Difference In Median Survival Research Articles

Positive lateral pelvic lymph nodes in low rectal cancer: should we change our practice now?

The role of lateral lymph node dissection (LLND) in the treatment of patients with low rectal cancer with enlarged lateral lymph nodes (LLN+) is under investigation. Enthusiasm for LLND stems from a perceived reduction in local recurrence (LR). We aimed to compare the LR rate for LLN+ patients with LLN- patients, treated with neoadjuvant chemoradiotherapy (nCRT) and surgery, in a hospital that does not perform LLND. A retrospective study of all patients with clinical stage 3 low rectal cancer who completed nCRT and surgery between 2008 and 2017 at Western Health was performed. Outcomes for LLN+ patients were compared with LLN- patients. The primary outcome was LR. Secondary outcomes included distant metastases, disease-free survival and overall survival. There were 110 patients treated for stage 3 low rectal cancer over 10 years. There was no significant difference in the LR rate, with one LR from 28 LLN+ patients and one LR from 82 LLN- patients (4% versus 1.2%, P=0.44). There were no significant differences in median disease-free survival (41 versus 52 months, P=0.19) or mean overall survival (62 versus 60 months, P=0.80). Of all patients studied, 21% developed distant metastases. LR after nCRT and surgery in patients with stage 3 rectal cancer is rare, irrespective of lateral pelvic node status. These data, along with the uncertain benefit and known risks of LLND, supports the continued use of standard therapy in these patients. Strategies to address distant failure in these patients should be explored.

Does direct invasion of peripancreatic lymph nodes impact survival in patients with pancreatic ductal adenocarcinoma? A retrospective dual-center study

BackgroundPancreatic ductal adenocarcinoma can directly invade the peripancreatic lymph nodes; however, the significance of direct lymph node invasion is controversial, and it is currently classified as lymph node metastasis. This study aimed to identify the impact of direct invasion of peripancreatic lymph nodes on survival in patients with pancreatic ductal adenocarcinoma. MethodsA total of 411 patients with resectable/borderline resectable pancreatic ductal adenocarcinoma who underwent pancreatic resection at two high-volume centers from 2006 to 2016 were evaluated retrospectively. ResultsSixty (14.6%) patients had direct invasion of the peripancreatic lymph nodes without isolated lymph node metastasis (N-direct group), 189 (46.0%) had isolated lymph node metastasis (N-met group), and 162 (39.4%) had neither direct invasion nor isolated metastasis (N0 group). There was no significant difference in median overall survival between the N-direct group (35.0 months) and the N0 group (45.6 month) (p = 0.409), but survival was significantly longer in the N-direct compared with the N-met group (25.0 months) (p = 0.003). Similarly, median disease-free survival was similar in the N-direct (21.0 months) and N0 groups (22.7 months) (p = 0.151), but was significantly longer in the N-direct compared with the N-met group (14.0 months) (p < 0.001). Multivariate analysis identified resectability, adjuvant chemotherapy, and isolated lymph node metastasis as independent predictors of overall survival. However, direct lymph node invasion was not a predictor of survival. ConclusionDirect invasion of the peripancreatic lymph nodes had no effect on survival in patients undergoing pancreatic resection for pancreatic ductal adenocarcinoma, and should therefore not be classified as lymph node metastasis.

P76.76 EGFR Tyrosine Kinase Inhibitors in Patients with Non-Small Cell Lung Cancer and the Role of Diabetes Mellitus and Metformin

The EGFR tyrosine kinase inhibitors (TKI) had increased survival in non-small cell lung cancer (NSCLC) patients in the presence of response predictive EGFR mutations. Previously, these drugs were used in wild type patients as a 2nd line or beyond. Some laboratory studies and phase I/II trials had demonstrated a possible synergistic effect between EGFR TKI and metformin. The aim of this study is to analyze patients treated with EGFR TKI and assessing the impact of diabetes mellitus (DM) and metformin on the outcomes. A retrospective study including 75 patients with stage IV NSCLC submitted to EGFR TKI between January 2013 and December 2019. Clinicopathological characteristics were described. The progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier with Log Rank test and Cox regression, with 5% statistical significance. Thirty-one patients (n=31, 41.3%) had EGFR mutations and were treated with EGFR TKI as 1st line treatment (group 1) and 44 (58.7%) were wild type, treated with EGFR TKI in 2nd line or beyond (group 2). Twenty patients had DM and 12 patients were on metformin. The median follow-up time was 54.73 months. In group 1, the median PFS and OS were 10.37 and 18.70 months, respectively. There were no statistically significant differences in PFS and OS between patients with or without DM (p=0.28 and p=0.53), and patients treated or not with metformin (p=0.20 and p=0.50). In group 2, the median PFS and OS were 2.73 and 9.87 months, respectively. Inversely from the group 1, the median PFS was superior in patients with DM: 5.77 vs 2.63 months, HR 0.44 (95%CI 0.21-0.91), p=0.023; and in patients on metformin: 5.77 vs 2.53 months, HR 0.43 (95%CI 0.20-0.95), p=0.031. The median OS was also superior in patients with DM: 14.90 vs 7.10 months, HR 0.44 (95%CI 0.22-0.89), p=0.019. Patients that received metformin had a median OS of 12.57 months vs 7.73 months in the remaining, HR 0.47 (95%CI 0.21-1.02), p=0.051. In group 1, there were no differences in median survival among patients with DM and on metformin. However, the number of patients with DM and on metformin in this group was very small. In group 2, the median PFS and OS were superior in patients with DM, and the median PFS was superior in patients on metformin. This study has some limitations: it is retrospective, with a limited sample and it includes patients that nowadays wouldn’t be treated with EGFR TKI following the current international guidelines. Nevertheless, it will be important to study the potential association between metformin and EGFR TKI in NSCLC, regarding the fact that this drug is easily accessed in daily practice.

T-wave peak-end interval and ratio of T-wave peak-end and QT intervals: novel arrhythmogenic and survival markers for dogs with myxomatous mitral valve disease

Introduction/objectivesIn the past few years, novel markers such as the interval between the peak and the end of T-wave (Tpte) and Tpte/QT ratio have been shown to have high sensitivity for ventricular arrhythmias and mortality. We analyzed these and other parameters of ventricular repolarization, such as QT interval, QT interval corrected for heart rate (QTc), and QT dispersion (QTd) in dogs with myxomatous mitral valve disease (MMVD). Additionally, we investigated their relationship with the progression of the disease, echocardiographic parameters, and ventricular arrhythmias and assessed their prognostic value with development of clinical signs or mortality as the final outcome. Animals, materials and methodsEpidemiological, clinical, echocardiographic, and electrocardiographic data were obtained from 236 dogs with MMVD and 15 healthy dogs. Prognostic and survival information was also recorded for the MMVD group. All ventricular repolarization indices were measured in 10 lead electrocardiographic recordings. ResultsWith the exception of the QT interval, most repolarization markers increased along with the frequency of arrhythmias and with the progression of MMVD. The parameters that best identified ventricular arrhythmias (AUC > 0.7) were Tpte (aVR, rV2, average rV2–V10, average rV2–V4) and Tpte/QT (II, aVR, rV2). In survival analysis, statistically significant markers with the highest differences in median survival were Tpte (maximum of any lead, maximum rV2–V10), QTc aVR, and Tpte rV2. ConclusionTpte and Tpte/QT are good non-invasive markers for clinical risk stratification in dogs with MMVD.

Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients

BackgroundCheckpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort.MethodsData from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3–4 hepatitis and outcome.Results2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44).ConclusionIncidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.

A Propensity Score–Matched Analysis of Thoracolaparoscopic vs Open McKeown’s Esophagectomy

BackgroundThe effectiveness and survival benefit of minimally invasive esophagectomy compared to open esophagectomy (OE) remain controversial. The aim of this study was to evaluate the safety, efficacy, and oncologic outcomes of McKeown’s total minimally invasive esophagectomy (tMIE) and McKeown’s OE in the treatment of patients with esophageal squamous cell carcinoma. MethodsA series of 917 consecutive patients (306 OE and 611 tMIE) who underwent McKeown’s esophagectomy for esophageal squamous cell carcinoma in the Department of Thoracic Surgery at Sun Yat-sen University Cancer Center from January 2011 to December 2016 were evaluated. We performed propensity matching between the tMIE and OE groups on the basis of estimated propensity scores for each patient. ResultsAfter propensity-matched analysis, 288 patients were selected from each group. The rate of postoperative complications, such as pneumonia, respiratory insufficiency, cervical anastomotic leakage, and wound infection, in the OE group was significantly higher than that in the tMIE group. Intraoperative blood loss and operative duration were not significantly different between the matched groups, whereas the tMIE group had a shorter length of intensive care unit stay and postoperative hospital stay than the OE group. The R0 resection rate and the number of lymph nodes harvested were not significantly different between groups. There was no significant difference in median overall survival between the 2 groups after matching. ConclusionsMcKeown’s tMIE was shown to be a safe and effective procedure with long-term survival comparable to that of OE for the patients with esophageal squamous cell carcinoma.

Association of diet with clinical outcomes in dogs with dilated cardiomyopathy and congestive heart failure

IntroductionDilated cardiomyopathy (DCM) in dogs has been associated with feeding of grain-free (GF), legume-rich diets. Some dogs with presumed diet-associated DCM have shown improved myocardial function and clinical outcomes following a change in diet and standard medical therapy. HypothesisPrior GF (pGF) diet influences reverse cardiac remodeling and clinical outcomes in dogs with DCM and congestive heart failure (CHF). Animals and methodsA retrospective study was performed with 67 dogs with DCM and CHF for which diet history was known. Dogs were grouped by diet into pGF and grain-inclusive (GI) groups. Dogs in the pGF group were included if diet change was a component of therapy. Survival was analyzed using Kaplan–Meier curves and the Cox proportional-hazards model. ResultsThe median survival time was 344 days for pGF dogs vs. 253 days for GI dogs (P = 0.074). Statistically significant differences in median survival were identified when the analysis was limited to dogs surviving longer than one week (P = 0.033). Prior GF dogs had a significantly worse outcome the longer a GF diet was fed prior to diagnosis (P = 0.004) or if they were diagnosed at a younger age (P = 0.017). Prior GF dogs showed significantly greater improvement in normalized left ventricular internal diastolic diameter (P = 0.038) and E-point septal separation (P = 0.031) measurements and significant decreases in their furosemide (P = 0.009) and pimobendan (P < 0.005) dosages over time compared to GI dogs. ConclusionsPrior GF dogs that survived at least one week after diagnosis of DCM, treatment of CHF, and diet change had better clinical outcomes and showed reverse ventricular remodeling compared to GI dogs.

Cediranib in addition to chemotherapy for women with relapsed platinum-sensitive ovarian cancer (ICON6): overall survival results of a phase III randomised trial

BackgroundCediranib, an oral anti-angiogenic VEGFR 1-3 inhibitor, was studied at a daily dose of 20 mg in combination with platinum-based chemotherapy and as maintenance in a randomised trial in patients with first relapse of ‘platinum-sensitive’ ovarian cancer and has been shown to improve progression-free survival (PFS).Patients and methodsICON6 (NCT00532194) was an international three-arm, double-blind, placebo-controlled randomised trial. Between December 2007 and December 2011, 456 women were randomised, using stratification, to receive either chemotherapy with placebo throughout (arm A, reference); chemotherapy with concurrent cediranib, followed by maintenance placebo (arm B, concurrent); or chemotherapy with concurrent cediranib, followed by maintenance cediranib (arm C, maintenance). Due to an enforced redesign of the trial in September 2011, the primary endpoint became PFS between arms A and C which we have previously published, and the overall survival (OS) was defined as a secondary endpoint, which is reported here.ResultsAfter a median follow-up of 25.6 months, strong evidence of an effect of concurrent plus maintenance cediranib on PFS was observed [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.44-0.72, P < 0.0001]. In this final update of the survival analysis, 90% of patients have died. There was a 7.4-month difference in median survival and an HR of 0.86 (95% CI: 0.67-1.11, P = 0.24) in favour of arm C. There was strong evidence of a departure from the assumption of non-proportionality using the Grambsch–Therneau test (P = 0.0031), making the HR difficult to interpret. Consequently, the restricted mean survival time (RMST) was used and the estimated difference over 6 years by the RMST was 4.8 months (95% CI: −0.09 to 9.74 months).ConclusionsAlthough a statistically significant difference in time to progression was seen, the enforced curtailment in recruitment meant that the secondary analysis of OS was underpowered. The relative reduction in the risk of death of 14% risk of death was not conventionally statistically significant, but this improvement and the increase in the mean survival time in this analysis suggest that cediranib may have worthwhile activity in the treatment of recurrent ovarian cancer and that further research should be undertaken.

ModelBuildR: an R package for model building and feature selection with erroneous classifications.

BackgroundModel building is a crucial part of omics based biomedical research to transfer classifications and obtain insights into underlying mechanisms. Feature selection is often based on minimizing error between model predictions and given classification (maximizing accuracy). Human ratings/classifications, however, might be error prone, with discordance rates between experts of 5–15%. We therefore evaluate if a feature pre-filtering step might improve identification of features associated with true underlying groups.MethodsData was simulated for up to 100 samples and up to 10,000 features, 10% of which were associated with the ground truth comprising 2–10 normally distributed populations. Binary and semi-quantitative ratings with varying error probabilities were used as classification. For feature preselection standard cross-validation (V2) was compared to a novel heuristic (V1) applying univariate testing, multiplicity adjustment and cross-validation on switched dependent (classification) and independent (features) variables. Preselected features were used to train logistic regression/linear models (backward selection, AIC). Predictions were compared against the ground truth (ROC, multiclass-ROC). As use case, multiple feature selection/classification methods were benchmarked against the novel heuristic to identify prognostically different G-CIMP negative glioblastoma tumors from the TCGA-GBM 450 k methylation array data cohort, starting from a fuzzy umap based rough and erroneous separation.ResultsV1 yielded higher median AUC ranks for two true groups (ground truth), with smaller differences for true graduated differences (3–10 groups). Lower fractions of models were successfully fit with V1. Median AUCs for binary classification and two true groups were 0.91 (range: 0.54–1.00) for V1 (Benjamini-Hochberg) and 0.70 (0.28–1.00) for V2, 13% (n = 616) of V2 models showed AUCs < = 50% for 25 samples and 100 features. For larger numbers of features and samples, median AUCs were 0.75 (range 0.59–1.00) for V1 and 0.54 (range 0.32–0.75) for V2. In the TCGA-GBM data, modelBuildR allowed best prognostic separation of patients with highest median overall survival difference (7.51 months) followed a difference of 6.04 months for a random forest based method.ConclusionsThe proposed heuristic is beneficial for the retrieval of features associated with two true groups classified with errors. We provide the R package modelBuildR to simplify (comparative) evaluation/application of the proposed heuristic (http://github.com/mknoll/modelBuildR).

Does race play a role in complications and outcomes of Philadelphia chromosome-negative myeloproliferative neoplasms?

BackgroundPhiladelphia chromosome-negative myeloproliferative neoplasms (MPN) are a group of hematologic malignancies with known vascular complications. The role race and ethnicity play in these complications is less defined. We aimed to further evaluate the role of race in patients without a history of previous thrombotic or hemorrhagic events. MethodsIn this retrospective study, 300 adult patients with MPN were included; 270 (90.0%) were White and 30 (10.0%) were non-White. The non-White group primarily consisted of African American or Black (26 patients), followed by others. Median age at diagnosis was 58 years for White patients and 61.5 years for non-White patients. The interaction between outcomes and vascular events with race was evaluated using multivariate logistical regression models. ResultsThe incidence of thrombotic events was inversely correlated with age at diagnosis, with younger patients demonstrating a higher rate of thrombotic events over time (p < .001). The incidence of thrombotic or hemorrhagic events did not differ between White and non-White patients. A statistically significant difference in median survival was observed between White and non-White patients: 29 years (95% confidence interval [CI]: 21.8–not reached) versus 13 years (95% CI: 5.7–22.7), respectively (p = .016). ConclusionThis study did not find a significant difference in the rate of thrombotic or hemorrhagic events between White and non-White patients with MPN but suggested that non-White patients had significantly shorter median survival than White patients. Such observations may inform future studies to further characterize racial disparities in outcomes.

Platinum-Based Treatment for Well- and Poorly Differentiated Pancreatic Neuroendocrine Neoplasms.

Pancreatic neuroendocrine neoplasms include well-differentiated tumors (PanNETs) and poorly differentiated carcinomas (PanNECs). Previous reports suggested a role for platinum-based therapy largely in PanNEC. We sought to investigate the role of platinum-based therapy in pancreatic neuroendocrine neoplasms regardless of tumor grade and differentiation. Patients with pancreatic neuroendocrine neoplasms treated with platinum-based therapy at Memorial Sloan Kettering (1994-2016) and Verona University Hospital (2008-2016) were retrospectively identified. Response to treatment by RECIST v1.1, overall survival, and progression-free survival were defined. Among patients with available tissue, DAXX, ATRX, Rb, and p53 expression was evaluated to support the histologic grade of differentiation. Fifty PanNETs, 29 PanNECs, and 22 high-grade tumors with undeterminable differentiation were included. No patients achieved complete response. Overall rate of partial response was 31%, 41% for PanNEC, and 20% for PanNETs. Among PanNETs, partial response was achieved in 33% of G1 (2/6), 10% of G2 (2/19), and 24% of G3 (6/25) tumors. Median overall survival was 29.3 months for PanNETs and 10.9 months for PanNEC (P < 0.001). There was no significant difference in median progression-free survival (P = 0.2). Platinum-based therapies demonstrated increased activity in PanNEC; however, promising efficacy was also observed in PanNETs, irrespective of grade.

Association of Race, Socioeconomic Factors, and Treatment Characteristics With Overall Survival in Patients With Limited-Stage Small Cell Lung Cancer

It has been established that disparities in race and socioeconomic status are associated with outcomes of non-small cell lung cancer. However, it remains unknown whether this extends to stage I, II, or III small cell lung cancer (SCLC), or limited-stage SCLC (L-SCLC). To investigate the associations of race, socioeconomic factors, and treatment characteristics with survival among patients with L-SCLC. Demographic information for patients with L-SCLC diagnosed between 2004 and 2014 was obtained from the National Cancer Database. The follow-up end point is death or last follow-up (date of last contact). Patients were divided into 5 mutually exclusive cohorts by race. Data analysis was performed in October 2019. Cox proportional hazards models were used to calculate univariable and multivariable models. Multivariable analyses were conducted to assess the associations of race and socioeconomic factors with risk-adjusted outcomes. Overall survival between groups was depicted by Kaplan-Meier curves. Of 72 409 patients analyzed (median [range] age, 67.0 [23.0-90.0] years), 40 289 (55.6%) were women. The distribution of disease stage was 10 619 patients (14.7%) with stage I disease, 7689 patients (10.6%) with stage II disease, and 54 101 patients (74.7%) with stage III disease. The median (range) duration of follow-up was 8.2 (2.4-15.8) months. Compared with White patients, the hazard of death decreased to 0.92 (95% CI, 0.89-0.95; P < .001) for African American patients and 0.83 (95% CI, 0.77-0.91; P < .001) for Asian patients. The difference in median survival among different racial groups was significant only among those with stage III SCLC. Other factors associated with better survival were female sex, high income, high education, private insurance, diagnostic confirmation by positive cytological analysis, increase in number of sampled regional lymph nodes, and earlier stage at diagnosis. This analysis highlights disparities in race and socioeconomic factors associated with outcomes of L-SCLC. Racial minorities, including African American and Asian patients, have better survival than White patients for L-SCLC after adjustment for sociodemographic factors.

Osteopontin Affects Oncological Outcome after Liver Resection for Colorectal Metastasis

Introduction: Osteopontin (OPN) - a chemoattractant and matrix protein - was previously described to be expressed by a variety of malignant tumors. As such, colorectal carcinoma was found to produce OPN. Further, a close relation of OPN to oncological outcome could be identified. Yet, OPN was not investigated in patients with colorectal cancer liver metastasis (CRCLM). Method: Within this analysis 48 patients undergoing liver resection for CRCLM were included. Circulating OPN was evaluated prior to the operation. Further, OPN was stained on tumor tissue gathered during liver resection. Patients were followed up for disease recurrence. Results: OPN expression in tumor tissue was tightly associated to circulating levels. Further, OPN was found to be significantly increased in patients that develop disease recurrence within two years after curative liver resection (median OPN no recurrence = 49.97 ng/mL vs median OPN recurrence = 72.38 ng/mL, p = 0.013). This difference was found to obtain a strikingly high predictive potential evaluated via receiver operating characteristics (AUC = 0.833, p = 0.015). Based on this analysis an optimal cut-off was identified at 60 ng/mL of OPN. Indeed, patients above this cut-off showed a significantly reduced disease-free survival when compared in a Kaplan-Meier analysis (difference in median disease-free survival = 1.3 years, p = 0.042). Conclusions: OPN is a marker for early disease recurrence in patients suffering from CRCLM. Thus, assessment of OPN might be a useful tool for preoperative patient evaluation and should hence be included in the work-up of this patient cohort.

Repeat hepatectomy outcomes for colorectal liver metastases from an international multicenter collaborative

Presenter: Cristian D Valenzuela MD | Wake Forest University Background: Resection of colorectal metastases to the liver has become the standard of care when feasible, prolonging survival. However, despite improved surgical approaches, subsequent isolated hepatic recurrences are not unusual. Repeat hepatectomy for Colorectal Liver Metastases (CLM) appears to be safe and effective for recurrent disease, but there is paucity of data with few reports from large studies. We report an experience in over one thousand surgical CLM cases in a multicenter database from five hepatobiliary institutions. Methods: An international collaborative of five institutions (Wake Forest, Mayo Clinic Jacksonville, University of California San Francisco, Yale, and University of Hong Kong) was formed to collect CLM cases performed at these locations from 2000-2018. Institutional review committees approved this project at all locations. A total of 1004 CLM hepatectomy cases were identified. Compiled data included: patient demographics, comorbidities, primary tumor and metastasis characteristics, pre-operative labs and imaging, operative characteristics including hepatectomy type, transfusions, tumor pathology features, complications, neoadjuvant and adjuvant therapies, surveillance strategies, recurrence characteristics, and survival. Kaplan-Meier analysis was performed with the Log Rank test to determine differences between subgroups. Complications were considered major if the Clavien-Dindo score was three or greater, and the Chi-Square test was used to compare subgroups. Results: For all cases, median overall survival after hepatectomy for CLM was 47.2 months, and disease-free survival was 19.0 months with a median follow-up of 32.0 months. Repeat hepatectomy was performed in 78 patients (7.9%): 51 (65%) were minor and 27 (35%) were major hepatectomies, similar to first-hepatectomies, in which 551 (61%) were minor and 358 (39%) were major. Ablations were performed as part of first-hepatectomy in 121 (13.3%) patients, and as part of second-hepatectomy in 6 patients (7.6%). From time of surgery, there was no significant difference in median overall survival (49.1 vs 47.2 months, p=0.830) or disease-free survival (19.6 vs. 19.3 months, p=0.288) after second hepatectomy compared to first hepatectomy. Patients who underwent repeat hepatectomy had improved median overall survival from time of cancer diagnosis compared to patients undergoing only one hepatectomy (87.5 vs 65.0 months, Log Rank χ2 =3.926, p= 0.048). Microscopic margin status was associated with outcomes after hepatectomy for CLM: median overall survival for R1 liver resections was 35.5 months versus 48.7 months for R0 resections (Log Rank χ2 = 11.06, p=0.001). Similarly, median disease-free survival was significantly worse for R1 resections compared to R0 resections (15.1 vs. 19.6 months; Log Rank χ2 = 5.074; p=0.024). Whether the hepatectomy was minor or major had no significant effect on median overall survival (49.7 vs. 43.6 months, Log Rank χ2 = 1.681; p=0.195). However, major hepatectomy was associated with a significantly higher number of major complications compared to minor hepatectomy (17.9% vs. 12.1%; p=0.0004). Conclusion: A second hepatectomy for recurrence was beneficial for patients with CLM, yielding improved survival compared to those only undergoing one hepatectomy. Generally, obtaining R0 margins during hepatectomy for CLM was important for overall survival. Major hepatectomy was associated with higher risk of severe complications, but was associated with similar survival compared to minor hepatectomy for CLM.

Biliary intervention rates during neoadjuvant therapy for adenocarcinoma of the pancreatic head

BackgroundNeoadjuvant therapy prior to resection of adenocarcinoma of the pancreatic head increases time to surgery and thus the possibility of biliary complications. We hypothesized that biliary complications during neoadjuvant therapy negatively impact clinical outcomes. MethodsWe completed a retrospective study of a cohort of borderline resectable patients consistently treated with neoadjuvant therapy from May 2014 through March 2019. Biliary complications were defined as new-onset biliary obstruction, existing stent failure, cholecystitis, and cholangitis. ResultsOf 59 patients that met inclusion criteria, 34 (57.6%) went on to resection. Biliary complications affected 16 patients (27%); 8 (50%) of these patients went on to surgical resection. Of those 43 patients who did not have a biliary intervention, 26 went on to surgical resection (60.4%). There was no significant effect of a biliary complication on total number of chemotherapy cycles (p = 0.12), proceeding to surgical resection (p = 0.56) or on median survival (p = 0.23). Among patients who did proceed to surgery, there was a notable difference in median survival for patients who required a biliary intervention (17.9 vs 31.0 months) that did not reach significance (p = 0.35). ConclusionThe need for further biliary interventions during neoadjuvant therapy for pancreatic adenocarcinoma is common, but does not appear to have a significant effect on number of cycles of neoadjuvant therapy or proceeding to surgical resection. Larger studies are necessary to determine if these events compromise overall survival.

Does age affect oesophagectomy survival: a cohort study

Curative oesophagectomy for oesophageal cancer is associated with considerable potential mortality. Surgeons are increasingly treating older patients presenting with oesophageal cancer as the population ages. The question remains as to the survival in an older population group, many of whom are not fit for combined multimodal therapy. This study aimed to assess the effect of age on overall survival and disease-free survival in patients undergoing curative oesophagectomy for cancer. Patient data were analysed from a prospectively maintained database. Demographic, surgical and survival outcomes were compared between groups according to age less than 75 years or 75 and older. Oesophagectomy was performed in 351 patients between 1990 and 2019 (283 patients <75 years, 68 patients ≥75 years). There was a higher rate of neoadjuvant chemotherapy in the younger group (37.7% versus 7.4%; P < 0.001). The 30-day mortality between younger and older groups was similar (2.5% and 2.9%; P = 0.827). There was no statistical difference in 5-year survival rates (50.3% versus 38.6%; P = 0.082) or median survival (22.6 versus 19.3 months; P = 0.053) between groups. There was no statistical difference in 5-year disease-free survival (45.1% and 35.7%; P = 0.180). Overall survival, disease-free survival and 30-day mortality rates in patients aged 75 years and older were not statistically different to their younger counterparts. On the basis of these results, older patients should not be precluded from consideration of potentially curative oesophagectomy on age alone, providing surgery may be performed at reasonable risk.

The importance of multimodal therapy in the management of nonmetastatic adenosquamous carcinoma of the pancreas: Analysis of treatment sequence and strategy

BackgroundAdenosquamous carcinoma of the pancreas has historically poor survival. We analyzed survival outcomes stratified by treatment regimen and sequence using an administrative dataset. MethodsAdult patients with nonmetastatic adenosquamous carcinoma of the pancreas were identified using the National Cancer Database (2010−2016). Multivariable analyses were used to determine factors associated with receipt of neoadjuvant or adjuvant chemotherapy. Overall survival was estimated by Kaplan-Meier analysis and a multivariable Cox model was used to evaluate factors associated with survival. ResultsA total of 838 patients with adenosquamous carcinoma of the pancreas were included in the analysis. The median age was 69 years and 64.7% of patients underwent pancreatectomy. Among patients who underwent pancreatectomy, 60.5% received adjuvant chemotherapy, 14.8% received neoadjuvant chemotherapy, and 24.7% underwent surgery alone. Older age and increasing comorbidity index were associated with a reduced likelihood of receiving neoadjuvant or adjuvant chemotherapy. Median survival of patients who received chemotherapy alone was similar compared with patients who underwent pancreatectomy alone (9.2 vs 7.2 months, P = .504). Survival was improved if patients received both chemotherapy and pancreatectomy (neoadjuvant = 19.6 months, hazard ratio = 0.58; adjuvant = 19.4 months, hazard ratio = 0.64) compared with pancreatectomy alone. ConclusionPatients with adenosquamous carcinoma of the pancreas who do not receive multimodal therapy have poor survival. The sequence of chemotherapy and pancreatectomy is not associated with survival, but 25% of patients who undergo surgery do not receive chemotherapy. Given that there is no difference in median survival between patients who undergo pancreatectomy alone or receive chemotherapy alone, our data question whether neoadjuvant chemotherapy should be considered in patients with potentially resectable adenosquamous carcinoma of the pancreas.

Surgical series of metastatic cerebral melanoma: Clinical association of resection, BRAF-mutation status, and survival

BackgroundMajor advances in the systemic treatment of metastatic cerebral melanoma have improved patient survival. The clinical relationship between gross total resection (GTR), BRAF-mutation status, and its effects on survival in the era of targeted/immunotherapy warrants further characterization. MethodWe retrospectively reviewed survival after craniotomy for melanoma metastases in patients who also received targeted/immunotherapy and cavity radiation at four neurosurgical hospitals in Queensland, Australia from 2012 to 2019. Results152 craniotomies were performed in 138 patients (98 male, 40 female), 42% were BRAF-mutant with differences in median age for BRAF-mutant vs BRAF-wildtype (52 vs 64 years; p = 0.001), and GTR rates for BRAF-mutant vs BRAF-wildtype (85% vs 73%; p = 0.03). Median survival difference between BRAF-mutant vs BRAF-wildtype was 15.4 vs 11.9 months (p = 0.11). The longest median survival occurred in BRAF-mutant with GTR while the shortest occurred in BRAF-wildtype with STR (23 vs 4.5 months; p = 0.001). At three years, the proportion alive for GTR and BRAF-mutant vs GTR and BRAF-wildtype (47.9% vs 41.6%) was higher than STR and BRAF-mutant vs STR and BRAF-wildtype (15% vs 28.4%; p = 0.03). ConclusionBRAF-mutant patients with cerebral metastases were younger, and more likely to have a higher GTR rate with greater survival than BRAF-wildtype if GTR is achieved. Gross total resection in both groups appears to be associated with survival even in the current era of more effective systemic therapies. Subtotal resection has particularly poor survival, especially for BRAF-mutant patients.

Bortezomib, lenalidomide, and dexamethasone with or without elotuzumab in patients with untreated, high-risk multiple myeloma (SWOG-1211): primary analysis of a randomised, phase 2 trial

The introduction of immunomodulatory agents, proteasome inhibitors, and autologous haematopoietic stem-cell transplantation has improved outcomes for patients with multiple myeloma, but patients with high-risk multiple myeloma have a poor long-term prognosis. We aimed to address optimal treatment for these patients. SWOG-1211 is a randomised phase 2 trial comparing eight cycles of lenalidomide (25 mg orally on days 1-14 every 21 days), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11 every 21 days), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days; RVd) induction followed by dose-attenuated RVd maintenance (bortezomib 1 mg/m2 subcutaneously on days 1, 8, and 15; lenalidomide 15 mg orally on days 1-21; dexamethasone 12 mg orally on days 1, 18, and 15 every 28 days) until disease progression with or without elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, on days 1 and 11 for cycles 3-8, and on days 1 and 15 during maintenance). Patients were randomly assigned (1:1) to either RVd or RVd-elotuzumab. High-risk multiple myeloma was defined by one of the following: gene expression profiling high risk (GEPhi), t(14;16), t(14;20), del(17p) or amp1q21, primary plasma cell leukaemia and elevated serum lactate dehydrogenase (two times the upper limit of normal or more). The primary endpoint was progression-free survival, and all analyses were done on intention-to-treat basis among eligible patients who were evaluable for response. This study is registered with ClinicalTrials.gov, NCT01668719. 100 (RVd n=52, RVd-elotuzumab n=48) patients were enrolled between Oct 27, 2013, and May 15, 2016, across 26 cooperative group institutions in the USA. Median age was 64 years (IQR 57-70, range 36-85). 74 (75%) of 99 had International Staging System stage II or stage III disease, 47 (47%) of 99 had amp1q21, 37 (37%) of 100 had del17p, 11 (11%) of 100 had t(14;16), eight (9%) of 90 were GEPhi, seven (7%) of 100 had primary plasma cell leukaemia, five (5%) of 100 had t(14;20), four (4%) of 100 had elevated serum lactate dehydrogenase, and 17 (17%) had two or more features. With a median follow-up of 53 months (IQR 46-59), no difference in median progression-free survival was observed (RVd 33·64 months [95% CI 19·55-not reached], RVd-elotuzumab 31·47 months [18·56-53·98]; hazard ratio 0·968 [80% CI 0·697-1·344]; one-sided p=0·45]. 37 (71%) of 52 patients in the RVd group and 37 (77%) of 48 in the RVd-elotuzumab group had grade 3 or worse adverse events. No significant differences in the safety profile were observed, although some notable results included grade 3-5 infections (four [8%] of 52 in the RVd group, eight [17%] of 48 in the RVd-elotuzumab group), sensory neuropathy (four [8%] of 52 in the RVd group, six [13%] of 48 in the RVd-elotuzumab group), and motor neuropathy (one [2%] of 52 in the RVd group, four [8%] of 48 in the RVd-elotuzumab group). There were no treatment-related deaths in the RVd group and one death in the RVd-elotuzumab group for which study treatment was listed as possibly contributing by the investigator. In the first randomised study of high-risk multiple myeloma reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, progression-free survival in both study groups exceeded the original statistical assumptions and supports the role for continuous proteasome inhibitors and immunomodulatory drug combination maintenance therapy for this patient population. National Institutes of Health, National Cancer Institute, Bristol Myers Squibb, Celgene, Leukemia and Lymphoma Society.

Inferring median survival differences in general factorial designs via permutation tests.

Factorial survival designs with right-censored observations are commonly inferred by Cox regression and explained by means of hazard ratios. However, in case of non-proportional hazards, their interpretation can become cumbersome; especially for clinicians. We therefore offer an alternative: median survival times are used to estimate treatment and interaction effects and null hypotheses are formulated in contrasts of their population versions. Permutation-based tests and confidence regions are proposed and shown to be asymptotically valid. Their type-1 error control and power behavior are investigated in extensive simulations, showing the new methods' wide applicability. The latter is complemented by an illustrative data analysis.