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.

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.

Single-port endoscopic mesocolic and mesorectal excision using an extraperitoneal approach.

BACKGROUND: The extraperitoneal rectal dissection via a transanal approach facilitates the mesorectal dissection. The retroperitoneal approach for mesocolic excision may also offer some similar advantages. To complete the lymphadenectomy of extraperitoneal mesorectal resection, we developed an innovative approach for upper rectal and mesocolic excision via an exclusive retroperitoneal dissection using a single-port access at the site of the future stomy. METHODS: This study was a prospective pilot study and was conducted between 2013 and 2015 at two oncologic centers. Five consecutive patients, with ano-rectal cancer requiring permanent stoma, underwent this procedure. RESULTS: The bowel was never touched or mobilized to perform the lymphadenectomy, and no Trendelenburg was required. The median operative duration was 300 min (range 205-310). The quality of the surgical plane was classified as good (mesorectal) in the five patients. The median circumferential and distal margins were, respectively, 5 mm (range 1-20) and 20 mm (range 5-25). The median number of harvested lymph nodes was 11 (range 5-18). No laparotomy or multiport laparoscopy was required. There was no death. Two patients had perineal wound dehiscence (one minor and one major). CONCLUSIONS: The mesocolic excision via a retroperitoneal approach is feasible, completes naturally the transanal mesorectal excision and may confer several advantages including no morbidity of small bowel manipulation or Trendelenburg position. Further studies are required to analyze this approach.

Huge pseudomyxoma peritonei: Surgical strategies and procedures to employ to optimize the rate of complete cytoreductive surgery.

BACKGROUND: Complete cytoreductive surgery (CCRS) plus Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is the best-known treatment for pseudomyxoma peritonei (PMP). In 30% of the cases, PMP realize a widespread involvement of the peritoneal cavity. In these extreme situations, we developed, devoted strategies to optimize the feasibility and safety of CCRS. This study describes the surgical resections required for CCRS and the consequent approaches that we propose to achieve CCRS. MATERIALS AND METHODS: We defined "huge PMP" by a peritoneal cancer index (PCI) ≥ 28. Surgical procedures of patients operated on between 1994 and 2014 were retrospectively reviewed from a prospective database in a single institution. RESULTS: During this period, 311 patients were operated on and 247 (79%) underwent CCRS + HIPEC. Among them, 100 patients presented "huge" PMP and 54 patients underwent CCRS + HIPEC. In patients with "huge" PMP, the rate of CCRS + HIPEC was 25% before 2002 and reached 71% between 2011 and 2014. We identified 3 conditions for CCRS 1) to guaranty a sufficient length of residual small bowel 2) to preserve the left gastric vessels in order to preserve the superior third of the stomach 3) to ensure that the hepatic pedicle can be entirely cleared from its tumor involvement. None of the other peritonectomy procedures were decisional for CCRS. CONCLUSION: Our learning curve improved the selection and completion rate of CCRS + HIPEC for "huge PMP". Some anatomical and physiological prerequisites guarantee the feasibility and safety of such extensive surgeries.

Peritoneal carcinomatosis from unusual cancer origins: Is there a role for hyperthermic intraperitoneal chemotherapy?

INTRODUCTION: Complete cytoreductive surgery (CCRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the gold standard for curative treatment of peritoneal carcinomatosis (PC) arising from colorectal cancer, peritoneal mesothelioma and peritoneal pseudomyxoma peritonei (PMP). The results of HIPEC remain controversial in PC that originates from ovarian cancer, stomach cancer, neuroendocrine tumors, or sarcoma. HIPEC has also been used, although very rarely, for other malignant carcinomatoses. Its use has been exceptional due either to the rarity of the tumor or because such disease is usually widespread and rarely confined to the peritoneum. The aim of this study was to evaluate the results of CCRS plus HIPEC in patients with PC of unusual origin. METHODS: We performed a retrospective analysis of all patients who underwent CCRS plus HIPEC for PC whose origin was neither gastric, ovarian or colorectal carcinoma, nor neuroendocrine tumor, mesothelioma, PMP or sarcoma. RESULTS: Between 1995 and 2013, 31 patients with 15 PC arising from unusual primary tumors underwent CCRS plus HIPEC. After a median follow-up of 90 months, 10 patients were alive and without recurrence. The overall survival rate at 5 years was 33% with a median survival of 37 months. In univariate analysis, factors of poor prognosis and predictors of recurrence were the performance of immediate postoperative intraperitoneal chemotherapy instead of HIPEC and a peritoneal index ≥ 12. No prognostic impact due to tumor origin could be demonstrated. CONCLUSION: The decision to perform CCRS plus HIPEC for PC arising from unusual cancer origins remains difficult. These patients should be prospectively entered into registries of rare tumors that involve the peritoneum in order to better define indications.

Genetic variants of kinase suppressors of Ras (KSR1) to predict survival in patients with ERα-positive advanced breast cancer.

In patients with breast cancer (BC), deregulation of estrogen receptor (ERα) activity may account for most resistance to endocrine therapies. Our previous study used a whole-human kinome siRNA screen to identify functional actors in ERα modulation and showed the implication of proteins kinase suppressors of ras (KSR1). From those findings we evaluated the clinical impact of KSR1 variants in patients with ERα+ BC treated with TAM. DNA was obtained from 222 patients with advanced ERα+ BC treated with TAM who had undergone surgery from 1981 to 2003. We selected three potentially functional relevant KSR1 polymorphisms; two within the 3'UTR (rs224190, rs1075952) and one in the coding exon 7 (rs2293180). The primary end points were overall survival (OS) and disease-free survival (DFS). After a 6.4-year median follow-up, patients carrying the rs2241906 TT genotype showed shorter DFS (2.1 vs 7.1 years, P=0.005) and OS (2.6 vs 8.4 years P=0.002) than those with the TC or TT genotypes. Those associations remained significant in the multivariable analysis adjusting age, lymph node status, LMTK3 and IGFR variants and HER2 status. The polymorphisms rs2241906 and rs1075952 were in linkage disequilibrium. No association was shown between rs2293180 and survival. Among the actors of ERα signaling, KSR1 rs2241906 variants may predict survival in patients with advanced ERα+ BC treated with adjuvant TAM.

Integrin genetic variants and stage-specific tumor recurrence in patients with stage II and III colon cancer.

Integrins (ITGs) are key elements in cancer biology, regulating tumor growth, angiogenesis and lymphangiogenesis through interactions of the tumor cells with the microenvironment. Moving from the hypothesis that ITGs could have different effects in stage II and III colon cancer, we tested whether a comprehensive panel of germline single-nucleotide polymorphisms (SNPs) in ITG genes could predict stage-specific time to tumor recurrence (TTR). A total of 234 patients treated with 5-fluorouracil-based chemotherapy at the University of Southern California were included in this study. Whole-blood samples were analyzed for germline SNPs in ITG genes using PCR-restriction fragment length polymorphism or direct DNA sequencing. In the multivariable analysis, stage II colon cancer patients with at least one G allele for ITGB3 rs4642 had higher risk of recurrence (hazard ratio (HR)=4.027, 95% confidence interval (95% CI) 1.556-10.421, P=0.004). This association was also significant in the combined stage II-III cohort (HR=1.975, 95% CI 1.194-3.269, P=0.008). The predominant role of ITGB3 rs4642 in stage II diseases was confirmed using recursive partitioning, showing that ITGB3 rs4642 was the most important factor in stage II diseases. In contrast, in stage III diseases the combined analysis of ITGB1 rs2298141 and ITGA4 rs7562325 allowed to identify three distinct prognostic subgroups (P=0.009). The interaction between stage and the combined ITGB1 rs2298141 and ITGA4 rs7562325 on TTR was significant (P=0.025). This study identifies germline polymorphisms in ITG genes as independent stage-specific prognostic markers for stage II and III colon cancer. These data may help to select subgroups of patients who may benefit from ITG-targeted treatments.

Prospective study of EGFR intron 1 (CA)n repeats variants as predictors of benefit from cetuximab and irinotecan in chemo-refractory metastatic colorectal cancer (mCRC) patients.

The number of CA tandem repeats (CA)n in a highly polymorphic region of EGFR (epidermal growth factor receptor) intron 1 may affect gene transcription; the potential impact of allelic variants on the efficacy of cetuximab in metastatic colorectal cancer (mCRC) patients is debated for long. This study aimed at prospectively estimating the impact of EGFR intron 1 (CA)n variants on clinical outcome in KRAS exon 2 and BRAF wild-type chemo-refractory mCRC patients, receiving cetuximab and irinotecan. Variants presenting

The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy.

Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.

Gender-specific profiling in SCN1A polymorphisms and time-to-recurrence in patients with stage II/III colorectal cancer treated with adjuvant 5-fluoruracil chemotherapy.

This study was designed to analyze the gender-related association between SCN1A polymorphisms (voltage-gated sodium channels; α-subunit) and time-to-recurrence (TTR) in patients with colorectal cancer (CRC) treated with 5-fluoruracil (5-FU)-based adjuvant chemotherapy. We enrolled from a prospective database patients with stage II and III CRC treated with adjuvant 5-FU-based chemotherapy. Genotypes for SCN1A rs3812718 and rs229877 were determined by direct DNA sequencing. One hundred twenty-seven males and 107 females were included in the study. In the univariate and multivariate analysis, the shortest TTR was associated with female patients carrying the rs3812718-TT genotype (hazard ratio (HR): 2.26 (95% confidence interval (CI): 0.89, 5.70), P=0.039) but with male patients carrying the rs3812718-CC genotype (HR: 0.49 (95% CI: 0.18, 1.38), P=0.048). For rs229877 the CT genotype was associated with a trend for shorter TTR in both gender populations. The study validated gender-dependent association between genomic SCN1A rs3812718 polymorphism and TTR in CRC patients treated with adjuvant 5-FU-based chemotherapy. This study confirms that voltage-gated Na+ channels may be a potential therapeutic target and a useful predictive biomarker before 5-FU infusion.

Placement of an arterial hepatic catheter after a major hepatectomy for colorectal liver metastases: is this safe?

BACKGROUND: Studies have suggested that hepatic arterial infusion of chemotherapy (HAI) after resection of colorectal liver metastasis (CRLM) may improve patient's survival. The placement of a catheter in the hepatic artery at the time of hepatic surgery should therefore be considered in patients at high risk of hepatic recurrence. The aim of this study was to compare post-operative outcomes in patients who underwent at least a major hepatectomy (≥3 segments) for CRLM with or without catheter placement. METHODS: From 2000 to 2010, 57 patients who underwent at least a major hepatectomy for CRLM resection were selected from a prospective database. Among them, 22 had had a catheter insertion during surgery. RESULTS: The two groups were similar in terms of age, body mass index (BMI), ASA score, and the average number of pre-operative courses of systemic chemotherapy (11 ± 5). The rate of overall complications was slightly higher after catheter insertion (63% vs. 51%) although not significant (p = 0.36). Two patients had died post-operatively from liver insufficiency; both had undergone catheter insertion after a major hepatectomy associated with contralateral procedures resulting in a small remnant liver volume with low outflow capacity. Thrombosis of the common hepatic artery and portal venous gas were depicted on both CT scan. CONCLUSION: Although the placement of an arterial catheter during a major hepatectomy does not significantly increase the rate of postoperative complications two patients died post-operatively in this study from vascular thrombosis. In case of extended and complex hepatectomy, with a higher risk of post-operative complications, delaying the catheter placement could be recommended.

[Patient education: state of the art of the programs in the region of Provence-Alpes-Côte d'Azur in 2008 before the publication of official documents relative to the authorizations of the Regional Health Agency (ARS)]. / Éducation thérapeutique du patient : état des lieux des programmes en région Provence-Alpes-Côte d'Azur en 2008 avant la parution des textes officiels sur les autorisations de l'Agence Régionale de Santé.

BACKGROUND: At the request of the Hospitalization Regional Agency (ARH)--in the context of the 2007-2011 plan aimed at improving the quality of life for patients affected by chronic diseases--the purpose of this work was to draw up a clear assessment of the 2008 Therapeutic Education programmes in the Provence-Alpes-Côte d'Azur (PACA) region. The study was carried out before the publication of the therapeutic education statutory orders and ARS (regional health agency) authorizations. METHODS: Cross-sectional study, carried out in the three sectors of medical management in the region--namely health-care institutions, ambulatory structures and health networks--made it possible to identify, first, which structures had actually launched therapeutic education programmes and then, how the procedures had been designed and set up. RESULTS: Among all the medical structures investigated, the study has listed 491 programmes, heterogeneously located throughout the PACA region. These programmes primarily target diabetes, respiratory and cardiovascular diseases. Their main objectives are the patients' quality of life, adherence to treatment and protective health behaviour (health improvement). The hospitalization sector programmes preferentially target the 30 to 60 years old, whereas the ambulatory and health networks programmes are more inclined to target the over 60 years old part of the population. More than 50% of the professionals involved in the programmes have never benefited from a specific training concerning the patients' therapeutic education. CONCLUSION: This study has pointed out a great number of important aspects which need drastic improvement in terms of therapeutic education organization - the involvement and training of health professionals, for instance.

Selecting the best targeted agent in first-line treatment of unresectable liver metastases from colorectal cancer: does the bench have the answers?

For physicians facing patients with organ-limited metastases from colorectal cancer, tumor shrinkage and sterilization of micrometastatic disease is the main goal, giving the opportunity for secondary surgical resection. At the same time, for the majority of patients who will not achieve a sufficient tumor response, disease control remains the predominant objective. Since FOLFOX or FOLFIRI have similar efficacies, the challenge is to define which could be the most effective targeted agent (anti-EGFR or anti-VEGF) to reach these goals. Therefore, a priori molecular identification of patients that could benefit from anti-EGFR or anti-VEGF monoclonal antibodies (i.e. the currently approved targeted therapies for metastatic colorectal cancer) is of critical importance. In this setting, the KRAS mutation status was the first identified predictive marker of response to anti-EGFR therapy. Since it has been demonstrated that tumors with KRAS mutation do not respond to anti-EGFR therapy, KRAS status must be determined prior to treatment. Thus, for KRAS wild-type patients, the choices that remain are either anti-VEGF or anti-EGFR. In this review, we present the most updated data from translational research programs dealing with the identification of biomarkers for response to targeted therapies.

The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer.

BACKGROUND: Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination. PATIENTS AND METHODS: DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; clinicaltrials.gov) and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher's exact test, Kaplan-Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate. RESULTS: There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92). CONCLUSION: Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.

Salvage colectomy for endoscopically removed malignant colon polyps: is it possible to determine the optimal number of lymph nodes that need to be harvested?

AIM: The total number of lymph nodes examined after salvage colectomy for endoscopically removed malignant polyps was evaluated and an attempt was made to determine whether there was an optimal number of lymph nodes that should be harvested. METHOD: From 2000 to 2009, 531 patients underwent segmental resection for non-metastatic colon cancer. Of these, 22 underwent a salvage colectomy for an endoscopically removed malignant polyp, the main indication for which was a resection margin of < 1 mm. The surgical procedure was identical to that used for all colon cancers. RESULTS: The mean number of lymph nodes examined was 11.6 ± 7.6 for the 22 patients with an endoscopically removed malignant polyp and 26.2 ± 13.9 for the remaining 509 patients (P = 0.0006). Fewer than 12 lymph nodes were examined in 62 (12%) of the 509 patients and in 13 (59%) of the 22 patients with an endoscopically removed malignant polyp (P < 0.0001). In the group of 22 patients who underwent a salvage colectomy, the total number of lymph nodes examined ranged from 2 to 33. At a mean follow up of 41 ± 15.6 months, no local or distant recurrence was observed in the 22 patients. CONCLUSION: The total number of lymph nodes examined after colectomy for endoscopically removed malignant polyps varies and is less than the recommended number of 12 in most cases: this does not appear to have long-term prognostic significance. There is no biological reason to explain this clinical observation.

[Analysis of bone-implant stress distribution. Finite element modeling]. / Analyse de la répartition des contraintes os-implant. Modélisation plane par éléments finis.

A two-dimensional finite element partial mandibular model allows a first comparison between two types of titanium cylindrical implants, one full, the other hollow. The study cases correspond to a distal edentulous rehabilitated with a three-unit bridge supported mesially by a healthy second premolar and distally by one of the two concerned implants. The model includes the mandible from the canine region to the condyle, and allow to investigate the interactions between implants and bone tissue, under a normal biting load (100 N) distributed over the different teeth of the model. On a general way, the highest stresses magnitudes are in the implants, so there are no pathologic actions in bone, even if the distal cervical region of the implants are more stressed than any place else of the alveolar bone. It is well known that bone resorptions are often found in that region. Furthermore the bone trunk of the hollow implant is no more stressed than the rest of the mandibular, that is good for bone affixing. The outcome of this work, over the first results exposed, is that it gives the opportunity to understand the complexity of such a problem.