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Background: Rosai-Dorfman disease (RDD) is a rare, nonmalignant histiocytosis. It typically occurs in lymph nodes, skin, and soft tissues, but numerous reports of central nervous system involvement exist in the literature. The peripheral nervous system has rarely been involved. In this study, the authors present a case of RDD isolated to the cauda equina. The presentation, management, surgical technique, and adjunctive treatment strategy are described., Observations: A 31-year-old female presented with 6 months of progressive left lower-extremity numbness involving the lateral aspect of the foot and weakness of the left toes. Magnetic resonance imaging of the lumbar spine demonstrated a homogeneously enhancing intradural lesion involving the cauda equina at the L2-3 levels. Histopathology after resection revealed a histiocytic infiltrate, positive for CD68 and S100, and emperipolesis consistent with RDD. No adjuvant therapy was administered, and the patient had full remission at the 1-year follow-up. Only five other cases of intradural RDD lesions of the cauda equina have been reported in the literature., Lessons: RDD of the cauda equina is an especially rare and challenging diagnosis that can mimic other dura-based lesions, such as meningiomas. A definitive diagnosis of RDD relies on pathognomonic histopathological and immunohistochemical findings.

In this randomized phase 2 trial, blockade of cytotoxic T-lymphocyte protein 4 (CTLA-4) with continuation of programmed death protein 1 (PD-1) blockade in patients with metastatic melanoma who had received front-line anti-PD-1 or therapy against programmed cell death 1 ligand 1 and whose tumors progressed was tested in comparison with CTLA-4 blockade alone. Ninety-two eligible patients were randomly assigned in a 3:1 ratio to receive the combination of ipilimumab and nivolumab, or ipilimumab alone. The primary endpoint was progression-free survival. Secondary endpoints included the difference in CD8 T cell infiltrate among responding and nonresponding tumors, objective response rate, overall survival and toxicity. The combination of nivolumab and ipilimumab resulted in a statistically significant improvement in progression-free survival over ipilimumab (hazard ratio = 0.63, 90% confidence interval (CI) = 0.41-0.97, one-sided P = 0.04). Objective response rates were 28% (90% CI = 19-38%) and 9% (90% CI = 2-25%), respectively (one-sided P = 0.05). Grade 3 or higher treatment-related adverse events occurred in 57% and 35% of patients, respectively, which is consistent with the known toxicity profile of these regimens. The change in intratumoral CD8 T cell density observed in the present analysis did not reach statistical significance to support the formal hypothesis tested as a secondary endpoint. In conclusion, primary resistance to PD-1 blockade therapy can be reversed in some patients with the combination of CTLA-4 and PD-1 blockade. Clinicaltrials.gov identifier: NCT03033576 ., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background and Objectives: Visceral angiosarcoma is rare and aggressive, accounting for 2% of soft tissue sarcomas. Using a national data set, we examine determinants of outcomes for patients presenting with this rare disease., Methods: The 2004-2015 National Cancer Database was queried for patients with visceral angiosarcoma. Trends in treatment and outcomes were examined. Factors affecting overall survival (OS) were assessed with log-rank and Cox regression., Results: Eight hundred and ninety-three patients with visceral angiosarcoma were identified (median age 65 years, male [63%], Charlson comorbidity index <1 [86%]). Tumor size was <5 cm in 20.7%, and 34.2% were moderate/high grade. Median OS was 3.8 months (95% CI: 3.4-4.4). By multivariate analysis, increased tumor grade and size, and liver/biliary origin demonstrated worse OS while surgery, radiation, and systemic chemotherapy demonstrated improved OS (all p < 0.001). Survival was similar between patients achieving R0 resection and those with R1/2 resection receiving chemotherapy by Kaplan-Meier analysis., Conclusions: Visceral angiosarcomas are rare tumors with poor outcomes. Liver/biliary origin, higher tumor grade, and larger tumor size demonstrate worse outcomes. While R0 resection remains the mainstay of treatment, patients with R1/R2 resection have improved survival with addition of chemotherapy. Consideration should be made for multimodal therapy in these patients., (© 2022 Wiley Periodicals LLC.)

Background: : Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC) [hazard ratio (HR)=0.84, 95% CI 0.73-0.98, P = 0.022]. Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters., Patients and Methods: Patient tumour tissue was classified as BRAF mutant, KRAS/NRAS (RAS) mutant, or RAS/BRAF wild-type. Left-CRC was defined as the splenic flexure, descending and sigmoid colon, and rectum; right-CRC included transverse, ascending colon, and cecum., Results: RAS/RAF mutation status was available for 85% of patients (912/1072) and primary tumour location was known for 94.4% of patients (1012/1072). A favourable and comparable ramucirumab treatment effect was observed for patients with RAS mutations (OS HR = 0.86, 95% CI 0.71-1.04) and patients with RAS/BRAF wild-type tumours (OS HR = 0.86, 95% CI 0.64-1.14). Among the 41 patients with BRAF-mutated tumours, the ramucirumab benefit was more notable (OS HR = 0.54, 95% CI 0.25-1.13), although, as with the other genetic sub-group analyses, differences were not statistically significant. Progression-free survival (PFS) data followed the same trend. Treatment-by-mutation status interaction tests (OS P = 0.523, PFS P = 0.655) indicated that the ramucirumab benefit was not statistically different among the mutation sub-groups, although the small sample size of the BRAF group limited the analysis. Addition of ramucirumab to FOLFIRI improved left-CRC median OS by 2.5 month over placebo (HR = 0.81, 95% CI 0.68-0.97); median OS for ramucirumab-treated patients with right-CRC was 1.1 month over placebo (HR = 0.97, 95% CI 0.75-1.26). The treatment-by-sub-group interaction was not statistically significant for tumour sidedness (P = 0.276)., Conclusions: In the RAISE study, the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumour sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumours, although the P-values were not statistically significant., Clinicaltrials.gov Number: NCT01183780.

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on "Signs and Symptoms of SCLC" and "Principles of Pathologic Review.", (Copyright © 2018 by the National Comprehensive Cancer Network.)

Background: The management of N2 non-small cell lung cancer (NSCLC) found at operation is controversial. Current guidelines recommend adjuvant chemotherapy or adjuvant chemoradiotherapy. We evaluated whether adjuvant chemoradiotherapy was associated with improved survival compared with adjuvant chemotherapy in patients with N2 NSCLC after complete resection., Methods: We queried the National Cancer Database for all patients with clinical N0, pathologic N2 NSCLC who did not receive preoperative therapy and underwent complete (R0) surgical resection, followed by adjuvant chemotherapy or chemoradiotherapy. We performed propensity matching to create a well-balanced cohort of patients with respect to age, sex, race, comorbidities, treating facility, tumor size, year of diagnosis, and number of positive nodes. Survival was examined using the Kaplan-Meier method with log-rank analysis., Results: We identified 2,031 eligible patients; 1,149 (56.6%) received adjuvant chemotherapy and 882 (43.4%) received chemoradiotherapy. Patients in the unmatched cohort who received chemoradiotherapy tended to be younger (64.2 vs 65.4 years) and to have a comorbidity score of 0 (57.5% vs 52.1%). Median survival was similar (3.9 years with chemoradiotherapy vs 3.8 years with adjuvant chemotherapy, p = 0.518). We then identified 848 well-matched pairs and again did not detect differences in median survival (3.9 years with chemoradiotherapy vs 3.8 years with adjuvant chemotherapy, p = 0.705)., Conclusions: In a large database study, the addition of radiotherapy to adjuvant chemotherapy after resection of N2 NSCLC was not associated with improved survival. Until more definitive data are available, consideration should be given to treating patients with N2 disease detected at resection with adjuvant chemotherapy only., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Nonislet cell tumor hypoglycemia is rare. We highlight the diagnosis and treatment of recurrent severe hypoglycemia in a 49-year-old woman with malignant solitary fibrous tumor of the pleura (Doege-Potter syndrome). The clinical, laboratory and radiologic findings of the case are presented and a brief literature review is provided. Of note, imaging studies showed a large mass in the right hemithorax and pathology and immunehistochemical stains confirmed a malignant solitary fibrous tumor of the pleura. She was a poor surgical candidate owing to a large tumor burden. She was treated with a combination of temozolomide and bevacizumab to which she responded with resolution of hypoglycemia. The treatment of choice for hypoglycemia in patients with the Doege-Potter syndrome is surgical excision. We here report that a combination of temozolomide and bevacizumab may be a viable option in patients with inoperable disease., (Copyright © 2018 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes., Patients and Methods: Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment., Results: Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5-15.6) versus 11.5 months (95% CI 10.1-12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7-14.0) versus 13.1 months (95% CI 11.8-17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers., Conclusions: The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing., Clinical Trials Registration: NCT01183780.

Background: This phase 2, single-arm, multicenter study was designed to determine the treatment activity and safety of single-agent pazopanib in patients with unresectable or metastatic liposarcoma., Methods: Eligible patients had high-grade or intermediate-grade liposarcoma with measurable tumors that were unresectable or metastatic, documented disease progression, and had received any number of prior treatments, excluding previous treatment with a vascular endothelial growth factor inhibitor or a tyrosine kinase inhibitor. Patients received oral pazopanib 800 mg once daily for 28-day cycles. Tumor response was evaluated by local radiology assessments every 3 cycles. The primary endpoint was the progression-free rate (PFR) at 12 weeks (PFR12)., Results: Forty-one patients were enrolled. The PFR12 was 68.3% (95% confidence interval [CI], 51.9%-81.9%), which was significantly greater than the null hypothesis value of 40% (P = .0002). At 24 weeks, 39% of patients (95% CI, 24.2%-55.5%) remained progression free, and 44% experienced tumor control (partial response or stable disease). The median progression-free survival was 4.4 months (95% CI, 3.2-6.5 months), and the median overall survival was 12.6 months (95% CI, 8.5-16.2 months). The most common adverse events overall were nausea (39%), hypertension (36.6%), diarrhea (34.1%), and fatigue (29.3%), which were typically less than grade 3. There were 5 deaths on study (12.2%), 3 of which were from possible complications of therapy., Conclusions: The current study provides evidence of potential activity of pazopanib in the liposarcoma subset of patients with soft tissue sarcoma that was specifically excluded from the phase 3 PALETTE trial of other soft tissue sarcoma types. Cancer 2017;123:4640-4647. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Introduction: The purpose of this study was to evaluate outcomes following pancreaticoduodenectomy(PD) for ampullary adenocarcinoma(AAC)., Methods: We evaluated patients having undergone PD for AAC and the impact of clinical/histopathologic factors and adjuvant therapy(AT) on survival., Results: 52 patients underwent potentially curative PD. Perineural and lymphovascular invasion were associated with decreased survival. There was no difference in survival between patients treated with PD vs. PD+AT, however, AT was more often administered to patients with N1 vs. N0 and stage II/III vs. I disease. Among patients receiving AT, we observed a trend towards improved survival when radiation was included. Recurrence occurred in 7/18(39%) stage I patients, only 2(7%) of which received AT., Conclusion: AT did not improve survival, however was more commonly administered in advanced disease. Stage I patients had high recurrence rates but rarely received AT. Prospective evaluation of appropriate AT regimens and use in early stage patients should be considered., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To characterize ramucirumab exposure-response relationships for efficacy and safety in patients with metastatic colorectal cancer (mCRC) using data from the RAISE study., Methods: Sparse pharmacokinetic samples were collected; a population pharmacokinetic analysis was conducted. Univariate and multivariate Cox proportional hazards models analyzed the relationship between predicted ramucirumab minimum trough concentration at steady state (C min,ss ) and survival. Kaplan-Meier analysis was used to evaluate survival from patients in the ramucirumab plus folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) treatment arm stratified by C min,ss quartiles (Q). An ordered categorical model analyzed the relationship between C min,ss and safety outcomes., Results: Pharmacokinetic samples from 906 patients were included in exposure-efficacy analyses; samples from 905 patients were included in exposure-safety analyses. A significant association was identified between C min,ss and overall survival (OS) and progression-free survival (PFS) (p < 0.0001 for both). This association remained significant after adjusting for baseline factors associated with OS or PFS (p < 0.0001 for both). Median OS was 11.5, 12.9, 16.4, and 16.7, and 12.4 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. Median PFS was 5.4, 4.6, 6.8, 8.5, and 5.2 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. The risk of Grade ≥3 neutropenia was associated with an increase in ramucirumab exposure., Conclusions: Exploratory exposure-response analyses suggested a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in patients from the RAISE study with mCRC over the ranges of exposures achieved by a dose of 8 mg/kg every 2 weeks in combination with FOLFIRI.

Background: The RAISE phase III clinical trial demonstrated that ramucirumab + (folinic acid plus 5-fluorouracil plus irinotecan) FOLFIRI significantly improved overall survival (OS) versus placebo + FOLFIRI for second-line metastatic colorectal carcinoma (mCRC) patients failing bevacizumab- and oxaliplatin-based chemotherapy (hazard ratio [HR] = 0.84, 95% CI = 0.73-0.98, P = 0.022). Post hoc analyses of RAISE patient data examined the association of carcinoembryonic antigen (CEA) subgroups with efficacy parameters., Methods: CEA subgroups (≤10 versus >10 ng/ml) were based on 2X upper limit of normal (ULN) (5 ng/ml). The Kaplan-Meier method estimated the median OS and the progression-free survival (PFS). Log-rank test compared the survival distributions within the subgroups. Hazard ratio (HR) (95% confidence interval [CI]) and treatment-by-subgroup interaction p-values were calculated by Cox proportional hazards model., Results: Ramucirumab treatment prolonged survival for the CEA ≤10 subgroup (HR = 0.68; 95% CI = 0.50-0.92; P = 0.013) and CEA >10 subgroup (HR = 0.90; 95% CI = 0.76-1.07; P = 0.233). However, the ramucirumab OS benefit over placebo was greater for the CEA ≤10 subgroup than for the CEA >10 subgroup (median OS: 3.6 versus 0.8 months greater, respectively). The interaction P-value between CEA level and treatment effect on OS was 0.088. This trend was observed across randomisation strata and to a lesser extent for PFS (P = 0.594)., Conclusions: Although patients in both high- and low-CEA subgroups derive OS and PFS benefits from ramucirumab treatment, the low baseline CEA level may identify a subgroup of patients with mCRC who obtain greater benefit from ramucirumab., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine., Methods: Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01183780.ld, Findings: We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4-14·5) for patients in the ramucirumab group versus 11·7 months (10·8-12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730-0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%])., Interpretation: Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable., Funding: Eli Lilly., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Prostate cancers (PCa) that relapse after androgen deprivation therapies [castration-resistant PCa (CRPC)] express high levels of androgen receptor (AR) and androgen-regulated genes, and evidence from several groups indicates that ErbB family receptor tyrosine kinases [epidermal growth factor (EGF) receptor (EGFR) and ErbB2] may contribute to enhancing this AR activity. We found that activation of these kinases with EGF and heregulin-beta1 rapidly (within 8 hours) decreased expression of endogenous AR and androgen-regulated PSA in LNCaP PCa cells. AR expression was similarly decreased in LAPC4 and C4-2 cells, but not in the CWR22Rv1 PCa cell line. The rapid decrease in AR was not due to increased AR protein degradation and was not blocked by phosphatidylinositol 3-kinase (LY294002) or MEK (UO126) inhibitors. Significantly, AR mRNA levels in LNCaP cells were markedly decreased by EGF and heregulin-beta1, and experiments with actinomycin D to block new mRNA synthesis showed that AR mRNA degradation was increased. AR mRNA levels were still markedly decreased by EGF and heregulin-beta1 in LNCaP cells adapted to growth in androgen-depleted medium, although AR protein levels did not decline due to increased AR protein stability. These findings show that EGFR and ErbB2 can negatively regulate AR mRNA and may provide an approach to suppress AR expression in CRPC.