Implementing DPYD*2A Genotyping in Clinical Practice: The Quebec, Canada, Experience.

BACKGROUND: Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice. METHODS: We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada. RESULTS: During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty-four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine-based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation. CONCLUSION: Upfront genotyping before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A. IMPLICATIONS FOR PRACTICE: Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.

Peritoneal carcinomatosis index predicts survival in colorectal patients undergoing HIPEC using oxaliplatin: a retrospective single-arm cohort study.

BACKGROUND: Peritoneal carcinomatosis (PC) from colorectal cancer is associated with poor prognosis. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has improved survival for patients with colorectal peritoneal carcinomatosis. However, standardization of HIPEC protocols, including which chemotherapeutic agent to use, is lacking in the literature. Therefore, we sought to report survival outcomes from colorectal cancer patients undergoing CRS/oxaliplatin-based HIPEC at our institution over the last 10 years. METHODS: Colorectal PC patients treated with CRS/oxaliplatin-based HIPEC 2004-2015 were included. Demographic, clinical, and oncologic data were abstracted from the medical record. Overall (OS) and disease-free survival (DFS) were calculated using Kaplan-Meier analysis. Univariate/multivariate Cox regression analysis was done. RESULTS: Laparotomy was performed in 113 patients for colorectal PC; 91 completed a curative intent CRS/HIPEC. At 3 and 5 years, OS for the CRS/HIPEC cohort was 75% and 55%, and DFS was 50% and 25%, respectively. On multivariate analysis, incremental increases in peritoneal carcinomatosis index (PCI) were associated with worse OS (p = 0.0001) and DFS (p = 0.0001). Grade III/IV complications were also associated with worse OS. CONCLUSIONS: A standardized regimen of CRS and oxaliplatin-based HIPEC for colorectal PC is effective with favorable OS and DFS and acceptable complication rates.

Optimizing treatment sequencing of chemotherapy for patients with rectal cancer: The KIR randomized phase II trial.

BACKGROUND: Randomized studies have shown low compliance to adjuvant chemotherapy in rectal cancer patients receiving preoperative chemotherapy and external beam radiation (CT/EBRT) with total mesorectal excision. We hypothesize that giving neoadjuvant CT before local treatment would improve CT compliance. METHODS: Between 2010-2017, 180 patients were randomized (2:1) to either Arm A (AA) with FOLFOX x6 cycles prior to high dose rate brachytherapy (HDRBT) and surgery plus adjuvant FOLFOX x6 cycles, or Arm B (AB), with neoadjuvant HDRBT with surgery and adjuvant FOLFOX x12 cycles. The primary endpoint was CT compliance to ≥85% of full-dose CT for the first six cycles. Secondary endpoints were ypT0N0, five-year disease free survival (DFS), local control and overall survival (OS). RESULTS: Patients were randomized to either AA (n = 120, median age (MA) 62 years) or AB (n = 60, MA 63 years). 175/180 patients completed HDRBT as planned (97.2%). In AA, two patients expired during CT; three patients post-randomization received short course EBRT because of progression under CT (n = 2, AA) or personal preference (n = 1, AB). ypT0N0 was 31% in AA and 28% in AB (p = 0.7). CT Compliance was 80% in AA and 53% in AB (p = 0.0002). Acute G3/G4 toxicity was 35.8% in AA and 27.6% in AB (p = 0.23). With a median follow-up of 48.5 months (IQR 33-72), the five-year DFS was 72.3% with AA and 68.3% with AB (p = 0.74), the five-year OS 83.8% for AA and 82.2% for AB (p = 0.53), and the five-year local recurrence was 6.3% for AA and 5.8% for AB (p = 0.71). CONCLUSION: We confirmed improved compliance to neoadjuvant CT in this study. Although there is no statistical difference in ypT0N0 rate, local recurrence, and DFS between the two arms, a trend towards favourable oncological outcomes is observed.

Long term survival analysis after hyperthermic intraperitoneal chemotherapy with oxaliplatin as a treatment for appendiceal peritoneal carcinomatosis.

BACKGROUND AND OBJECTIVES: Complete cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) have been proven to lengthen survival in appendiceal peritoneal carcinomatosis (PC-A). The aim of this study was to analyze survival results of this therapy in our institution over the last 10 years. METHODS: Data was retrospectively reviewed and analyzed. Treatment consisted of CRS plus HIPEC with oxaliplatin. Ronnett's histologic classification was used (peritoneal mucinous carcinomatosis (PMCA), PMCA with intermediate features (PMCA-I) and disseminated peritoneal adenomucinosis (DPAM)). Overall survival (OS) and disease-free survival (DFS) estimates were calculated using Kaplan-Meier survival curves. RESULTS: 109 patients with PC-A underwent laparotomy with curative intent. Of those, 92 underwent CRS plus HIPEC. Median follow-up was 42 months. The 5 and 10-year OS rates for the HIPEC group were 82.2% and 76.5%. The 5 and 10-year OS estimates for DPAM and PMCA-I subgroups were 100% and 100%, 78.1% and 72.9%, respectively. For the PMCA subgroup, the 3 and 5-year OS were 61.4% and 40.1%, respectively. The 5 and 10-year DFS estimates were 71.9% and 42.7%. CONCLUSION: CRS plus HIPEC with oxaliplatin represent an effective therapeutic approach for PC-A. Long term OS estimates for patients treated at our institution are encouraging.

Morbidity, toxicity, and mortality classification systems in the local regional treatment of peritoneal surface malignancy.

To reach a consensus for reporting complications related to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Reporting the adverse events related to CRS + HIPEC is not standardized yet. Post-operative complications can be divided in two categories: the effects of surgical manipulation per se and the toxic effects of the heated intraoperative chemotherapy. Additive and/or synergistic effects also exist. Different centers have published their experience with regard to the complications associated with the procedure. Various classification systems have been used which makes a temptative comparison of the different techniques and results almost impossible. An effort was made here to review the existing major classification systems: The Bozzetti classification, the Clavien classification (and two proposed modifications from Feldman et al. and Elias et al.) and the Common terminology criteria for adverse events (CTCAE) version 3.0 of the National Institute of Health (NIH) criteria. A related document was sent to an international panel of experts. The CTCAE was adopted by the panel of experts as the unique classification system to be used for reporting complications related to CRS + HIPEC.

Hepatocyte transplantation in the Long Evans Cinnamon rat model of Wilson's disease.

Wilson's disease (WD), caused by a mutation in the P-type copper transporting ATPase (Atp7b) gene, results in excessive accumulation of copper in the liver. Long Evans Cinnamon rats (LEC) bear a mutation in the atp7b gene and share clinical characteristics of human WD. To explore hepatocyte transplantation (HT) as therapy for metabolic liver diseases, 8-week-old LEC rats (n = 12) were transplanted by intrasplenic injection of hepatocytes from donor Long Evans (LE) rats. Immunosuppression was maintained with intraperitoneal tacrolimus. The success of HT was monitored at 24 weeks of life. Serum aminotransferases and bilirubin peaked at 14-21 weeks in both HT rats and nontransplanted controls, but at 24 weeks, survival was 97% in LEC-HT versus 63% in controls. All transplanted rats showed restored biliary copper excretion and reduced liver iron concentration associated with increased ceruloplasmin oxidase activity. Liver tissue expressed atp7b mRNA (11.9 +/- 13.6%) indicative of engraftment of normal cells in 7 of 12 HT rats, associated with a reduced liver copper concentration compared to untreated LEC rats. Periportal islets of normal appearing hepatocytes, recognized by atp7b antibody, were observed in transplanted livers while lobular host cells showed persistent pleomorphic changes and inflammatory infiltrates. In conclusion, transplantation of normal hepatocytes prevented fulminant hepatitis, reduces chronic inflammation, and improved 6-month survival in LEC rats. Engraftment of transplanted cells, which express atp7b mRNA, repopulated the recipient liver with normal functional capacity.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with oxaliplatin for peritoneal mesothelioma: preliminary results and survival analysis.

BACKGROUND: Peritoneal mesothelioma is a rare disease with poor prognosis. The present study reports single center experience with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy with oxaliplatin (HIPEC-OX) over an eight-year period. METHODS: Prospectively collected data of all consecutive patients with epithelial or multicystic peritoneal mesothelioma from August 2004 to October 2012 was analyzed. Patients with sarcomatoid or biphasic peritoneal mesothelioma were not included due to general poor prognosis. Treatment consisted in CRS and HIPEC-OX (460 mg/m(2)) at 43 °C during 30 min. For statistical analysis, Kaplan-Meier survival curves were plotted and compared using log-rank tests. Cox proportional-hazards regression model was used to analyze the influence of different variables on survival. RESULTS: Nineteen patients with peritoneal mesothelioma underwent laparotomy with CRS and HIPEC-OX with curative intent (15 epithelial, and 4 multicystic). Mean follow-up was 36.7 months. The estimated one-year and three-year overall survival rates were respectively 100% and 91%. The estimated one-year and three-year disease-free survival rates were respectively 77% and 50%. Complications were graded according to the Clavien-Dindo classification [1] and major complications occurred in 57% of cases. There was no postoperative mortality. Histological grade was not a prognostic factor of disease-free survival (p = 0.37). CONCLUSION: When comparing survival results as well as morbidity-mortality rates, the present study shows that CRS and HIPEC-OX is a valid treatment for peritoneal mesothelioma.

Factors Predictive of Re-excision After Oncoplastic Breast-conserving Surgery.

BACKGROUND: Oncoplastic surgery (OPS) consists of breast-conserving surgery (BCS) that allows for oncologically safe breast conservation and breast remodeling, thus reducing postoperative deformities. The purpose of the present study was to identify factors determining the risk of re-excision and complications after OPS. PATIENTS AND METHODS: A retrospective analysis was conducted on patients who underwent OPS between 2009 and 2013, regardless of whether neoadjuvant chemotherapy was administered. Clinical and pathological factors were evaluated. Recursive partitioning analysis (RPA) was used to build regression trees for the prediction of re-excision. RESULTS: Amongst the 129 patients treated by OPS procedures, 30.3% required re-excision. Predictive factors for re-excision were: being overweight (p=0.02), the presence of microcalcifications on mammography (p=0.003), and tumor multifocality (p=0.03). The RPA identified five terminal nodes based on microcalcifications on mammography, being overweight and the presence of ductal carcinoma in situ. Another model included minimal invasive margins (p<0.001), being overweight (p=0.02) and the presence of microcalcifications (p=0.01) on mammography yielded a model with an area under the receiver operating characteristic curve of 0.875. CONCLUSION: Microcalcifications, tumor multifocality and being overweight were the factors identified as predictors of re-excision after OPS. These factors can serve as decisional tools before surgery.

Quilting Sutures Reduces Seroma in Mastectomy.

BACKGROUND: Drainage duration and seroma formation occurring after mastectomy with or without axillary surgery lengthens hospitalization and delays adjuvant treatment. The aim of the study was to evaluate the effect of quilting in the prevention of seroma after mastectomy for breast cancer. PATIENTS AND METHODS: Eighty-two breast cancer patients about to undergo mastectomy with or without axillary surgery lymphadenectomy were enrolled in the study. We conducted an observational comparison between 41 patients in whom quilting with closed suction drainage was used and 41 patients in whom drainage only was used. RESULTS: The mean drained volume was significantly lower in the quilting group compared with the control group on days 1 and 2 (day 1: 107.1 mL vs. 156.5 mL; P = .02; day 2: 108.4 mL vs. 162.8 mL; P = .01). The mean drainage period was shorter in the quilting group (4.6 vs. 5.3 days; P = .046). There were fewer needle aspirations for seroma in the padding group (n = 14, 34.1% vs. n = 24, 58.5%; P = .03). CONCLUSION: The use of padding after mastectomy seems to reduce seroma formation, volume drained, and length of drainage time.

Atrial fibrillation after pulmonary transplantation: incidence, impact on mortality, treatment effectiveness, and risk factors.

BACKGROUND: Atrial fibrillation (AF) is common after thoracic surgery. Limited data exist concerning the incidence of AF, its impact on mortality, the effectiveness of therapy, and the risk factors of AF after pulmonary transplantation. METHODS AND RESULTS: We reviewed the medical files of 224 consecutive lung transplant recipients who underwent surgery over a 10-year period at a large Canadian center. We collected patient characteristics, in-hospital treatments, and outcomes. Time-to-event analysis was used to account for in-hospital follow-up and models generated to assess the impact of AF on mortality and independent risk factors of AF after transplantation. Postoperative AF occurred in 65 patients (29%). AF was more likely to occur with complications such as pneumonia, mediastinitis, and bronchial dehiscence and was not an independent risk factor of mortality (hazard ratio=1.56; 95% confidence interval, 0.52-4.63). Pharmacological or electric therapy for rhythm or rate control of AF was administered to 97% of patients. Intravenous amiodarone was used in 46%, electric cardioversion in 28%, and heparin in 26%. Only 1 patient remained in AF at discharge. Age (hazard ratio=1.08 by year; 95% confidence interval, 1.05-1.12), bilateral transplantation (hazard ratio=1.87; 95% confidence interval, 1.03-3.42), and a history of AF before the transplantation (hazard ratio=4.48; 95% confidence interval, 1.05-19.11) were found to be independently associated with an increased incidence of postoperative AF. CONCLUSIONS: AF is fairly common after pulmonary transplantation, transient, and relatively benign. It is not independently associated with increased in-hospital mortality. Most patients return to sinus rhythm before discharge. Age, prior AF, and bilateral transplantation increase the risk of postoperative AF.