, samples from 100 healthy donors and 40 patients with adenomatous polyps were also included as control groups. Genotyping in the samples from patients and controls was performed using polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP). A significant association was revealed between all four polymorphisms and cancer. Individuals with homozygous mutant (tt, aa, ff or bb) genotypes were more susceptible to the disease (p < 0.001). All of the mutant genotypes detected were also significantly associated with stage IV (p < 0.001), leading to significantly decreased survival (p < 0.001). Moreover, all four polymorphisms were significantly associated with KRAS (Kirsten ras oncogene) mutations and Toll-like receptor (TLR2, TLR4 and TLR9) genetic variants. In multivariate analysis, tt, aa and ff genotypes emerged as independent factors associated with decreased overall survival (OS) (p = 0.001, p < 0.001 and p = 0.001, respectively). The detection of higher frequencies of the VDR polymorphisms in CRC patients highlights the role of these polymorphisms in cancer development and progression.

Consensus statement of the Hellenic and Cypriot Gastric Cancer Study Group on the diagnosis, staging and management of gastric cancer.

Gastric Cancer epidemics have changed over recent decades, declining in incidence, shifting from distal to proximal location, transforming from intestinal to diffuse histology. Novel chemotherapeutic agents combined with modern surgical operations hardly changed overall disease related survival. This may be attributed to a substantial inherent geographical variation of disease genetics, but also to a failure to standardize and implement treatment protocols in clinical practice. To overcome these drawbacks in Greece and Cyprus, a Gastric Cancer Study Group under the auspices of the Hellenic Society of Medical Oncology (HeSMO) and Gastrointestinal Cancer Study Group (GIC-SG) merged their efforts to produce a consensus considering ethnic parameters of healthcare system and the international proposals as well. Utilizing structured meetings of experts, a consensus was reached. To achieve further consensus, statements were subjected to the Delphi methodology by invited multidisciplinary national and international experts. Sentences were considered of high or low consensus if they were voted by ≥ 80%, or < 80%, respectively; those obtaining a low consensus level after both voting rounds were rejected. Forty-five statements were developed and voted by 71 experts. The median rate of abstention per statement was 9.9% (range: 0-53.5%). At the end of the process, one statement was rejected, another revised, and all the remaining achieved a high consensus. Forty-four recommendations covering all aspects of the management of gastric cancer and concise treatment algorithms are proposed by the Hellenic and Cypriot Gastric Cancer Study Group. The importance of centralization, care by a multidisciplinary team, adherence to guidelines, and individualization are emphasized.

Consensus statement of the Hellenic and Cypriot Oesophageal Cancer Study Group on the diagnosis, staging and management of oesophageal cancer.

In spite of recent advances in the diagnosis and management of oesophageal cancer, the overall survival of the disease worldwide remains disappointingly low. In Greece and Cyprus, this may be partly due to a failure of health care providers to implement standardised treatment protocols in clinical practice. Development of clinical practice guidelines was undertaken as a joint project between the Hellenic Society of Medical Oncology (HeSMO) and Gastro-Intestinal Cancer Study Group (GIC-SG) in an effort to provide guidance for Greek and Cypriot clinicians in all aspects of the management of oesophageal cancer. A study group was formed comprising clinicians from different disciplines with a special interest in the management of oesophageal cancer. Following extensive review of the literature, the members of the group met in person and consensus statements were developed, which were later subjected to the Delphi survey process by invited national and international experts. Statements that achieved a rate of voting consensus > 80% were adopted. Those that reached a voting consensus of < 80% were revised or rejected. In total, 46 sentences were developed and subjected to the voting process. Of those, 45 sentences achieved a rate of consensus > 80% during the first voting round. One sentence that did not reach a satisfactory rate of consensus was revised by the members of the study group and subsequently incorporated to the final statement. Forty-six recommendations covering all aspects of the management of oesophageal cancer and concise treatment algorithms are proposed by the Hellenic and Cypriot Oesophageal Cancer Study Group. In particular, centralisation of services, care by multidisciplinary teams and adherence to clinical guidelines are strongly recommended.

Evaluation of the detection of Toll-like receptors (TLRs) in cancer development and progression in patients with colorectal cancer.

BACKGROUND: Toll-like receptors (TLRs) play essential role in innate and acquired immunity, are expressed in various cell types, and are associated with altered susceptibility to many diseases, and cancers. The aim of this study was to investigate TLR2 (-196 to-174del), TLR4 (Asp299Gly and Thr399Ile) and TLR9 (T1237C and T1486C) gene polymorphisms at risk of colorectal cancer (CRC) development and progression. METHODS: Peripheral blood was obtained from 397 patients with adjuvant (stage II/III, n = 202) and metastatic (n = 195) CRC. Moreover, blood samples from 50 healthy volunteers and 40 patients with adenomatous polyps were also included as control groups. DNA from patients and controls was analyzed using PCR and PCR-RFLP for genotyping functional polymorphism within TLR2, TLR4 and TLR9 genotypes. RESULTS: TLR2-196 to-174del/del genotype was detected in 76.6% of the patients and was significantly higher that the controls groups (p<0.001). TLR4 Asp299Gly, TLR4 Thr399Ile, TLR9 T1237C and T1486C homozygous genotypes were detected in 70.5%, 70.5%, 61.5% and 61.5% of the patients respectively, and were also significantly higher than that in the control groups (p<0.001). All polymorphisms detected were also significantly associated with the metastatic disease (p<0.001) leading to shorter overall survival (p<0.001); whereas, TLR4 Asp299Gly and Thr399Ile polymorphisms were significantly associated with KRAS mutations. CONCLUSIONS: The detection of higher frequencies of the TLR2, TLR4 and/or TLR9 polymorphisms in CRC patients compared with the control groups highlight the role of these polymorphism in CRC development and cancer progression.