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The risk of colorectal cancer (CRC) depends on environmental and genetic factors. Among environmental factors, an imbalance in the gut microbiota can increase CRC risk. Also, microbiota is influenced by host genetics. However, it is not known if germline variants influence CRC development by modulating microbiota composition. We investigated germline variants associated with the abundance of bacterial populations in the normal (non-involved) colorectal mucosa of 93 CRC patients and evaluated their possible role in disease. Using a multivariable linear regression, we assessed the association between germline variants identified by genome wide genotyping and bacteria abundances determined by 16S rRNA gene sequencing. We identified 37 germline variants associated with the abundance of the genera Bacteroides, Ruminococcus, Akkermansia, Faecalibacterium and Gemmiger and with alpha diversity. These variants are correlated with the expression of 58 genes involved in inflammatory responses, cell adhesion, apoptosis and barrier integrity. Genes and bacteria appear to be involved in the same processes. In fact, expression of the pro-inflammatory genes GAL , GSDMD and LY6H was correlated with the abundance of Bacteroides , which has pro-inflammatory properties; abundance of the anti-inflammatory genus Faecalibacterium correlated with expression of KAZN, with barrier-enhancing functions. Both the microbiota composition and local inflammation are regulated, at least partially, by the same germline variants. These variants may regulate the microenvironment in which bacteria grow and predispose to the development of cancer. Identification of these variants is the first step to identifying higher-risk individuals and proposing tailored preventive treatments that increase beneficial bacterial populations.

Background Human Leukocyte Antigen (HLA)-E is a non-classical class I HLA molecule that can be stabilized by ligands donated by other classical (HLA-A, -B, -C) and non-classical (HLA-G) family members. HLA-E engages a variety of immune receptors expressed by cytotoxic T lymphocytes (CTLs), Natural killer (NK) cells and NK-CTLs. In view of the opposing outcomes (activation or inhibition) of the different HLA-E receptors, the preferred role (if any) of HLA-E expressed in vivo on tumor cells remains to be established. Methods Taking advantage of MEM-E/02, a recently characterized antibody to denatured HLA-E molecules, HLA-E expression was assessed by immunohistochemistry on an archival collection (formalin-fixed paraffin-embedded) of 149 colorectal primary carcinoma lesions paired with their morphologically normal mucosae. Lymphoid infiltrates were assessed for the expression of the HLA-E-specific, inhibitory, non-rearranging receptor NKG2A. Results High HLA-E expression did not significantly correlate with the expression of classical HLA-B and HLA-C molecules, but it did correlate with high expression of its preferential ligand donor HLA-A. In addition, it correlated with lymphoid cell infiltrates expressing the inhibitory NKG2A receptor, and was an independent predictor of good prognosis, particularly in a subset of patients whose tumors express HLA-A levels resembling those of their paired normal counterparts (HLA-A). Thus, combination phenotypes (HLA-E lo-int /HLA-AE and HLA-E hi /HLA-AE) of classical and non-classical class I HLA molecules mark two graded levels of good prognosis. Conclusions These results suggest that HLA-E favors activating immune responses to colorectal carcinoma. They also provide evidence in humans that tumor cells entertain extensive negotiation with the immune system until a compromise between recognition and escape is reached. It is implied that this process occurs stepwise, as predicted by the widely accepted 'immunoediting' model.

Background Sexual dysfunction following surgery for rectal cancer may be frequent and often severe. The aim of the present study is to evaluate the occurrence of this complication from both a clinical point of view and by means of neurophysiological tests. Methods We studied a group of 57 patients submitted to rectal resection for adenocarcinoma. All the patients underwent neurological, psychological and the following neurophysiological tests: sacral reflex (SR), pudendal somatosensory evoked potentials (PEPs), motor evoked potential (MEPs) and sympathetic skin responses (SSRs). The results were compared with a control group of 67 rectal cancer patients studied before surgery. Only 10 of these patients could be studied both pre- and postoperatively. 10 patients submitted to high dose preoperative chemoradiation were studied to evaluate the effect of this treatment on sexual function. Statistical analysis was performed by means of the two-tailed Student's t test for paired observations and k concordance test. Results 59.6% of patients operated reported sexual dysfunction, while this symptom occurred in 16.4% in the control group. Moreover, a significantly higher rate of alterations of the neurophysiological tests and longer mean latencies of the SR, PEPs, MEPs and SSRs were observed in the patients who had undergone resection. In the 10 patients studied both pre and post-surgery impotence occurred in 6 of them and the mean latencies of SSRs were longer after operation. In the 10 patients studied pre and post chemoradiation impotence occurred in 1 patient only, showing the mild effect of these treatments on sexual function. Conclusion Patients operated showed severe sexual dysfunctions. The neurophysiological test may be a useful tool to investigate this complication. The neurological damage could be monitored to decide the rehabilitation strategy.

Background Liposarcoma is one of the most common soft tissue sarcoma of adult life, usually occurring in the retroperitoneum and the extremities. Primary liposarcoma of the colon is very rare. The optimal treatment has not been established due to the small number of cases reported. We report a case of primary liposarcoma of the colon presenting as a massive intraluminal lesion. Case presentation A 79-year-old woman presented with abdominal pain, progressive constipation and weight loss. A CT scan and a colonoscopy revealed an intraluminal mass in the transverse colon and multiple intraperitoneal lesions. The patient underwent surgical resection of the lesions. Pathologic examination was consistent with pleomorphic liposarcoma of the colon. Conclusion Although no guidelines are available for the management of liposarcoma of the colon, surgical resection should be performed when feasible. Our patient's overall survival was satisfactory in spite of the multiple negative prognostic factors.

Purpose The major improvements in the diagnosis and treatment of colorectal cancer (CRC) over the past decades increased the patients’ survival rates. Despite this, patients and clinicians still need to address the long-term physical and psychosocial effects over time. This paper aims to prospectively assess CRC patients’ HR-QoL psychological distress and sexual functioning and identify clinical, demographic, and psychological predictors. Methods In total, 55 patients were evaluated from diagnosis to 5-year follow-up with the following instruments: EORTC QLQ-C30 and QLQ-C38 for QoL and sexuality; HADS for psychological distress; and specific questions to detect psychological variables. Results QoL worsened after diagnosis and returned to baseline values after 5 years. Sexual function significantly deteriorated over time (with no recovery, especially in women), while borderline/severe anxiety and depression decreased. A better HR-QoL at baseline was associated with better physical, social and sexual functioning, positive body image and sexual pleasure after 5 years. Conclusion HR-QoL allows the early detection of patients at risk, favoring prompt patient-centered interventions.

Background: The adequate distal resection margin is still controversial in rectal cancer treated by neoadjuvant chemoradiotherapy (nCRT). The aim of this study was to assess the impact of a distal margin of ≤1 mm on locoregional recurrence-free survival (LRRFS). Methods: Among 255 patients treated with nCRT and surgery at the National Cancer Institute of Milan, 83 (32.5%) had a distal margin of ≤1 mm and 172 (67.5%) had a distal margin of >1 mm. Survival analyses were performed to assess the impact of distal margin on 5-year LRRFS, as well as Cox survival analysis. The role of distal margin on survival was analyzed according to different tumor regression grades (TRGs). Results: The overall 5-year LRRFS rate was 77.6% with a distal margin of ≤1 mm vs. 88.3% with a distal margin of >1 mm (Log-rank p = 0.09). Only stage ypT4 was an independent predictor of worse LRRFS (HR 15.14, p = 0.026). The 5-year LRRFS was significantly lower in TRG3–5 patients with a distal margin of ≤1 mm compared to those with a distal margin of >1 mm (68.5% vs. 84.2%, p = 0.027), while no difference was observed in case of TRG1–2 (p = 0.77). Conclusions: Low-responder rectal cancers after nCRT still require a distal margin of >1 mm to reduce the high likelihood of local relapse.

Background Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screenings not cost-effective yet. Recently, we developed a straightforward, rapid, and inexpensive test based on p53 mitotic centrosomal localization (p53-MCL) in peripheral blood mononuclear cells (PBMCs) that diagnoses mutant ATM zygosity and recognizes tumor-associated ATM polymorphisms. Methods Fresh PBMCs from 496 cancer patients were analyzed by p53-MCL: 90 cases with familial BRCA1/2- positive and -negative breast and/or ovarian cancer, 337 with sporadic cancers (ovarian, lung, colon, and post-menopausal breast cancers), and 69 with breast/thyroid cancer. Variants were confirmed by ATM sequencing. Results A total of seven individuals with ATM variants were identified, 5/65 (7.7 %) in breast cancer cases of familial breast and/or ovarian cancer and 2/69 (2.9 %) in breast/thyroid cancer. No variant ATM carriers were found among the other cancer cases. Excluding a single case in which both BRCA1 and ATM were mutated, no p53-MCL alterations were observed in BRCA1/2 -positive cases. Conclusions These data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers.

In a prospective multicenter phase II trial of radioembolization with yttrium-90 ( 90 Y-RE) in chemorefractory liver-dominant metastatic colorectal cancer (mCRC), we showed that median survival was 12.6 months (95% CI 7.0–18.3) with 48% of 50 patients achieving disease control. In this extension retrospective study, we analyzed whether a panel of biomarkers, known to be associated to an adverse clinical outcome, underwent variations in CRC liver metastases pre and post 90 Y-RE. Of the 50 patients included in the study, 29 pre- 90 Y-RE therapy and 15 post- 90 Y-RE had liver biopsy specimens available. In these series we investigated survivin, p53, Bcl-2 and Ki-67 expression pre- and post- 90 Y-RE by immuhistochemistry (IHC). Our findings evidenced a decrease of survivin (77% vs 33%), p53 (93% vs 73%), Bcl-2 (37% vs 26%) expression as well as of Ki-67 proliferation index (62.5% vs 40%) on liver biopsies collected post- 90 Y-RE as compared to pre- 90 Y-RE. In the subset of 13 matched liver metastases we further confirmed the reduction of survivin (92.3% vs 53.8%; p = 0.06), p53 (100% vs 69.2%; p = 0.05) and Bcl-2 (69.2% vs 53.8%; p = 0.05) expression post- 90 Y-RE. This biomarker modulation was accompanied by morphological changes as steatohepatitis, hepatocyte necrosis, collagen deposition, proliferating and/or bile duct ectasia, focal sinusoidal dilatation and fibrosis. Although our analysis was conducted in a very limited number cases, these changes appear strictly related to the response to 90 Y-RE therapy and may deserve further investigation on a larger series of patients.

In original publication of this article [1], the data for \"Pat#7\" in Additional file 1 was listed as \"c.4436+24G>A\" in the \"Nucleotide change\" column. Instead, the number should have been c.4436+24A>G.