Impact of p53 expression and microsatellite instability on stage III colon cancer disease-free survival in patients treated by 5-fluorouracil and leucovorin with or without oxaliplatin.

BACKGROUND: The aim was to determine the values of p53 tumour expression and microsatellite instability (MSI) phenotype to predict benefit from adjuvant chemotherapy of colon cancer by 5-fluorouracil and leucovorin (FL) alone or with oxaliplatin (FOLFOX). PATIENTS AND METHODS: This retrospective study included 233 unselected patients with stage III colon cancer treated by FL (n = 124) or FOLFOX (n = 109). The impact of p53 expression and MSI on disease-free survival (DFS) was defined using univariate and multivariate analyses. A Cox proportional hazards model was specifically designed to evaluate the interaction between chemotherapy and these genetic alterations. RESULTS: In univariate analyses, addition of oxaliplatin significantly improved DFS provided that tumour overexpressed p53 [hazard ratio (HR) 0.39; 95% confidence interval (CI) 0.19-0.82; P = 0.01] or displayed MSI phenotype (HR 0.17; 95% CI 0.04-0.68; P = 0.01). In multivariate analyses, p53 was confirmed as an independent factor predictive of benefit from FOLFOX (P = 0.03), while the interaction of MSI with chemotherapy could not be determined in the absence of relapse in the MSI group treated with FOLFOX. CONCLUSION: Our observations indicate that MSI status and p53 expression may influence the impact of oxaliplatin on adjuvant treatment of stage III colon cancer patients.

Model predicting the ypN0 status after good response to chemoradiotherapy in rectal cancer.

BACKGROUND: The purpose of this study was to identify the predictive factors for ypN0 status in tumors with good pathologic response to chemoradiotherapy (CRT). METHODS: A retrospective chart review was conducted on patients at two tertiary cancer center who underwent rectal resection after good response to CRT between 2000 and 2013. RESULTS: No preoperative treatment (oxaliplatin use, radiotherapy boost of 5,4 Gy, delay CRT-surgery) impacted on the ypN status. In the multivariate analysis, only a ypT<3 (HR 7.5 [2,9-19.5]) was significant and no lymphovascular invasion (HR 8,9 [1.6-49.8]) was limited to significance.The best model predicting the ypN0 status used only the ypT status<3. The major part (92.2%) of patients with ypT0-2 tumors had no LN invasion. CONCLUSION: The risk of lymph node involvement metastases was only 7.8% for the patients with an ypT0-2 status. A fullthickness transanal resection coud be the futur treatment of these patients.

TCF-4 isoforms absent in TCF-4 mutated MSI-H colorectal cancer cells colocalize with nuclear CtBP and repress TCF-4-mediated transcription.

TCF-4 is the main effector of the Wnt/Wingless signalling pathway. As with other TCF/LEF factors, numerous alternative splicings at its 3' end affect its expression. Such a mechanism leads to the synthesis of numerous TCF-4 isoforms among which some contain binding domains for CtBP, an ubiquitous transcriptional corepressor. Of interest, we described a frequent TCF-4 frameshift mutation in mismatch-repair deficient colorectal cancers (MSI-H cancers) that leads to the selective loss of TCF-4 isoforms with CtBP binding abilities. We provide here data that argue for a partial colocalization of CtBP with TCF-4 isoforms containing CtBP binding domains in cellulo, and for a functional role of CtBP in repressing TCF-4 mediated transcription. We also demonstrate that such a colocalization is not observed in MSI-H colorectal cancer cells that harbour the TCF-4 frameshift mutation, and that CtBP is not able to repress TCF-4-mediated transcription in this context. Taken together, our results strongly suggest that CtBP would play a role in regulating TCF-4 mediated transcription upon its binding with some TCF-4 isoforms encoded by alternatively spliced mRNA. They also suggest a role for TCF-4 frameshift mutation during MSI-H colorectal tumour progression, by regulating the relative proportion of the different TCF-4 isoforms.

Long-term survival after aggressive treatment of relapsed serosal or distant pseudomyxoma peritonei.

INTRODUCTION: Complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have dramatically changed the prognosis of patients with pseudomyxoma peritonei (PMP). However, recurrences can still occur and no consensus has been reached regarding their optimal treatments. This study aimed to analyze the patterns of recurrence after CCRS plus HIPEC for PMP and potential subsequent treatments of these lesions. PATIENTS AND METHODS: Between 1992 and 2014, patients who had relapsed after treatment of PMP were selected from a prospective database of 251 patients who had undergone CCRS plus HIPEC with a curative intent. RESULTS: After a median follow-up of 85 months, 66 patients (26%) had relapsed with a median free interval of 25 months. The first recurrence was mostly located in the peritoneum, isolated in 50 patients (76%) and associated with extraperitoneal disease in 6 patients. Curatively intended treatment of the relapse, combining surgery and chemotherapy was achievable in 76% of the patients, leading to a 5-year overall survival (OS) rate of 83% from the date of treatment of the first recurrence. In contrast, the 5-year OS rate was only 27% (p < 0.001) for patients treated with non-curative therapy. An isolated peritoneal recurrence was predictive of greater amenability to curative therapy and a better prognosis. CONCLUSION: After CCRS plus HIPEC, serosal recurrences were more common than their distant counterparts. Distant relapses' emergence has raised the question of their optimal treatments. Very long-term survival can be obtained after further treatment of recurrent PMP for patients with limited disease and good general status.

Immunohistochemical evaluation of two antibodies against PD-L1 and prognostic significance of PD-L1 expression in epithelioid peritoneal malignant mesothelioma: A RENAPE study.

BACKGROUND: Epithelioid peritoneal malignant mesothelioma (EPMM) is the most common subtype of this aggressive tumor. We compared two antibodies against PD-L1, a recent theranostic biomarker, and evaluated the prognostic value of PD-L1 expression by mesothelial and immune cells in EPMM. METHODS: Immunohistochemistry was performed on 45 EPMM. Clinical and pathological data were extracted from the RENAPE database. Using E1L3N and SP142 clones, inter-observer agreement, PD-L1 expression by mesothelial and immune cells and inter-antibody agreement were evaluated. The prognostic relevance of PD-L1 expression was evaluated in 39 EPMM by univariate and multivariate analysis of overall survival (OS) and progression-free survival (PFS). RESULTS: Inter-observer agreement on E1L3N immunostaining was moderate for mesothelial and immune cells, and fair for mesothelial and poor for immune cells using SP142. Using E1L3N, 31.1% of mesothelial and 15.6% of immune cells expressed PD-L1, and 22.2% of mesothelial and 26.7% of immune cells using SP142. Inter-antibody agreement was moderate. In most positive cases, 1-5% of tumor cells were positive. Using E1L3N, PD-L1 expression by lymphocytes was associated with better OS and PFS by both univariate and multivariate analysis. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy predicted better prognosis than other treatments. Solid subtype was an independent prognostic factor for worse OS. CONCLUSION: E1L3N appeared easier to use than SP142 to evaluate PD-L1 expression. A minority of EPMM expressed PD-L1, and only a few cells were positive. PD-L1 expression by immune cells evaluated with E1L3N was an independent prognostic factor in EPMM.

Simple criteria to predict margin involvement after chemoradiotherapy and sphincter-sparing for low rectal cancer.

BACKGROUND: Low rectal cancers carry a high risk of circumferential margin involvement (CRM+). The anatomy of the lower part of the rectum and a long course of chemoradiotherapy (CRT) limit the accuracy of imaging to predict the CRM+. Additional criteria are required. METHODS: Eighty six patients undergoing rectal resection with a sphincter-sparing procedure after CRT for low rectal cancer between 2000 and 2013 were retrospectively reviewed. Risk factors of CRM+ and the cut-off number of risk factors required to accurately predict the CRM+ were analyzed. RESULTS: The CRM+ rate was 9.3% and in the multivariate analysis, the significant risk factors were a tumor size exceeding 3 cm, poor response to CRT and a fixed tumor. The best cut-off to predict CRM+ was the presence of 2 risk factors. Patients with 0-1 and 2-3 risk factors had a CRM+ respectively in 1.3% and 50% of cases and a 3-year recurrence rate of 7% and 35% after a median follow-up of 50 months. CONCLUSIONS: Poor response, a residual tumor greater than 3 cm and a fixed tumor are predictive of CRM+. Sphincter sparing is an oncological safety procedure for patients with 0-1 criteria but not for patients with 2-3 criteria.

Liver, lung and peritoneal metastases in colorectal cancers: is the patient still curable? What should the radiologist know.

Regardless of the advances in chemotherapy, the only curative treatment for colorectal metastases is surgery, which must be complete and excise all of the metastatic sites of disease. Thanks to advances in neoadjuvant chemotherapy and also to alternative techniques, such as radiofrequency ablation, however, surgical treatments have become available to a larger number of patients and have improved patient survival. The aim of this article is to describe the different treatment strategies for colorectal metastases and to examine the role of imaging in defining the resect ability of these metastases. The key factors in the radiological report in the initial and post-chemotherapy assessments are described.

Modified selection criteria for complete cytoreductive surgery plus HIPEC based on peritoneal cancer index and small bowel involvement for peritoneal carcinomatosis of colorectal origin.

BACKGROUND: Complete cytoreductive surgery (CCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is on the verge of becoming the gold standard treatment for selected patients presenting peritoneal metastases (PM) of colorectal origin. PM is scored with the peritoneal cancer index (PCI), which is the main prognostic factor. However, small bowel (SB) involvement could exert an independent prognostic impact. AIM: To define an adequate cut-off for the PCI and to appraise whether SB involvement exerts an impact on this cut-off. PATIENTS AND METHODS: Patients (n = 139) treated with CCRS plus HIPEC were prospectively verified and retrospectively analyzed. One hundred presented with SB involvement of different extents and at different locations. RESULTS: All the patients with a PCI ≥ 15 exhibited SB involvement. Five-year overall survival was 48% when the PCI was <15 vs 12% when it was ≥ 15 (p < 0.0001. The multivariate analysis retained two prognostic factors: PCI ≥ 15 (p = 0.02, HR = 1.8), and the involvement of area 12 (lower ileum) (p = 0.001, HR = 3.1). When area 12 was invaded, it significantly worsened the prognosis: 5-year overall survival of patients with a PCI <15 and area 12 involved was 15%, close to that of patients with a PCI ≥ 15 (12%) and far lower than that of patients with a PCI <15 and no area 12 involvement (70%). CONCLUSION: A PCI greater than 15 appears to be a relative contraindication for treatment of colorectal PM with CCRS + HIPEC. Involvement of the lower ileum is also a negative prognostic factor to be taken into consideration.

Role of hyperthermic intraoperative peritoneal chemotherapy in the management of peritoneal metastases.

The peritoneal cavity must be oncologically considered as an organ in its own right and peritoneal metastases (PM) must be treated with the same curative intent (and the same results) as liver metastases. The package combining complete cytoreductive surgery (CCRS) (treating the visible disease) plus hyperthermic intraoperative peritoneal chemotherapy (HIPEC) (treating the remaining non-visible disease) achieves cure in many patients. Twenty years of publication allow us to assemble sufficient background information and data to point out the good and poor indications for CCRS+HIPEC. HIPEC is the standard of care for the treatment of peritoneal pseudomyxomas and peritoneal mesotheliomas and also, recently for the treatment of colorectal PM with limited peritoneal extension. HIPEC is in the evaluation phase for gastric PM and ovarian PM after initially disappointing results, but it is highly probable that it will be useful in particular settings. PM from neuroendocrine tumours are in the same situation. HIPEC is not currently indicated for the treatment of PM from sarcomas, from GIST, and for small round-cell desmoplastic tumours, given the poor results obtained. HIPEC can be useful, on a case-by-case basis, to treat rare tumours complicated by isolated peritoneal diffusion (e.g. Frantz's tumours). HIPEC can be used in the prophylactic setting to prevent PM in patients with a high risk of developing PM, and the first results of the 'second-look' approach are promising. Finally, CCRS+HIPEC appear to be indispensable tools in the oncologist's armentarium.

Comprehensive study of ovarian metastases in young women with peritoneal pseudomyxoma: is a preservation of fertility possible?

OBJECTIVE: To determine whether ovaries can be preserved in selected young women with peritoneal pseudomyxoma (PMP). BACKGROUND DATA: The traditional rule is to systematically perform a bilateral oophorectomy. PATIENTS AND METHODS: A new policy was developed to preserve the ovaries when they are macroscopically normal in young women with PMP, strongly desiring a future pregnancy. RESULTS: Thirty-three women younger than 41 years were selected after undergoing complete cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for PMP. A normal ovary was preserved in 6 of them, but in 6 of the 14 women who strongly desired a future pregnancy. Subsequently, ovarian preservation was only performed in cases of grade-1 PMP. Ovarian invasion was correlated with the grade (p < 0.05) and with the extent of peritoneal disease (p < 0.01). After a median follow-up of 54 months, none of the 6 women with preserved ovaries has developed an ovarian or a peritoneal recurrence. One woman became pregnant and egg harvesting and cryopreservation were performed for 4 women with a partially normal ovary. CONCLUSION: This new policy allowed ovarian preservation in 43% of the young women desiring a future pregnancy and has already resulted in one birth. It exclusively concerned low-grade PMP. Recurrence in the preserved ovary was 0% with our selection criteria.

Value of cardiophrenic angle lymph node for the diagnosis of colorectal peritoneal carcinomatosis.

BACKGROUND: Cardiophrenic angle lymph nodes (CPALN) have been reported in patients with abdominopelvic malignancies. We aimed to assess whether the presence of CPALN is associated with peritoneal carcinomatosis (PC) in colorectal cancer. PATIENTS AND METHODS: Between 2007 and 2011, 550 patients with colorectal cancer, including 165 (30%) with PC, had undergone surgery with complete peritoneal exploration. We retrospectively reviewed preoperative CT scans for the presence of CPALN and assessed its association with confirmed PC by univariate and multivariate analyses. RESULTS: CPALN were present in 123 (75%) patients with PC, but absent in 263 (68%) patients without PC (Se: 0.72; Sp: 0.68; PPV: 0.49; NPV: 0.85; [OR], 3.3; p<0.001). PC was the only factor independently associated with CPALN in the multivariate analysis. CPALN was not correlated with the presence of liver metastases. 99 of the 165 patients with PC (62%) had visible signs of PC on CT scan. Among the remaining 66 patients, CPALN were the only potential sign of PC in 41 (62%), (Se 0.62, Sp 0.68, PPV 0.24, and NPV 0.92). CONCLUSION: The detection of CPALN on CT may be of valuable help for the diagnosis of PC in patients with CRC.

Peritoneal carcinomatosis from solid pseudopapillary neoplasm (Frantz's tumour) of the pancreas treated with HIPEC.

Solid pseudopapillary neoplasm (SPN) is a rare malignant tumour accounting for 0.1% to 2.7% of all pancreatic neoplasms and affecting young women. Peritoneal carcinomatosis (PC) is even rarer, with only 11 reported cases. We describe a twelfth case occurring 13 years after the resection of an SPN which ruptured peroperatively. This 35-year-old woman had first undergone complete cytoreductive surgery (CCRS) alone and disease had relapsed within 8 months. Ultimately, further CCRS was combined with hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin and irinotecan. The patient is now alive and disease free 31 months after her last operation. In the literature, the surgical treatment of PC from an SPN has yielded disappointing results, with a 58% recurrence rate at intervals ranging from 1 to 19 years. As none of these patients developed distant metastases, indicating a strictly peritoneal disease, HIPEC might be a solution for preventing such recurrences.

Central retroperitoneal recurrences from colorectal cancer: are lymph node and locoregional recurrences the same disease?

BACKGROUND: Central retroperitoneal recurrences (CRRs) from colorectal carcinoma carry a poor prognosis. A CRR is sometimes defined as a locoregional recurrence (LR) and sometimes as a lymph node recurrence (NR). This study was conducted to determine the nature of CRR and evaluate prognostic factors after complete CRR resection. METHODS: Between January 1988 and December 2008, 31 patients underwent a complete resection of CRR. CRRs were divided into NR (n = 23) and LR (n = 8), whether pathological examination disclosed lymph node involvement or not. RESULTS: No differences were found between LR and NR regarding TNM stage, primary tumour location, time interval from primary tumour resection to CRR, number of metastatic sites, number of metastatic lesions and therapeutic management. The median preoperative CEA level was higher in the NR group (p = 0.003). After a median follow-up of 47 months NRs were associated with better overall survival (OS) (p = 0.03). Three-year OS and disease-free survival (DFS) in the LR and NR groups were 27% and 0% versus 81% and 26%, respectively. Twenty-seven (87%) patients developed a re-recurrence within a median interval of 15 months. The number of metastatic sites or lesions, the size of the CRR, the type of chemotherapy, radiotherapy, the interval between the primary resection and CRR and the TNM stage had no impact on OS. CONCLUSION: LR in patients with CRR had a poorer prognosis than NR. A multimodality approach with complete resection may yield long-term survival for NR.

STAT3 transcription factor is constitutively activated and is oncogenic in nasal-type NK/T-cell lymphoma.

Nasal-type natural killer (NK) cell lymphoma is an infrequent aggressive malignant disease with very poor prognosis. We aimed to explore the possible role of the transcription factor STAT3 in the pathophysiology of this malignancy, as it was involved in oncogenesis and chemoresistance. For this, we established and characterized a continuous interleukin 2-dependent NK cell line (MEC04) from a patient with a fatal nasal-type NK-cell lymphoma. Cells harbored poor cytotoxic activity against K562 cells, and spontaneously secreted interferon-gamma, interleukin-10 and vascular-endothelium growth factor in vitro. STAT3 was phosphorylated in Y705 dimerization residue in MEC04 cells and restricted to the nucleus. Y705 STAT3 phosphorylation involved JAK2, as exposure of cells to AG490 inhibitor inhibited Y705 STAT3 phosphorylation. By using recombinant transducible TAT-STAT3-beta (beta isoform), TAT-STAT3Y705F (a STAT3 protein mutated on Y705 residue, which prevents STAT3 dimerization) and peptides inhibiting specifically STAT3 dimerization, we inhibited STAT3 phosphorylation and cell growth, with cell death induction. Finally, STAT3 was phosphorylated in Y705 residue in the nuclei of lymphoma cells in eight/nine patients with nasal-type NK/T-cell lymphoma and in YT, another NK cell line. Our results suggest that STAT3 protein has a major role in the oncogenic process of nasal-type NK-cell lymphomas, and may represent a promising therapeutical target.