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Definitive radiotherapy has been suggested as a treatment alternative to surgical resection in Merkel cell carcinoma (MCC). Patients with MCC were identified from the National Cancer Database. Propensity score matching accounting for age, Charlson-Deyo score, grade, and AJCC stage was used to match patients in 1:1 fashion by primary treatment (surgery vs. radiotherapy). There were 1227 patients in each group. Median overall survival was improved with surgical resection in stage I/II (76 vs. 25 months, p < 0.001) and stage III disease (30 vs. 15 months, p < 0.001). For stage I/II, 5- and 8-year overall survival were 61% and 42%, in the surgical resection and 32% and 25% in the definitive radiotherapy groups, respectively. For stage III, 5- and 8-year overall survival were 34% and 21% for surgical resection and 19% and 16% in the radiotherapy group, respectively. Surgical resection for MCC improves median survival compared to definitive radiotherapy while marginally improving long-term survival. •Surgical resection improves median survival in merkel cell carcinoma.•Resection provides modest benefit compared with definitive radiotherapy.•Long-term survival is achievable in select patient with definitive radiotherapy alone.

Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2–6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7–14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.

We evaluated neoadjuvant ipilimumab in patients with surgically operable regionally advanced melanoma in order to define markers of activity in the blood and tumor as assessed at baseline (before ipilimumab) and early on-treatment. Patients were treated with ipilimumab (10 mg/kg intravenously every 3 weeks ×2 doses) bracketing surgery. Tumor and blood biospecimens were obtained at baseline and at surgery. Flow cytometry and immunohistochemistry for select biomarkers were performed. Thirty five patients were enrolled; IIIB (3; N2b), IIIC (32; N2c, N3), IV (2). Worst toxicities included Grade 3 diarrhea/colitis (5; 14%), hepatitis (2; 6%), rash (1; 3%), elevated lipase (3; 9%). Median follow up was 18 months: among 33 evaluable patients, median progression free survival (PFS) was 11 months, 95% CI (6.2-19.2). There was a significant decrease in circulating myeloid derived suppressor cells (MDSC). Greater decrease in circulating monocyte gate MDSC Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associated with improved PFS (p = 0.03). There was a significant increase in circulating regulatory T cells (Treg; CD4⁺CD25hi⁺Foxp3⁺) that, unexpectedly, was associated with improved PFS (HR = 0.57; p = 0.034). Baseline evidence of fully activated type I CD4⁺ and CD8⁺ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) and melanocytic lineage (MART-1, gp100) antigens was detected and was significantly potentiated after ipilimumab. In tumor, there was a significant increase in CD8⁺ T cells after ipilimumab (p = 0.02). Ipilimumab induced increased tumor infiltration by fully activated (CD69⁺) CD3⁺/CD4⁺ and CD3⁺/CD8⁺ T cells with evidence of induction/potentiation of memory T cells (CD45RO⁺). The change in Treg observed within the tumor showed an inverse relationship with clinical benefit and greater decrease in tumor MDSC subset Lin1-/HLA-DR-/CD33⁺/CD11b⁺ was associated with improved PFS at one year. Neoadjuvant evaluation revealed a significant immunomodulating role for ipilimumab on Treg, MDSC and effector T cells in the circulation and tumor microenvironment that warrants further pursuit in the quest for optimizing melanoma immunotherapy.

BackgroundColorectal cancer leads to peritoneal metastases (CRPM) in 10% of cases. Cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) improves survival. Primary tumor location and abnormalities in RAS, BRAF, and mismatch repair/microsatellite stability (MMR/MSI) may affect post-CRS-HIPEC survival, but studies have not been consistent. We estimated the effects of primary tumor site and genomic alterations on post-CRS-HIPEC survival.MethodsThis retrospective cohort study included CRS-HIPEC cases for CRPM at a high-volume center from 2001 to 2020. Next-generation sequencing and microsatellite testing defined the RAS, BRAF, and MMR/MSI genotypes. Adjusted effects of tumor sidedness and genomics on survival were evaluated using a multivariable Cox proportional hazards model. We analyzed these variables’ effects on progression-free survival and the effects of immune checkpoint-inhibitors.ResultsA total of 250 patients underwent CRS-HIPEC with testing for RAS, BRAF, and MMR/MSI; 50.8% of patients were RAS-mutated, 12.4% were BRAF-mutated, and 6.8% were deficient-MMR/MSI-high (dMMR/MSI-H). Genomic alterations predominated in right-sided cancers. After adjustment for comorbidities and oncological and perioperative variables, rectal origin [hazard ratio (HR) 1.9, p = 0.01], RAS mutation (HR 1.6, p = 0.01), and BRAF mutation (HR 1.7, p = 0.05) were associated with worse survival. RAS mutation was also associated with shorter progression-free survival (HR 1.6, p = 0.01 at 6 months post-operatively), and dMMR/MSI-H status was associated with superior survival (HR 0.3, p = 0.01 at 2 years). dMMR/MSI-H patients receiving immune checkpoint-inhibitors trended toward superior survival.ConclusionsRectal origin, RAS mutations, and BRAF mutations are each associated with poorer survival after CRS-HIPEC for CRPM. Patients with CRPM and dMMR/MSI-H status have superior survival. Further research should evaluate benefits of immune checkpoint-inhibitors in this subgroup.

Background Normal carcinoembryonic antigen (CEA) levels (≤ 2.5 ng/ml) after resection of localized colorectal cancer or liver metastases are associated with improved survival, however, these trends are understudied for colorectal peritoneal metastases (CRPM). Patients and Methods We conducted a retrospective single-institution study of patients with CRPM undergoing cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS/HIPEC) with and without neoadjuvant chemotherapy (NACT). CEA was measured before and after NACT and within 3 months after CRS/HIPEC. Results A total of 253 patients (mean age 55.3 years) with CRPM undergoing CRS/HIPEC had complete CEA data and 191 also underwent NACT with complete data. The median peritoneal carcinomatosis index score (PCI) of the overall cohort was 12 and 82.7% of patients had complete cytoreduction (CC0). In total, 64 (33.5%) patients had normal CEA levels after NACT with a median overall survival (OS) of 45.2 months compared with those with an elevated CEA (26.4 months, p = 0.004). Patients with normal CEA after NACT had a lower PCI found at the time of surgery than those with elevated CEA (10 versus 14, p < 0.001), 68 (26.9%) patients with an elevated preoperative CEA level experienced normalization after CRS/HIPEC, and 118 (46.6%) patients had elevated CEA after CRS/HIPEC. Patients who experienced normalization demonstrated similar OS to patients that had normal CEA levels pre- and post-surgery and improved OS compared with those with elevated postop CEA (median 41.9 versus 47 months versus 17.1 months, respectively, p < 0.001). Conclusions Normal CEA levels after NACT and/or CRS/HIPEC are associated with improved survival for patients with CRPM. Patients that normalize CEA levels after surgery have similar survival to those with normal preoperative levels.

BackgroundMultifocal intrahepatic cholangiocarcinoma (ICC) has traditionally been treated with surgical resection when amenable. Intra-arterial therapy (IAT) for multifocal ICC has not been directly compared with surgical resection.MethodsA single-center, retrospective review of consecutive patients treated for multifocal ICC was conducted. Patients with distant metastases or treatment with systemic chemotherapy alone were excluded. Patients were divided into two groups: surgical resection versus IAT; IAT included transarterial chemoembolization (TACE), transarterial radioembolization (TARE), and hepatic arterial infusion (HAI) pump therapy. Subjects were also analyzed by surgical resection, TACE, and HAI pump therapy.ResultsOverall, 116 patients with multifocal ICC were studied, 57 in the surgical resection group and 59 in the IAT group (TACE = 41, HAI pump = 16, TARE = 2). The IAT group was characterized by a higher incidence of bilobar disease (88.1% vs. 47.4%, p < 0.001), larger tumors (median 10.6 vs. 7.5 cm, p = 0.004), higher incidence of macrovascular invasion (44.1% vs. 24.6%, p = 0.027), and higher rate of nodal metastases (57.6% vs. 28.6%, p = 0.002). Median overall survival for surgical resection was 20 months versus 16 months for IAT (p = 0.627). Multivariate analysis found that macrovascular invasion [hazard ratio (HR) 2.52, 95% confidence interval (CI) 1.56–4.09] and non-receipt of systemic chemotherapy (HR 3.81, 95% CI 2.23–6.52) were independent poor prognostic risk factors. Surgical resection was not associated with a survival advantage over IAT on multivariate analysis (p = 0.242).ConclusionDespite selection bias for use of surgical resection compared with IAT, no survival advantage was conferred in the treatment of multifocal ICC.

BackgroundCytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS HIPEC) can offer significant survival advantage for select patients with colorectal peritoneal metastases (CRPM). Low socioeconomic status (SES) is implicated in disparities in access to care. We analyze the impact of SES on postoperative outcomes and survival at a high-volume tertiary CRS HIPEC center.Patients and MethodsWe conducted a retrospective cohort study examining patients who underwent CRS HIPEC for CRPM from 2000 to 2018. Patients were grouped according to SES. Baseline characteristics, perioperative outcomes, and survival were examined between groups.ResultsA total of 226 patients were analyzed, 107 (47%) low-SES and 119 (53%) high-SES patients. High-SES patients were younger (52 vs. 58 years, p = 0.01) and more likely to be White (95.0% vs. 91.6%, p = 0.06) and privately insured (83% vs. 57%, p < 0.001). They traveled significantly further for treatment and had lower burden of comorbidities and frailty (p = 0.01). Low-SES patients more often presented with synchronous peritoneal metastases (48% vs. 35%, p = 0.05). Following CRS HIPEC, low-SES patients had longer length of stay and higher burden of postoperative complications, 90-day readmission, and 30-day mortality. Median overall survival following CRS HIPEC was worse for low-SES patients (17.8 vs. 32.4 months, p = 0.02). This disparity persisted on multivariate survival analysis (low SES: HR = 1.46, p = 0.03).ConclusionsDespite improving therapies for CRPM, low-SES patients remain at a significant disadvantage. Even patients who overcome barriers to care experience worse short- and long-term outcomes. Improving access and addressing these disparities is crucial to ensure equitable outcomes and improve patient care.

Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemoperfusion (HIPEC) is routinely used to treat certain peritoneal carcinomatoses (PC), but it can be associated with relatively high complication rates, prolonged hospital length of stay, and potential mortality. Our objective was to determine the learning curve (LC) of CRS/HIPEC in our high-volume institution. Methods A total of 370 patients with PC from mucinous appendiceal neoplasms (MAN = 282), malignant peritoneal mesothelioma (MPM = 60), and gastric cancer (GC = 24) were studied. Outcomes analyzed included incomplete cytoreduction (IC), severe morbidity (SM), 60-day mortality, progression-free survival (PFS), and overall survival (OS). Risk-adjusted sequential probability ratio test (RA-SPRT) was employed to assess the LC of CRS/HIPEC for IC and SM using prespecified odds ratio (OR) boundaries derived from previously published data. Risk adjusted-cumulative average probability (RA-CAP) was used to analyze 1-year PFS and 2-year OS. Results Complete cytoreduction, severe morbidity, and 60-day mortality were 84.2, 30, and 1.9 % respectively. Higher simplified peritoneal cancer index was the major independent risk factor for IC, whereas high-grade histology, IC, and diagnosis of MPM and GC (compared with MAN) were predictors of SM after CRS/HIPEC ( p  < 0.05). RA-SPRT showed that approximately 180 cases are needed to achieve the lowest risk of IC and SM. Ninety cases were needed to achieve a steady 1-year PFS and 2-year OS in RA-CAP plots. Conclusions The completeness of cytoreduction, morbidity, and mortality rates for CRS/HIPEC at our institution are comparable to previously reported data. Approximately 180 and 90 procedures are required to improve operative and oncologic outcomes respectively.

Introduction We hypothesized that repeat cytoreductive surgery-hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) for peritoneal metastases (PM) may be associated with suboptimal resection, more frequent postoperative complications, and worse oncologic outcomes. Methods Using a prospectively maintained database, we compared clinicopathologic, perioperative, and oncologic outcome data in patients undergoing single or repeat CRS-HIPEC procedures. The Kaplan–Meier method was used to estimate survival. Multivariate analyses identified associations with perioperative and oncologic outcomes. Results Of the 1294 patients undergoing CRS-HIPEC procedures at our institution, only one CRS-HIPEC procedure (single HIPEC cohort) was performed in 1169 patients (90.3%), whereas 125 patients (9.7%) underwent repeat CRS-HIPEC procedures (repeat HIPEC cohort). Of the 1440 CRS-HIPEC procedures at our institution, a first CRS-HIPEC procedure was performed in 1294 patients (89.9%), whereas subsequent second, third, and fourth CRS-HIPEC procedures were performed in 125 patients (8.7%), 18 patients (1.3%), and 3 patients (0.2%), respectively. Progression-free survival (PFS) following the second CRS-HIPEC procedure was negatively impacted by shorter PFS following the first CRS-HIPEC procedure, independent of other significant variables related to the second procedure, including completeness of cytoreduction and postoperative complications. Patients undergoing multiple CRS-HIPEC procedures were not at higher risk for suboptimal resection or postoperative complications and demonstrated equivalent PFS following each successive procedure compared to the first procedure. Conclusions Repeat CRS-HIPEC procedures for PM were not associated with suboptimal perioperative and oncologic outcomes. Our data confirmed our ability to select patients appropriately for repeat CRS-HIPEC procedures.