Pathogenic alterations in PIK3CA and KMT2C are frequent and independent prognostic factors in anal squamous cell carcinoma treated with salvage abdominoperineal resection.

The management of anal squamous cell carcinoma (ASCC) has yet to experience the transformative impact of precision medicine. Conducting genomic analyses may uncover novel prognostic biomarkers and offer potential directions for the development of targeted therapies. To that end, we assessed the prognostic and theragnostic implications of pathogenic variants identified in 571 cancer-related genes from surgical samples collected from a homogeneous, multicentric French cohort of 158 ASCC patients who underwent abdominoperineal resection treatment. Alterations in PI3K/AKT/mTOR, chromatin remodeling, and Notch pathways were frequent in HPV-positive tumors, while HPV-negative tumors often harbored variants in cell cycle regulation and genome integrity maintenance genes (e.g., frequent TP53 and TERT promoter mutations). In patients with HPV-positive tumors, KMT2C and PIK3CA exon 9/20 pathogenic variants were associated with worse overall survival in multivariate analysis (Hazard ratio (HR)KMT2C = 2.54, 95%CI = [1.25,5.17], P value = .010; HRPIK3CA = 2.43, 95%CI = [1.3,4.56], P value = .006). Alterations with theragnostic value in another cancer type was detected in 43% of patients. These results suggest that PIK3CA and KMT2C pathogenic variants are independent prognostic factors in patients with ASCC with HPV-positive tumors treated by abdominoperineal resection. And, importantly, the high prevalence of alterations bearing potential theragnostic value strongly supports the use of genomic profiling to allow patient enrollment in precision medicine clinical trials.

Hybrid Minimally Invasive Esophagectomy for Esophageal Cancer.

BACKGROUND: Postoperative complications, especially pulmonary complications, affect more than half the patients who undergo open esophagectomy for esophageal cancer. Whether hybrid minimally invasive esophagectomy results in lower morbidity than open esophagectomy is unclear. METHODS: We performed a multicenter, open-label, randomized, controlled trial involving patients 18 to 75 years of age with resectable cancer of the middle or lower third of the esophagus. Patients were randomly assigned to undergo transthoracic open esophagectomy (open procedure) or hybrid minimally invasive esophagectomy (hybrid procedure). Surgical quality assurance was implemented by the credentialing of surgeons, standardization of technique, and monitoring of performance. Hybrid surgery comprised a two-field abdominal-thoracic operation (also called an Ivor-Lewis procedure) with laparoscopic gastric mobilization and open right thoracotomy. The primary end point was intraoperative or postoperative complication of grade II or higher according to the Clavien-Dindo classification (indicating major complication leading to intervention) within 30 days. Analyses were done according to the intention-to-treat principle. RESULTS: From October 2009 through April 2012, we randomly assigned 103 patients to the hybrid-procedure group and 104 to the open-procedure group. A total of 312 serious adverse events were recorded in 110 patients. A total of 37 patients (36%) in the hybrid-procedure group had a major intraoperative or postoperative complication, as compared with 67 (64%) in the open-procedure group (odds ratio, 0.31; 95% confidence interval [CI], 0.18 to 0.55; P<0.001). A total of 18 of 102 patients (18%) in the hybrid-procedure group had a major pulmonary complication, as compared with 31 of 103 (30%) in the open-procedure group. At 3 years, overall survival was 67% (95% CI, 57 to 75) in the hybrid-procedure group, as compared with 55% (95% CI, 45 to 64) in the open-procedure group; disease-free survival was 57% (95% CI, 47 to 66) and 48% (95% CI, 38 to 57), respectively. CONCLUSIONS: We found that hybrid minimally invasive esophagectomy resulted in a lower incidence of intraoperative and postoperative major complications, specifically pulmonary complications, than open esophagectomy, without compromising overall and disease-free survival over a period of 3 years. (Funded by the French National Cancer Institute; ClinicalTrials.gov number, NCT00937456 .).

Health-related Quality of Life Following Hybrid Minimally Invasive Versus Open Esophagectomy for Patients With Esophageal Cancer, Analysis of a Multicenter, Open-label, Randomized Phase III Controlled Trial: The MIRO Trial.

BACKGROUND: Hybrid minimally invasive esophagectomy (HMIE) has been shown to reduce major postoperative complications compared with open esophagectomy (OE) for esophageal cancer. OBJECTIVES: The aim of this study was to compare short- and long-term health-related quality of life (HRQOL) following HMIE and OE within a randomized controlled trial. METHODS: We performed a multicenter, open-label, randomized controlled trial at 13 study centers between 2009 and 2012. Patients aged 18 to 75 years with resectable cancers of the middle or lower third of the esophagus were randomized to undergo either transthoracic OE or HMIE. Patients were followed-up every 6 months for 3 years postoperatively and global health assessed with EORTC-QLQC30 and esophageal symptoms assessed with EORTC-OES18. RESULTS: The short-term reduction in global HRQOL at 30 days specifically role functioning [-33.33 (HMIE) vs -46.3 (OE); P = 0.0407] and social functioning [-16.88 (HMIE) vs -35.74 (OE); P = 0.0003] was less substantial in the HMIE group. At 2 years, social functioning had improved following HMIE to beyond baseline (+5.37) but remained reduced in the OE group (-8.33) (P = 0.0303). At 2 years, increases in pain were similarly reduced in the HMIE compared with the OE group [+6.94 (HMIE) vs +14.05 (OE); P = 0.018]. Postoperative complications in multivariate analysis were associated with role functioning, pain, and dysphagia. CONCLUSIONS: Esophagectomy has substantial effects upon short-term HRQOL. These effects for some specific parameters are, however, reduced with HMIE, with persistent differences up to 2 years, and maybe mediated by a reduction in postoperative complications.

Right Colectomy with Absorbable Mesh Repair as a Salvage Solution for the Management of Giant Incisional Hernia with Loss of Domain: Results of a Bicentric Study.

BACKGROUND: Incisional hernia (IH) may occur in 20% of patients after laparotomy. The hernia sac volume may be of significance, with reintegration of visceral contents potentially leading to repair failure or abdominal compartment syndrome. The present study aimed to evaluate a two-step surgical strategy comprising right colectomy for hernia reduction with synchronous absorbable mesh repair followed by definitive non-absorbable mesh repair in recurrence. METHODS: Patients operated between 2012 and 2017 at two university centers were retrospectively included. Volumetric evaluation of the IH was performed by CT imaging. RESULTS: Eleven patients were included. The mean BMI was 43 kg/m2 (23-52 kg/m2). Progressive preoperative pneumoperitoneum was performed in 82% of patients, with complications in 22%. The mean volumetric ratio of the volume of the hernia to the volume of the abdominal cavity was 70% (48-100%). The first parietal repair was performed using an synthetic absorbable mesh (36%), a biologic mesh (27%), or a slowly absorbable mesh (36%). No patients died as a result of the procedure. Seven (64%) patients developed grade III-IV complications, including one case of an anastomotic fistula. Recurrence occurred in eight (73%) patients after the first repair. Of these, four (50%) patients were reoperated using a non-absorbable mesh, leading to solid repair in 75% of cases. After 27 ± 18 months of follow-up, the residual IH rate was 46%. CONCLUSIONS: Right colectomy for volume reduction in IH with loss of domain potentially represents an appropriate salvage option, supporting bowel reintegration and temporary hernia repair with absorbable material.

Can we classify ampullary tumours better? Clinical, pathological and molecular features. Results of an AGEO study.

BACKGROUND: Ampullary adenocarcinoma (AA) originates from either intestinal (INT) or pancreaticobiliary (PB) epithelium. Different prognostic factors of recurrence have been identified in previous studies. METHODS: In 91 AA patients of the AGEO retrospective multicentre cohort, we evaluated the centrally reviewed morphological classification, panel markers of Ang et al. including CK7, CK20, MUC1, MUC2 and CDX2, the 50-gene panel mutational analysis, and the clinicopathological AGEO prognostic score. RESULTS: Forty-three (47%) of the 91 tumours were Ang-INT, 29 (32%) were Ang-PB, 18 (20%) were ambiguous (Ang-AMB) and one could not be classified. Among these 90 tumours, 68.7% of INT tumours were Ang-INT and 78.2% of PB tumours were Ang-PB. MUC5AC expression was detected in 32.5% of the 86 evaluable cases. Among 71 tumours, KRAS, TP53, APC and PIK3CA were the most frequently mutated genes. The KRAS mutation was significantly more frequent in the PB subtype. In multivariate analysis, only AGEO prognostic score and tumour subtype were associated with relapse-free survival. Only AGEO prognostic score was associated with overall survival. CONCLUSIONS: Mutational analysis and MUC5AC expression provide no additional value in the prognostic evaluation of AA patients. Ang et al. classification and the AGEO prognostic score were confirmed as a strong prognosticator for disease recurrence.

Does A Longer Waiting Period After Neoadjuvant Radio-chemotherapy Improve the Oncological Prognosis of Rectal Cancer?: Three Years' Follow-up Results of the Greccar-6 Randomized Multicenter Trial.

OBJECTIVE: The aim of this study was to report the 3-year survival results of the GRECCAR-6 trial. SUMMARY BACKGROUND DATA: Current data on the effect of an extended interval between radiochemotherapy (RCT) and resection for rectal cancer on the rate of complete pathological response (pCR = ypT0N0) is controversial. Furthermore, its effect on oncological outcomes is unknown. METHODS: The GRECCAR-6 trial was a phase III, multicenter, randomized, open-label, parallel-group, controlled trial. Patients with cT3/T4 or TxN+ tumors of the mid or lower rectum who had received RCT (45-50 Gy with 5-fluorouracil or capecitabine) were included and randomized into a 7- or 11-week waiting period. Primary endpoint was the pCR rate. Secondary endpoints were 3-year overall (OS), disease-free survival (DFS), and recurrence rates. RESULTS: A total of 265 patients from 24 participating centers were enrolled. A total of 253 patients underwent a mesorectal excision. Overall pCR rate was 17% (43/253). Mean follow-up from surgical resection was 32 ±â€Š8 months. Twenty-four deaths occurred with an 89% OS at 3 years. DFS was 68.7% at 3 years (75 recurrences). Three-year local and distant recurrences were 7.9% and 23.8%, respectively. The randomization group had no impact on the 3-year OS (P = 0.8868) or DFS (P = 0.9409). Distant (P = 0.7432) and local (P = 0.3944) recurrences were also not influenced by the waiting period. DFS was independently influenced by 3 factors: circumferential radial margin (CRM) ≤1 mm [hazard ratio (HR) = 2.03; 95% confidence interval (CI), 1.17-3.51], ypT3-T4 (HR = 2.69; 95% CI, 1.19-6.08) and positive lymph nodes (HR = 3.62; 95% CI, 1.89-6.91). CONCLUSION: Extending the waiting period by 4 weeks following RCT has no influence on the oncological outcomes of T3/T4 rectal cancers.

Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer.

IL-1 family cytokines play a dual role in the gut, with different family members contributing either protective or pathogenic effects. IL-36γ is an IL-1 family cytokine involved in polarizing type-1 immune responses. However, its function in the gut, including in colorectal cancer pathogenesis, is not well appreciated. In a murine model of colon carcinoma, IL-36γ controls tertiary lymphoid structure formation and promotes a type-1 immune response concurrently with a decrease in expression of immune checkpoint molecules in the tumor microenvironment. Here, we demonstrate that IL-36γ plays a similar role in driving a pro-inflammatory phenotype in human colorectal cancer. We analyzed a cohort of 33 primary colorectal carcinoma tumors using imaging, flow cytometry, and transcriptomics to determine the pattern and role of IL-36γ expression in this disease. In the colorectal tumor microenvironment, we observed IL-36γ to be predominantly expressed by M1 macrophages and cells of the vasculature, including smooth muscle cells and high endothelial venules. This pattern of IL-36γ expression is associated with a CD4+ central memory T cell infiltrate and an increased density of B cells in tertiary lymphoid structures, as well as with markers of fibrosis. Conversely, expression of the antagonist to IL-36 signaling, IL-1F5, was associated with intratumoral expression of checkpoint molecules, including PD-1, PD-L1, and CTLA4, which can suppress the immune response. These data support a role for IL-36γ in the physiologic immune response to colorectal cancer by sustaining inflammation within the tumor microenvironment.

Multicenter phase III randomized trial comparing laparoscopy and laparotomy for colon cancer surgery in patients older than 75 years: the CELL study, a Fédération de Recherche en Chirurgie (FRENCH) trial.

BACKGROUND: Several multicenter randomized controlled trials comparing laparoscopy and conventional open surgery for colon cancer have demonstrated that laparoscopic approach achieved the same oncological results while improving significantly early postoperative outcomes. These trials included few elderly patients, with a median age not exceeding 71 years. However, colon cancer is a disease of the elderly. More than 65% of patients operated on for colon cancer belong to this age group, and this proportion may become more pronounced in the coming years. In current practice, laparoscopy is underused in this population. METHODS: The CELL (Colectomy for cancer in the Elderly by Laparoscopy or Laparotomy) trial is a multicenter, open-label randomized, 2-arm phase III superiority trial. Patients aged 75 years or older with uncomplicated colonic adenocarcinoma or endoscopically unresectable colonic polyp will be randomized to either colectomy by laparoscopy or laparotomy. The primary endpoint of the study is overall postoperative morbidity, defined as any complication classification occurring up to 30 days after surgery. The secondary endpoints are: 30-day and 90-day postoperative mortality, 30-day readmission rate, quality of surgical resection, health-related quality of life and evolution of geriatric assessment. A 35 to 20% overall postoperative morbidity rate reduction is expected for patients operated on by laparoscopy compared with those who underwent surgery by laparotomy. With a two-sided α risk of 5% and a power of 80% (ß = 0.20), 276 patients will be required in total. DISCUSSION: To date, no dedicated randomized controlled trial has been conducted to evaluate morbidity after colon cancer surgery by laparoscopy or laparotomy in the elderly and the benefits of laparoscopy is still debated in this context. Thus, a prospective multicenter randomized trial evaluating postoperative outcomes specifically in elderly patients operated on for colon cancer by laparoscopy or laparotomy with curative intent is warranted. If significant, such a study might change the current surgical practices and allow a significant improvement in the surgical management of this population, which will be the vast majority of patients treated for colon cancer in the coming years. TRIAL REGISTRATION: ClinicalTrials.gov NCT03033719 (January 27, 2017).

Postoperative morbidity and mortality for malignant colon obstruction: the American College of Surgeon calculator reliability.

BACKGROUND: The American College of surgical risk calculator (SRC) score has never been validated specifically for surgery in emergency. The objective was to evaluate the reliability of this calculator in patients with malignant colon obstruction. MATERIALS AND METHODS: We retrospectively have analyzed the morbidity and mortality observed in operated patients. Risk factors for postoperative morbidity and mortality were analyzed by logistic regression model. We have compared the morbidity and mortality estimated by the SRC score with that observed using the Brier Score (BS). A BS of 0 indicated perfect prediction, whereas a BS of 1 indicated the poorest prediction. RESULTS: Sixty-nine patients aged 75 y (41-93) have been operated on emergency from November 2001 to August 2015. The tumor was localized in the sigmoid in 33 cases (48%), in the splenic flexure in nine cases (13%), and in the right colon in 17 cases (25%). The surgical procedures were as follows: right colectomy with anastomosis (29%), diverting proximal iliac colostomy (23%), and subtotal colectomy with anastomosis (19%). The SRC score indicated a good predictivity for mortality (9.8% predicted versus 8.7% observed, BS = 0.058), for morbidity (33.4% versus 40.6%, BS = 0.209), and for serious morbidity (25.5% versus 17.4%, BS = 0.131). In multivariate analysis, SRC was an independent risk factor for mortality (P = 0.030 odds ratio [OR] = 1.07 [1.01-1.15]) and morbidity (P = 0.001 OR = 1.16 [1.08-1.27]). CONCLUSIONS: SRC score is a reliable tool for assessing the morbidity and mortality of obstructive colon cancer and could help with adapting the surgical gesture to the risks predicted.

Radiofrequency ablation for colorectal cancer liver metastases initially greater than 25 mm but downsized by neo-adjuvant chemotherapy is associated with increased rate of local tumor progression.

BACKGROUND: Radiofrequency ablation (RFA) is a valid treatment for liver metastases from colorectal cancer (CRLM) smaller than 25 mm and unsuitable for surgical resection. Tumor size is predictive for local tumor progression (LTP). The aim of this study was to evaluate whether RFA is indicated for lesions >25 mm at presentation but <25 mm after chemotherapy. METHOD: Patients who underwent RFA for CRLM after chemotherapy (January 2004-December 2012) were reviewed. Metastases were classified according to their size. Group 1: ≤25 mm before and after chemotherapy. Group 2A: >25 mm before but ≤25 mm after chemotherapy. Group 2B: >25 mm before and after chemotherapy. RESULTS: 133 CRLM were ablated in 83 patients (median follow-up 56 months). At 1-year, the LTP rate was higher in group 2A than in group 1 (32% vs. 16%, p ≤ 0.001). The highest rate of 1-year LTP was 64% in group 2B. Time to LTP (TLTP) was shorter in group 2A than in group 1 (HR: 2.89; 95% CI [1.04-8.01]; p = 0.004). Following multivariate analysis, the group type was the only predictive factor for TLTP (p < 0.001). CONCLUSIONS: RFA is not the optimal treatment for CRLM > 25 mm at presentation.

[Colorectal cancer surgery in the elderly]. / Chirurgie du cancer colorectal chez la personne âgée.

Colorectal cancer risk factors increase with age, comorbidities, delayed diagnosis, obstruction, emergency and frailty. Surgery is the standard treatment as the survival rate for this pathology is the same as in young patients. It would appear that there is an excess morbidity and mortality of colorectal cancer surgery in the elderly. Early rehabilitation is to be favoured during the postoperative period.

Prognostic Value of Sterilized Lymph Nodes After Preoperative Chemoradiotherapy for Patients with ypN0 Rectal Cancer.

BACKGROUND: Patients with ypN0 rectal cancer who have received preoperative chemoradiotherapy can be divided into those who initially were node negative and those whose positive nodes have been sterilized by preoperative therapy. The long-term prognosis for ypN0 patients with sterilized lymph nodes (LNS) is unknown. This study aimed to assess the prognostic value of LNS after preoperative chemoradiotherapy for patients with ypN0 rectal cancer. METHODS: From January 2007 to March 2014, 206 patients with ypN0 tumors of the mid or lower rectum treated by chemoradiotherapy and radical surgery were enrolled in the study. Of these 206 patients, 49 had ypN0 tumors with LNS (LNS+ group), and 157 had ypN0 tumors without LNS (LNS- group). The patients in both groups were comparable in terms of tumor characteristics, type of chemoradiotherapy, type of surgery, R0 resection rate, and postoperative complication rate. RESULTS: The mean follow-up period was 40.5 ± 27 months. The 1- and 3-year OS rates in the LNS+ group were respectively 100 and 95.5% versus 99.4 and 91.6% in the LNS- group (P = 0.549). The 1- and 3-year DFS rates in the LNS+ group were respectively 100 and 94.2% versus 94.7 and 87.1% in the LNS- group (P = 0.117). The multivariate analysis showed that the presence of LNS did not affect OS (P = 0.918) or DFS (P = 0.209). CONCLUSIONS: The prognosis is excellent for patients with ypN0 rectal cancer who have LNS after preoperative chemoradiotherapy. The presence of LNS in ypN0 rectal cancer patients after chemoradiotherapy should not be considered a factor for a poor prognosis.

Sigmoid resection with primary anastomosis and ileostomy versus laparoscopic lavage in purulent peritonitis from perforated diverticulitis: outcome analysis in a prospective cohort of 40 consecutive patients.

PURPOSE: This prospective study aimed to compare outcomes after laparoscopic peritoneal lavage (LPL) and sigmoid resection with primary colorectal anastomosis (RPA). METHODS: From June 2010 to June 2015, 40 patients presenting with Hinchey III peritonitis from perforated diverticulitis underwent LPL or RPA. Patients with Hinchey II or IV peritonitis and patients who underwent an upfront Hartmann procedure were excluded. Primary endpoint was overall 30-day or in-hospital postoperative morbidity after surgical treatment of peritonitis. RESULTS: Twenty-five patients underwent RPA and 15 LPL. Overall postoperative morbidity and mortality rates were not significantly different after RPA and LPL (40 vs 67 %, p = 0.19; 4 vs 6.7 %, p = 1, respectively). Intra-abdominal morbidity and reoperation rates were significantly higher after LPL compared to RPA (53 vs 12 %, p < 0.01; 40 vs 4 %, p = 0.02, respectively). Multivariate analysis showed that LPL (p = 0.028, HR = 18.936, CI 95 % = 1.369-261.886) was associated with an increased risk of postoperative intra-abdominal septic morbidity. Among 6 patients who underwent reoperation after LPL, 4 had a Hartmann procedure. All surviving patients who had a procedure requiring stoma creation underwent stoma reversal after a median delay of 92 days after LPL and 72 days after RPA (p = 0.07). CONCLUSION: LPL for perforated diverticulitis is associated with a high risk of inadequate intra-abdominal sepsis control requiring a Hartmann procedure in up to 25 % of patients. RPA appears to be safer and more effective. It may represent the best option in this context.

Concepts of the rectovaginal septum: implications for function and surgery.

INTRODUCTION: In the pelvis, the rectogenital septum (RGS) separates the urogenital compartment from the digestive compartment. In men, it corresponds to Denonvilliers' rectoprostatic fascia or rectovesical septum (RVS). Its purpose-and, indeed, its existence-are controversial in women. The purpose of this review was to update knowledge about the RGS in women and, in particular, to clarify its relationship to pelvic nerves in order to deduce practical consequences of pelvic surgery and compare it to the RVS in men. METHODS: A review of the anatomical and surgical literature was undertaken. Evidence for embryological origin, composition, and surgical importance of the RGS in women and men is suggested. RESULTS: This manuscript presents evidence of the existence of the RGS in both women (rectovaginal septum, RVaS) and men (rectovesical septum, RVS). It originates from the genital structures and extends from the rectogenital pouch to the perineal body. It is composed of connective tissue associated with bundles of smooth muscle cells and has lateral expansions in close contact with neurovascular bundles originating from the inferior hypogastric plexus. During pelvic surgery for carcinoma, preservation of nerve fibers of erectile bodies is necessary if possible. The RGS is thus an important surgical landmark during urogenital sinus surgery, prolapse surgery, and proctectomy in women as well as during proctectomy and prostatectomy in men. CONCLUSIONS: The RGS is present in women as well as in men, with great similarities between the two sexes. It represents an important surgical landmark during pelvic nerve-sparing surgery.

Variations of BRAF mutant allele percentage in melanomas.

BACKGROUND: BRAF mutations are present in 40% of human skin melanomas. Mutated tumors with an increased percentage of BRAF mutant alleles (BRAF-M%) may have a better response to RAF/MEK inhibitors. We evaluated the BRAF-M% in melanomas, and the genetic causes of its variation. METHODS: BRAF-M% was quantified by pyrosequencing, real-time PCR (rtPCR) and/or picoliter-droplet PCR (dPCR). BRAF mutant expression was detected by immunohistochemistry. Chromosomal alterations were analyzed with fluorescence in situ hybridization (FISH), and single nucleotide polymorphism (SNP) arrays. RESULTS: BRAF-M% quantification obtained with pyrosequencing was highly correlated (R = 0.94) with rtPCR, and with dPCR. BRAF-M% quantified from DNA and RNA were also highly correlated (R = 0.98). Among 368 samples with >80% tumor cells, 38.6% had a BRAF (V600E) mutation. Only 66.2% cases were heterozygous (BRAF-M% 30 to 60%). Increased BRAF-M% (>60%) was observed in 19% of cases. FISH showed a polysomy of chromosome 7 in 13.6%, 35.3% and 54.5% of BRAF wild-type, heterozygous and non-heterozygous BRAF-mutated samples, respectively (P < 0.005). Amplification (5.6%) and loss (3.2%) of BRAF locus were rare. By contrast, chromosome 7 was disomic in 27/27 BRAF-mutated nevi. CONCLUSIONS: BRAF-M% is heterogeneous and frequently increased in BRAF-mutant melanomas. Aneuploidy of chromosome 7 is more frequent in BRAF mutant melanomas, specifically in those with high BRAF-M%.

[Surgical treatment of colorectal cancer]. / Traitement chirurgical du cancer colorectal.

Any therapeutic decision in colorectal cancer must be taken by multidisciplinary coordination meeting. The treatment of non-metastatic colon cancer based on the first surgery with complete excision, dissection and respect distal margins. In case of node-adjuvant chemotherapy improves survival. For rectal cancer, surgery may be preceded by chemo radiotherapy for locally advanced cancers. The sphincter preservation rate in entrained teams can reach 90%. The abdominoperineal resection is indicated in cases of tumor invading the external sphincter. In colorectal cancer the most important prognostic factor is the histological stage (invasion of the intestinal wall and lymph node involvement). If the breach only affects the mucosal healing is 100%. If the entire wall is reached, node negative the survival is 60%. However, if the lymph nodes are affected survival drop 30-40%. Finally in the presence of synchronous liver metastases curative treatment options can be considered and must be defined in the multidisciplinary coordination meeting. Surgery of liver metastases can achieve cure rates of 30% at 5 years.

Copy-neutral loss of heterozygosity and chromosome gains and losses are frequent in gastrointestinal stromal tumors.

BACKGROUND: A KIT gain of function mutation is present in 70% of gastrointestinal stromal tumors (GISTs) and the wild-type (WT) allele is deleted in 5 to 15% of these cases. The WT KIT is probably deleted during GIST progression. We aimed to identify the mechanism of WT KIT loss and to determine whether other genes are involved or affected. METHODS: Whole-genome SNP array analyses were performed in 22 GISTs with KIT exon 11 mutations, including 11 with WT loss, to investigate the mechanisms of WT allele deletion. CGH arrays and FISH were performed in some cases. Common genetic events were identified by SNP data analysis. The 9p21.3 locus was studied by multiplex quantification of genomic DNA. RESULTS: Chromosome instability involving the whole chromosome/chromosome arm (whole C/CA) was detected in 21/22 cases. The GISTs segregated in two groups based on their chromosome number: polyGISTs had numerous whole C/CA gains (mean 23, range [9 to 43]/3.11 [1 to 5]), whereas biGISTs had fewer aberrations. Whole C/CA losses were also frequent and found in both groups. There were numerous copy-neutral losses of heterozygosity (cnLOH) of whole C/CA in both polyGIST (7/9) and biGIST (9/13) groups. cnLOH were frequent on 4q, 11p, 11q, 1p, 2q, 3p and 10, and never involved 12p, 12q, 20p, 20q or 19q. Other genetic alterations included segmental chromosome abnormalities, complete bi-allelic deletions (homozygous deletions) and, more rarely, amplifications. Nine of 11 GISTs with homozygous KIT exon 11 mutations had cnLOH of chromosome 4. CONCLUSION: The cnLOH of whole C/CA is a frequent genetic alteration in GISTs and is closely associated with homozygous mutations of KIT and WT allele deletion.

Surgery for Infrarenal Retroperitoneal Node Metastases from Colon Cancer.

PURPOSE: Treatment of retroperitoneal lymph node metastases (RPN) from colon cancer (CC) is a therapeutic challenge. Available evidence supporting a curative approach is weak and uncertainties remain concerning the extent of the dissection, the optimal timing for surgery, and the role of adjuvant radiotherapy. We report the outcomes of a curative intent strategy in a recent monocentric series of patients. METHODS: We did a retrospective review of all curative intent surgical treatment of RPN from CC performed consecutively in a French university hospital from June 2015 to April 2021. Demographics, clinicopathological, and molecular characteristics were evaluated. We describe recurrence-free and overall survival and factors related to recurrence. RESULTS: Records from 18 patients were reviewed. The median age was 69 years. Most of the patients were male (55%), ASA 1-2 (94%), had a left-sided primary colon cancer (73%), and had metachronous RPN (62%). Thirteen patients (72%) experienced recurrence. Recurrence was often limited to RPN (27%) or liver (22%). Four patients underwent a second surgery for RPN recurrence. Median disease-free and overall survival were 22 months and 50 months after RPN surgery. We did not find any factor associated with recurrence. Short-term recurrence (< 6 months) was associated with shorter overall survival (0.031). CONCLUSION: The current results suggest that RPN resection is feasible and associated with long survival in selected patients. Further studies evaluating the benefit of curative strategies including radical surgery for patients with potentially resectable RPN are warranted.

Radiofrequency Combined with Intratumoral Immunotherapy: Preclinical Results and Safety in Metastatic Colorectal Carcinoma.

Radiofrequency ablation (RFA) of cancer induces an anti-tumor immunity, which is insufficient to prevent recurrences. In mice, RFA-intratumoral immunotherapy by granulocyte-macrophage colony-stimulating factor (GM-CSF) and Bacillus Calmette-Guerin resulted in complete metastases regression. Infectious risk in human needs replacement of live vaccines. Intratumoral purified protein derivatives (PPD) have never been tested in digestive cancers, and the safety of intratumoral immunotherapy after RFA has not yet been validated in human models. We investigated the therapeutic efficacy of combined radiofrequency ablation (RFA) and intratumoral immunotherapy (ITI) using an immune-muco-adherent thermogel (IMT) in a mouse model of metastatic colorectal cancer (CRC) and the safety of this approach in a pig model. Intratumoral stability of the immunogel was assessed using magnetic resonance imaging (MRI) and bioluminescent imaging. Seventy-four CT26 tumor-bearing female BALB/c mice were treated with RFA either alone or in combination with intratumoral IMT. Regression of distant metastasis and survival were monitored for 60 days. Six pigs that received liver radiofrequency and intralesional IMT injections were followed for 15 days. Experimental gel embolisms were treated using an intravascular approach. Pertinent rheology of IMT was confirmed in tumors, by the signal stability during 3 days in MRI and 7 days in bioluminescence imaging. In mice, the abscopal effect of RFA-intratumoral immunotherapy resulted in regression of distant lesions completed at day 16 vs. a volume of 350 ± 99.3 mm3 in the RFA group at day 25 and a 10-fold survival rate at 60 days. In pigs, injection of immunogel in the liver RFA area was safe after volume adjustment without clinical, hematological, and liver biology disorder. Flow cytometry showed an early increase in CD3 TCRγδ+T cells at D7 (p < 0.05) and a late decrease in CD29+-CD8 T cells at D15 (p < 0.05), reflecting the inflammation status changes. Systemic GM-CSF release was not detectable. Experimental caval and pulmonary thermogel embolisms were treated by percutaneous catheterism and cold serum infusion. RFA-intratumoral immunotherapy as efficient and safe mini-invasive interventional oncology is able to improve ablative treatment of colorectal liver metastases.

Contemporary Outcomes for the Curative Treatment of Colorectal Cancer Pulmonary Metastases.

PURPOSE: Treatment of pulmonary metastases (PM) from colorectal cancer (CRC) is the standard of care by several guidelines from Europe and the USA, but the validity of this strategy has been recently questioned, and the available evidence supporting this strategy is weak. We report the outcomes of a curative intent strategy in a very recent and homogenous series of patients. METHODS: We did a retrospective review of all curative intent surgical or ablative treatment of PM from CRC performed consecutively in 3 French institutions from January 2015 to December 2019. Demographics, clinicopathological, and molecular characteristics were evaluated. Cox regression models were used to identify prognostic factors related to local recurrence and disease-free survival. RESULTS: Records from 152 patients were reviewed. One-hundred thirty-five patients (88%) had surgical metastasectomy. Median age was 67 years. Most of the patients had a single lesion (66%), and 16% had synchronous PM. Eighty-one patients (53%) experienced recurrence, and the thorax was the most common site of recurrence. Median disease-free survival and overall survival were 35 months and 78 months after PM treatment. At the end of the study, only 17% of the patients died. Pulmonary tumor burden was correlated with disease-free survival in univariate analysis, but multivariate analysis did not find any prognostic factor independently associated with local recurrence or survival. CONCLUSION: Our finds corroborate existing recommendation for the invasive treatment of PM from CRC in selected patients.