Targeting the Wnt Pathway and Cancer Stem Cells with Anti-progastrin Humanized Antibodies as a Potential Treatment for K-RAS-Mutated Colorectal Cancer.

Purpose: Patients with metastatic colorectal cancer suffer from disease relapse mainly due to cancer stem cells (CSC). Interestingly, they have an increased level of blood progastrin, a tumor-promoting peptide essential for the self-renewal of colon CSCs, which is also a direct ß-catenin/TCF4 target gene. In this study, we aimed to develop a novel targeted therapy to neutralize secreted progastrin to inhibit Wnt signaling, CSCs, and reduce relapses.Experimental Design: Antibodies (monoclonal and humanized) directed against progastrin were produced and selected for target specificity and affinity. After validation of their effectiveness on survival of colorectal cancer cell lines harboring B-RAF or K-RAS mutations, their efficacy was assessed in vitro and in vivo, alone or concomitantly with chemotherapy, on CSC self-renewal capacity, tumor recurrence, and Wnt signaling.Results: We show that anti-progastrin antibodies decrease self-renewal of CSCs both in vitro and in vivo, either alone or in combination with chemotherapy. Furthermore, migration and invasion of colorectal cancer cells are diminished; chemosensitivity is prolonged in SW620 and HT29 cells and posttreatment relapse is significantly delayed in T84 cells, xenografted nude mice. Finally, we show that the Wnt signaling activity in vitro is decreased, and, in transgenic mice developing Wnt-driven intestinal neoplasia, the tumor burden is alleviated, with an amplification of cell differentiation in the remaining tumors.Conclusions: Altogether, these data show that humanized anti-progastrin antibodies might represent a potential new treatment for K-RAS-mutated colorectal patients, for which there is a crucial unmet medical need. Clin Cancer Res; 23(17); 5267-80. ©2017 AACR.

Robotic versus laparoscopic rectal resection for sphincter-saving surgery: pathological and short-term outcomes in a single-center analysis of 130 consecutive patients.

BACKGROUND: Minimally invasive sphincter-saving rectal resection represents a challenging procedure. Robotic surgery for rectal cancer has several advantages over conventional surgery in performing precise dissection and was proved to be safe and effective in previous studies. However, comparison between laparoscopic and robotic rectal resection has drawn contradictory results. The aim of the present study was to compare robotic and laparoscopic sphincter-saving rectal resections for short-term and pathological outcomes. METHODS: Between January 2013 and May 2016, we performed a total of 258 robotic surgeries, including 146 colorectal resections (56%). For this study, we included the first 65 sphincter-saving robotic resections and compared them to the last 65 consecutive laparoscopic resections. The laparoscopic group was constituted by the last 65 consecutively operated patients who matched the inclusion criteria. RESULTS: Patients' baseline characteristics were similar in both the groups. Conversion rate was greater in the laparoscopic group (17 vs. 5%, p=0.044). Reoperation rate, overall and severe morbidity, and median hospital stay were similar in both the groups. Quality of mesorectal excision specimen was considered complete or near complete in 97 and 96% in the laparoscopic and robotic groups, respectively. There was no difference in the rates of negative circumferential radial margin, distal margin, and surgical success measured by composite criteria. CONCLUSION: The main finding of this study was that robotic proctectomy for sphincter-saving procedures offers similar quality of TME with a statistically significant lower rate of conversion when compared to laparoscopic proctectomy.

CDH1 germline mutations and the hereditary diffuse gastric and lobular breast cancer syndrome: a multicentre study.

INTRODUCTION: CDH1 predisposes primarily to diffuse gastric cancer (DGC). Multiple DGC cases in a family, DGC at a young age in an individual or the combination of DGC andlobular breast cancer (LBC) in an individual or a family define the hereditary DGC syndrome (HDGC), and testing for germline CDH1 mutations is warranted in HDGC. METHODS AND RESULTS: We report all index cases from Ile-de-France in which a germline CDH1 mutation has been identified. Out of 18 cases, 7 do not fulfil the HDGC-defining criteria. Three of them are women who presented initially with bilateral LBC below age 50, without personal or family history of DGC, and who subsequently developed symptomatic DGC. DISCUSSION: Our series of CDH1 mutation carriers is the largest to date and demonstrates that LBC might be the first manifestation of HDGC. A personal or family history of multiple LBCs at a young age, even without DGC, should prompt CDH1 mutation screening. It is paramount to identify mutation carriers early, so that they can benefit from prophylactic gastrectomy before they develop symptomatic, highly lethal DGC. We recommend a revision of the HDGC-defining criteria and propose for consideration the name 'Hereditary Diffuse Gastric and Lobular Breast Cancer' instead of HDGC.

Death during laparoscopy: can 1 gas push out another? Danger of argon electrocoagulation.

We report the death of a young man during a laparoscopic partial splenectomy performed with an argon plasma coagulator to remove a benign cyst. The report analyzes the very particular mechanism of a gas embolism, which caused death here. This analysis leads us to recommend a close attention on the use of argon coagulators during laparoscopy. The aim of this article is to draw surgeons' attention to the conclusions of a court-ordered expert assessment intended to elucidate the mechanisms responsible for the death of a 20-year-old man during a laparoscopic partial splenectomy performed with an argon plasma coagulator to remove a benign cyst.

[Hereditary diffuse gastric cancer]. / Cancer gastrique héréditaire diffus.

Some diffuse type gastric cancers are of hereditary origin. Their histological characteristics are poor cell differentiation and the presence of signet-ring cells. The cause is a mutation of the CDH1 gene which is responsible for abnormal E-cadherin. The transmission mode is autosomal dominant. Because of serious prognosis of symptomatic hereditary diffuse gastric cancer (HDGC), the high penetrance of the gene (67% in men and 83% in women) and the young age of onset of these tumors (before the age of 40), a prophylactic gastrectomy is recommended to the mutation carriers. The search for the genetic mutation should be recommended to families corresponding to clinical criteria such as the number of affected family members, degree of relationship and age of onset of these tumors.

Long-term survival with consolidation intraperitoneal chemotherapy for patients with advanced ovarian cancer with pathological complete remission.

OBJECTIVES: The goal of this study was to evaluate the long-term outcome after consolidation intraperitoneal (IP) chemotherapy in patients with a negative second-look laparotomy (SLL) following first-line intravenous chemotherapy for advanced ovarian cancer. METHODS: This study included patients with FIGO stage III-IV ovarian cancer who entered into four prospective trials (1984-1995) including intravenous chemotherapy based on cisplatin (six cycles) and anthracycline, early debulking surgery after three cycles of chemotherapy in the case of initial residual disease >2 cm, SLL, and IP consolidation chemotherapy. Among 218 patients, 68 with biopsy-negative SLL received every 4 weeks three consolidation cycles of IP chemotherapy (mitoxantrone, cisplatin, etoposide) via a totally implantable port. Long-term outcome of these patients is reported. RESULTS: Mean age was 56 years (33-72 years). Overall, 51% of the patients had at least a grade 3 or 4 toxic effect. Main toxic effects were leukopenia, abdominal pain related to the catheter, and nausea and vomiting. Only 13 patients (19%) did not receive the full three cycles. The median progression-free survival (PFS) for the whole population is 34 months, 34% of the patients being estimated to be free of disease at 5 years. The median overall survival is 73 months, and the 5-year survival is 58%. CONCLUSIONS: In this selected population treated with IP consolidation chemotherapy, prolonged survival was observed. However, the occurrence of late relapses in this most favorable patient category underlines the need to improve the consolidation therapy options in ovarian cancer.

Results of definitive irradiation in a series of 305 epidermoid carcinomas of the anal canal.

PURPOSE: To evaluate our data concerning the prognostic factors for locoregional control, survival, late complications, and sphincter conservation in a series of epidermoid cancers of the anal canal without clinical evidence of metastasis. METHODS AND MATERIALS: Between June 1972 and January 1997, 305 patients were treated with curative-intent radiotherapy (RT). The T stage according to the 1987 International Union Against Cancer classification was T1 in 26, T2 in 141, T3 in 104, and T4 in 34. Forty-nine patients had nodal involvement at presentation. The pretreatment anal function score, according to our in-house system, was 0 for 22 patients, 1 for 182, 2 for 74, 3 for 7, and 4 for 11 patients; for 9 patients, scores were unavailable. The treatment started with external beam radiotherapy (EBRT) in 303 patients (median dose 45 Gy). After a rest period of 4-6 weeks, a boost of 20 Gy was delivered by EBRT in 279 patients and by interstitial (192)Ir brachytherapy in 17 patients. Seven patients received only one course of EBRT (mean dose 49.5 Gy), and 2 patients were treated with interstitial (192)Ir brachytherapy alone (55 Gy and 60 Gy). Concomitant chemotherapy (5-fluorouracil and either mitomycin C or cisplatin) was delivered to 19 patients. The mean follow-up was 103 months (median 84). RESULTS: At the end of RT, the local tumor clinical complete response rate was 96% for T1, 87% for T2, 79% for T3, and 44% for T4. Of the 61 locally progressive tumors, 27 (44%) were salvaged with abdominoperineal resection. The rate of local tumor relapse was 12%. Among 37 local tumor relapses, 20 (54%) were salvaged with abdominoperineal resection and one with interstitial (192)Ir brachytherapy. The overall local control rate (with or without salvage local therapy) was 84%. The local control rate with good anal function (score 0 or 1) was 56.5%. Of 181 available patients with their anus preserved, 94% had good anal function. For a subgroup of 15 patients with a tumor length of <2 cm and without nodal involvement, the clinical complete response rate after RT completion was 100%, the local control rate with or without local salvage treatment was 100%, and among 13 available patients with their anus preserved, the anal function score was good in 12 patients (92%). The 10-year disease-free survival rate was 74%. After multivariate analysis, three independent predictive factors significantly influenced disease-free survival: the interval between the two courses of RT (>38 days vs. < or =38 days, p = 0.0025), pretreatment anal function score (0 vs. 1 vs. 2 vs. 3 vs. 4, p = 4.4.10(-6)), and clinical complete response after RT completion (no complete response vs. complete response, p = 2.5.10(-14)). CONCLUSION: We confirm the excellent results with RT in T1 and T2 lesions. However, to improve survival without colostomy with good anal sphincter function, chemoradiotherapy should be preferred for tumors > or =2 cm in length and for locally advanced tumors.

[Radiofrequency ablation of an unresectable abdominal tumor]. / Apport de la radiofréquence dans l'exérèse d'une tumeur abdominale initialement inextirpable.

Remnant malignant tissue is left behind after conventional surgery for an unresectable intraperitoneal malignant tumor. Standard radiotherapy or chemotherapy rarely enables good tumor control. We report the case of a 74-year-old man who developed a local recurrence of a sigmoid tumor located 5 to 6 cm from the anus. The tumor was fixed to the pelvic wall and could not be totally eradicated with conventional surgery. Preoperative peroperative assessment confirmed the absence of metastatic spread. Radiotherapy could not be performed due to risk of bowel injury. Peroperative radiofrequency ablation was followed by surgical colorectal resection without restoration of intestinal continuity, leaving only tumor tissue destroyed by radiofrequency. No adjuvant treatment was proposed because of intolerance to chemotherapy. Clinical assessment and thoracic and abdominal CT scan confirmed the absence of recurrence 26 months after radiofrequency ablation. Serum markers remained normal.