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PDF file - 88K, Supplemental Figure 3. PBMCs from metastatic melanoma patients treated with ipilimumab depleted of CD14-expressing cells were stimulated to proliferate with OKT-3 and IL-2. CFSE dilution of CD3+ T cells in the culture is measured in the absence of CD14+ cells or with CD14+ cells added back.

PDF file - 101K, Supplemental Figure 4. Different summary statistics can be applied to measure HLA-DR expression on lineage negative, CD14+CD11b+ cells and assess relationship to overall survival (using maximum logrank statistics as described in Methods). CV was used as a self-normalizing measurement that was preferred to eliminate non-biological variation in clinical measurements (e.g. day-to-day variation, differences in sample handling and FACS acquisition).

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PDF file - 103K, Supplemental table 1. Univariate analysis of relationship between m-MDSC and overall survival at pre-treatment baseline and week 6 after ipilimumab treatment at 10mg/kg and 3mg/kg.

Evaluation of myeloid-derived suppressor cells (MDSC), a cell type implicated in T-cell suppression, may inform immune status. However, a uniform methodology is necessary for prospective testing as a biomarker. We report the use of a computational algorithm-driven analysis of whole blood and cryopreserved samples for monocytic MDSC (m-MDSC) quantity that removes variables related to blood processing and user definitions. Applying these methods to samples from patients with melanoma identifies differing frequency distribution of m-MDSC relative to that in healthy donors. Patients with a pretreatment m-MDSC frequency outside a preliminary definition of healthy donor range (+ T-cell expansion following ipilimumab. Algorithm-driven analysis may enable not only development of a novel pretreatment biomarker for ipilimumab therapy, but also prospective validation of peripheral blood m-MDSCs as a biomarker in multiple disease settings. Cancer Immunol Res; 2(8); 812–21. ©2014 AACR.

PDF file - 58K, Supplemental Figure 2. PBMCs available in multiple aliquots were serially analyzed over 3 weeks to evaluate day-to-day reproducibility of CVHLA-DR measures. A standard error of measurement of 1.4% and 0.7%, respectively for QC sample 1 and 2 was detected.

PDF file - 142K, Supplemental Figure 1. m-MDSC gating strategy using various HLA-DR cutoffs based on expression of HLA-DR in lineage positive cells yields differing m-MDSC frequencies and is susceptible to inter-user variability.

Background & Aims: Colorectal cancer (CRC) screening guidelines include screening colonoscopy and sequential high-sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening colonoscopy compared with sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening colonoscopy vs sequential and nonsequential HSgFOBTs. Methods: Participants aged 40–69 years were enrolled at 3 centers representing different clinical settings. Participants were randomized into a single screening colonoscopy arm vs sequential HSgFOBT arm composed of 4–7 rounds. Initial adherence to screening colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SERs) were measured. Results: There were 3523 participants included in the trial; 1761 and 1762 participants were randomized to the screening colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening colonoscopy arm vs 1288 (73.1%) for the HSgFOBT arm after 1 round (relative risk [RR], 1.14; 95% CI, 1.10–1.19; P ≤.001), but only 674 (38.3%) over 4 sequential HSgFOBT rounds (RR, 2.19; 95% CI, 2.05–2.33). Overall adherence to any screening increased to 1558 (88.5%) in the screening colonoscopy arm during the entire study period and 1493 (84.7%) in the HSgFOBT arm (RR, 1.04; 95% CI, 1.02–1.07). Four hundred thirty-six participants (24.7%) crossed over to screening colonoscopy during the first 4 rounds. ADN-SERs were detected in 121 of the 1473 participants (8.2%) in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas detection of ADN-SERs among those who were not sequentially adherent (n = 709) to HSgFOBT was subpar (0.6%) (RR, 14.72; 95% CI, 5.46–39.67) compared with those who were sequentially adherent (3.3%) (n = 647) (RR, 2.52; 95% CI, 1.61–3.98) to HSgFOBT in the first 4 rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (n = 1483), 5.5% of ADN-SERs were detected (RR, 1.50; 95% CI, 1.15–1.96) in the first 4 rounds. Conclusions: Observed adherence to sequential rounds of HSgFOBT was suboptimal compared with a single screening colonoscopy. Detection of ADN-SERs was inferior when nonsequential HSgFOBT adherence was compared with sequential adherence. However, the greatest number of ADN-SERs was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of an HSgFOBT screening program may be enhanced if crossover to screening colonoscopy is permitted. ClinicalTrials.gov, Number: NCT00102011.

BACKGROUND: Biomarkers are needed to estimate which patients benefit most from combination ipilimumab and nivolumab immunotherapy. Rigorous biomarker analyses from prior ipilimumab randomized studies without nivolumab are likely to inform which biomarker analyses should be prioritized when examining patients treated with the combination. For the first time, the current analyses investigate absolute lymphocyte count (ALC) in randomized, controlled trials of ipilimumab without nivolumab to assess whether ALC is prognostic or predictive of ipilimumab treatment benefit. METHODS: Data included patients (n=1136) treated in the two randomized, controlled phase III studies MDX010–20 and CA184–024. ALC was measured at pre-treatment baseline and every 3 weeks for up to 12 weeks, prior to each dose of ipilimumab. Cox proportional hazards models were used to estimate and test associations between ALC measures and overall survival (OS). RESULTS: In both randomized studies, baseline ALC and ALC halfway through induction (at week 6) were associated with OS not only in ipilimumab-treated patients, but also in patients treated with non-ipilimumab control treatments. ALC increased in patients receiving ipilimumab, but this degree of change was not predictive of ipilimumab treatment benefit. CONCLUSIONS: Using data from randomized, controlled studies, we were able to conclude for the first time that baseline ALC, ALC halfway through induction (week 6), and the degree of ALC change from baseline to week 6 are prognostic biomarkers in melanoma patients, and do not appear to be predictive of ipilimumab treatment benefit. This now more comprehensive understanding of ALC as a biomarker from ipilimumab trials will inform subsequent biomarker investigations in ongoing ipilimumab combination studies such as ipilimumab in combination with nivolumab.

Background The use of real-world data to generate evidence requires careful assessment and validation of critical variables before drawing clinical conclusions. Prospective clinical trial data suggest that anatomic origin of colon cancer impacts prognosis and treatment effectiveness. As an initial step in validating this observation in routine clinical settings, we explored the feasibility and accuracy of obtaining information on tumor sidedness from electronic health records (EHR) billing codes. Methods Nine thousand four hundred three patients with metastatic colorectal cancer (mCRC) were selected from the Flatiron Health database, which is derived from de-identified EHR data. This study included a random sample of 200 mCRC patients. Tumor site data derived from International Classification of Diseases (ICD) codes were compared with data abstracted from unstructured documents in the EHR (e.g. surgical and pathology notes). Concordance was determined via observed agreement and Cohen’s kappa coefficient (κ). Accuracy of ICD codes for each tumor site (left, right, transverse) was determined by calculating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), and corresponding 95% confidence intervals, using abstracted data as the gold standard. Results Study patients had similar characteristics and side of colon distribution compared with the full mCRC dataset. The observed agreement between the ICD codes and abstracted data for tumor site for all sampled patients was 0.58 (κ = 0.41). When restricting to the 62% of patients with a side-specific ICD code, the observed agreement was 0.84 (κ = 0.79). The specificity (92–98%) of structured data for tumor location was high, with lower sensitivity (49–63%), PPV (64–92%) and NPV (72–97%). Demographic and clinical characteristics were similar between patients with specific and non-specific side of colon ICD codes. Conclusions ICD codes are a highly reliable indicator of tumor location when the specific location code is entered in the EHR. However, non-specific side of colon ICD codes are present for a sizable minority of patients, and structured data alone may not be adequate to support testing of some research hypotheses. Careful assessment of key variables is required before determining the need for clinical abstraction to supplement structured data in generating real-world evidence from EHRs. Electronic supplementary material The online version of this article (10.1186/s12874-019-0824-7) contains supplementary material, which is available to authorized users.

The-Cancer-Genome-Atlas data on colorectal carcinoma have provided a comprehensive view of the tumor’s genomic alterations and their tumorigenic roles. Tumor morphology, however, has not been fully integrated into the analysis. The aim of this study was to explore relevant associations between tumor morphology and the newly characterized genomic alterations in colorectal carcinoma. Two-hundred-and-seven colorectal carcinomas that had undergone whole exome sequencing as part of The-Cancer-Genome-Atlas project and had adequate virtual images in the cBioPortal for Cancer Genomics http://www.cbioportal.org/ constituted our study population. Upon analysis, a tight association between “microsatellite instability-high histology” and microsatellite instability-high (p

The aim of this study was to evaluate and validate the proposed 8th edition American Joint Committee on Cancer (AJCC) system for T and N staging of pancreatic adenocarcinoma.Investigators have questioned the clinical relevance and reproducibility of previous AJCC staging for pancreatic adenocarcinoma.Prospective databases at Memorial Sloan Kettering (MSK), Massachusetts General Hospital (MGH), and Johns Hopkins Hospital (JHH) were queried for patients who had undergone resection for pancreatic adenocarcinoma. Patients who underwent a margin-negative (R0) resection, and who had previously undergone pathologic review, were included. Patients were staged according to 7th edition AJCC criteria, as well as the proposed 8th edition system that includes different definitions of tumor size (T) and nodal status (N). The dataset was randomly split into training and test sets.Two thousand three hundred eighteen patients were identified who met inclusion criteria. Recursive partitioning on the training set (n = 1551) identified statistically appropriate cutoffs for tumor size (2.2 cm, ≥4.8 cm,) and nodal status (no positive nodes, 1 to 3 positive nodes, ≥4 positive nodes) that supported the proposed 8th edition changes. Median survival in patients staged as T3, N0 by the 7th edition definitions was different between institutions (median Center 1, 24 mo; Center 2, 37 mo; Center 3, 29 mo; P = 0.054). This difference was not observed when patients were staged as T3, N0 by 8th edition criteria. Stage, and stage-specific outcome (7th edition), on the test set revealed a predominance of patients (68%) within the IIB subgroup, and a concordance probability estimate (CPE) of 0.57 for stage-specific survival. When assessed with 8th edition criteria, no stage subgroup had a majority of patients, and the CPE was 0.58.The proposed 8th edition changes for T and N classification were statistically valid and may allow a more reproducible system of T staging. This system also stratifies patients more evenly across stages without sacrificing prognostic accuracy.

Background Resection of hepatocellular carcinoma (HCC) offers a chance of cure, but recurrence is common and survival is often limited. The clinical and pathological characteristics of long-term survivors have not been well studied.

Background Despite the rapid adoption of immunotherapies in advanced non–small cell lung cancer (advNSCLC), knowledge gaps remain about their real‐world (rw) performance. Methods This retrospective, observational, multicenter analysis used the Flatiron Health deidentified electronic health record‐derived database of rw patients with advNSCLC who received treatment with PD‐1 and/or PD‐L1 (PD‐[L]1) inhibitors before July 1, 2017 (N = 5257) and had ≥6 months of follow‐up. The authors investigated PD‐(L)1 line of treatment and PD‐L1 testing rates and the relationship between overall survival (OS) and rw intermediate endpoints: progression‐free survival (rwPFS), rw time to progression (rwTTP), rw time to next treatment (rwTTNT), and rw time to discontinuation (rwTTD). Results First‐line PD‐(L)1 inhibitor use increased from 0% (in the third quarter of 2014 [Q3 2014]) to 42% (Q2 2017) over the study period. PD‐L1 testing also increased (from 3% in Q3 2015 to 70% in Q2 2017). The estimated median OS was 9.3 months (95% CI, 8.9‐9.8 months), and the estimated rwPFS was 3.2 months (95% CI, 3.1‐3.3 months). Longer OS and rwPFS were associated with ≥50% PD‐L1 percentage staining results. Correlations (⍴) between OS and intermediate endpoints were ⍴ = 0.75 (95% CI, 0.73‐0.76) for rwPFS and ⍴ = 0.60 (95% CI, 0.57‐0.63) for rwTTP, and, for treatment‐based intermediate endpoints, correlations were ⍴ = 0.60 (95% CI, 0.56‐0.64) for rwTTNT (N = 856) and ⍴ = 0.81 (95% CI, 0.80‐0.82) for rwTTD. Conclusions The use of first‐line PD‐(L)1 inhibitors and PD‐L1 testing has substantially increased, with better outcomes for patients who have ≥50% PD‐L1 percentage staining. Intermediate rw tumor‐dynamics estimates were moderately correlated with OS in patients with advNSCLC who received immunotherapy, highlighting the need for optimizing and standardizing rw endpoints to enhance the understanding of patient outcomes outside clinical trials., Immunotherapy adoption in non–small cell lung cancer has been rapid. The evaluation of progression endpoints in large cohorts of real‐world patients is feasible and can assess real‐world immunotherapy performance.

Desmoid-type fibromatosis can arise in patients with familial adenomatous polyposis (FAP), therefore patients with desmoids often undergo colonoscopy to rule out FAP. Because finding FAP is uncommon, we sought to define subsets of desmoid patients in whom colonoscopy frequently identified FAP. Patients with desmoid-type fibromatosis were identified from surgery and pathology databases at a single institution, and information on colonoscopy and FAP diagnosis was collected retrospectively. CTNNB1 mutation status was defined by Sanger sequencing and digital polymerase chain reaction of archived specimens. Among 626 patients with desmoids, 26 were diagnosed with FAP. In 20 patients, FAP diagnosis predated the desmoid diagnosis. Among patients without prior FAP diagnosis, 161 underwent colonoscopy, which identified only six cases of FAP (diagnostic yield 3.7%). Yields were substantially higher among patients with four characteristics: age

BACKGROUND Therapeutic antibodies against programmed cell death receptor 1 (PD-1) are considered front-line therapy in metastatic melanoma. The efficacy of PD-1 blockade for patients with biologically distinct melanomas arising from acral and mucosal surfaces has not been well described. METHODS A multi-institutional, retrospective cohort analysis identified adults with advanced acral and mucosal melanoma who received treatment with nivolumab or pembrolizumab as standard clinical practice through expanded access programs or published prospective trials. Objective responses were determined using investigator-assessed Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Progression-free survival and overall survival were assessed using the Kaplan-Meier method. RESULTS Sixty individuals were identified, including 25 (42%) with acral melanoma and 35 (58%) with mucosal melanoma. Fifty-one patients (85%) had received previous therapy, including 77% who had previously received ipilimumab. Forty patients (67%) received pembrolizumab at a dose of 2 mg/kg or 10 mg/kg, and 20 (33%) received nivolumab at a doses ranging from 0.3 to 10 mg/kg every 2 to 3 weeks. The objective response rate was 32% (95% confidence interval, 15%-54%) in patients with acral melanoma and 23% (95% confidence interval, 10%-40%) in those with mucosal melanoma. After a median follow-up of 20 months in the acral melanoma group and 10.6 months in the mucosal melanoma group, the median progression-free survival was 4.1 months and 3.9 months, respectively. Only 2 patients (3%) discontinued treatment because of toxicity. CONCLUSIONS Response rates to PD-1 blockade in patients with acral and mucosal melanomas were comparable to the published rates in patients with cutaneous melanoma and support the routine use of PD-1 blockade in clinical practice. Further investigation is needed to identify the mechanisms of response and resistance to therapy in these subtypes. Cancer 2016;122:3354–3362. © 2016 American Cancer Society.

Myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS) are aggressive, genetically complex sarcomas. The minimum myxoid component used as a criterion for myxofibrosarcoma varies widely, so we determined the optimal myxoid component cutpoints for stratifying outcomes of UPS and myxofibrosarcoma. We also analyzed clinicopathologic factors associated with outcome. Review of a prospective, single-institution database identified 197 patients with primary, high-grade extremity/truncal myxofibrosarcoma or UPS resected during 1992–2013. Histology was reviewed and percent myxoid component determined for each tumor. Disease-specific survival (DSS) and distant recurrence-free survival (DRFS) were analyzed using the Kaplan–Meier method, log-rank test, and Cox regression. Median follow-up for survivors was 6.4 years. In minimum p value analysis of myxoid component, the best cutpoint for both DSS and DRFS was 5 % (adjusted p ≤ 0.001), followed by 70 %. Therefore, sarcomas with

Objectives: The role of maximum standard uptake value (SUVmax) at baseline and after induction chemotherapy (CT) on positron emission tomography (PET) as an imaging biomarker has not been well established in oesophageal squamous cell carcinoma (SCC). In this retrospective analysis, we investigated the prognostic significance of various PET metrics in oesophageal SCC patients treated with induction chemotherapy followed by concurrent chemoradiotherapy (CRT). Methods: A total of 57 patients were treated with CRT; 52 patients received induction chemotherapy and 10 patients underwent surgery following CRT. Scans were independently analysed by a nuclear medicine physician blinded to patient outcome. Using region of interest analysis, SUVmax and metabolic tumour volume (MTV) were calculated for the index lesion and lymph node metastases in each patient. Kaplan–Meier analysis was used to evaluate overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Cox proportional hazards regression was used to assess correlation between outcomes and PET metrics. Results: Median follow-up for those who are alive was 4.4 years, with a median survival for all patients of 2.9 years. The 3-year OS, DFS, DMFS and LRFS rates were 47, 40, 44 and 36%, respectively. Using a pre-established cutoff of a 35% decrease in SUVmax from baseline to post-induction PET, 3-year OS for responders (⩾35% decrease from baseline) was 64%, whereas non-responders (

The majority of US adult cancer patients today are diagnosed and treated outside the context of any clinical trial (that is, in the real world). Although these patients are not part of a research study, their clinical data are still recorded. Indeed, data captured in electronic health records form an ever-growing, rich digital repository of longitudinal patient experiences, treatments, and outcomes. Likewise, genomic data from tumor molecular profiling are increasingly guiding oncology care. Linking real-world clinical and genomic data, as well as information from other co-occurring data sets, could create study populations that provide generalizable evidence for precision medicine interventions. However, the infrastructure required to link, ensure quality, and rapidly learn from such composite data is complex. We outline the challenges and describe a novel approach to building a real-world clinico-genomic database of patients with cancer. This work represents a case study in how data collected during routine patient care can inform precision medicine efforts for the population at large. We suggest that health policies can promote innovation by defining appropriate uses of real-world evidence, establishing data standards, and incentivizing data sharing.

CTNNB1 mutations or APC abnormalities have been observed in ∼85% of desmoids examined by Sanger sequencing and are associated with Wnt/β-catenin activation. We sought to identify molecular aberrations in "wild-type" tumors (those without CTNNB1 or APC alteration) and to determine their prognostic relevance. CTNNB1 was examined by Sanger sequencing in 117 desmoids; a mutation was observed in 101 (86%) and 16 were wild type. Wild-type status did not associate with tumor recurrence. Moreover, in unsupervised clustering based on U133A-derived gene expression profiles, wild-type and mutated tumors clustered together. Whole-exome sequencing of eight of the wild-type desmoids revealed that three had a CTNNB1 mutation that had been undetected by Sanger sequencing. The mutation was found in a mean 16% of reads (vs. 37% for mutations identified by Sanger). Of the other five wild-type tumors sequenced, two had APC loss, two had chromosome 6 loss, and one had mutation of BMI1. The finding of low-frequency CTNNB1 mutation or APC loss in wild-type desmoids was validated in the remaining eight wild-type desmoids; directed miSeq identified low-frequency CTNNB1 mutation in four and comparative genomic hybridization identified APC loss in one. These results demonstrate that mutations affecting CTNNB1 or APC occur more frequently in desmoids than previously recognized (111 of 117; 95%), and designation of wild-type genotype is largely determined by sensitivity of detection methods. Even true CTNNB1 wild-type tumors (determined by next-generation sequencing) may have genomic alterations associated with Wnt activation (chromosome 6 loss/BMI1 mutation), supporting Wnt/β-catenin activation as the common pathway governing desmoid initiation.

The prognostic and predictive implications of programmed death-ligand 1 (PD-L1) is unknown in sarcoma. We sought to examine the immune milieu in sarcoma specimens. We evaluated PD-L1 expression by immunohistochemistry in sarcoma specimens and quantified tumor-infiltrating lymphocytes (TIL). We correlated expression with clinical parameters and outcomes. Fifty sarcoma patients treated at Memorial Sloan Kettering Cancer Center were selected. Using the DAKO PD-L1 immunohistochemistry assay and archival formalin-fixed paraffin-embedded tissue specimens; PD-L1 expression was examined. Macrophage and lymphocyte PD-L1 status was determined qualitatively. TIL was quantified. Associations between PD-L1 expression in tumor, macrophages and lymphocytes, TIL and clinical-pathological characteristics were performed. The median age was 46 years (range, 22-76), and 66% of patients were men. Tumor, lymphocyte and macrophage PD-L1 expression was noted in 12%, 30% and 58%, respectively, with the highest prevalence in gastrointestinal stromal tumors (29%). Lymphocyte and macrophage infiltration was present in 98% and 90%, respectively. There was no association between clinical features, overall survival and PD-L1 expression in tumor or immune infiltrates. Lymphocyte and macrophage infiltration is common in sarcoma, but PD-L1 tumor expression is uncommon in sarcoma with the highest frequency observed in gastrointestinal stromal tumors. There was no association between PD-L1 expression, TIL and clinicopathological features and overall survival; however, this is limited by the heterogenous patient sample and minimal death events in the studied cohort.

Purpose Immunotherapy is a standard of care for children with high-risk neuroblastoma, where bone marrow (BM) is the predominant metastatic site. Early response markers of minimal residual disease (MRD) in the BM that are also predictive of survival could help individualize patient therapies. Patients and Methods After achieving first remission (n = 163), primary refractory disease (n = 102), or second remission (n = 95), children with stage 4 neuroblastoma received anti-GD2 3F8 antibody immunotherapy. BM MRD before 3F8 treatment and after cycle 2 (postMRD) was measured using a four-marker panel (B4GALNT1, PHOX2B, CCND1, and ISL1) by quantitative reverse transcription polymerase chain reaction. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Prognostic variables were tested in both univariable and multivariable analyses, and MRD markers were further assessed individually and in combination as binary composite (postMRD: 0 and 1) and as equal sum (postMRDSum: 0 to 4) using the Cox regression models, and their predictive accuracy was determined by the concordance index. Results When BM was evaluated after cycle 2, individual markers were highly predictive of PFS and OS. The prediction accuracy improved when they were combined in postMRDSum. A multivariable model taking into account all the variables significant in the univariable analyses identified postMRDSum to be independently predictive of PFS and OS. When the model for OS also included missing killer immunoglobulin-like receptor ligand, human antimouse antibody response, and the enrollment disease status, the concordance index was 0.704. Conclusion BM MRD after two cycles of immunotherapy was confirmed as an early response marker and a consistent independent predictor of survival.

Background and Objectives Soft tissue sarcomas of the head and neck (STSHN) comprise a rare group of malignancies. Our objective is to determine the utility of soft tissue sarcoma staging systems within the head and neck, and to validate an individualized soft tissue sarcoma nomogram within head and neck primary sites. Methods Previously-untreated patients with STSHN diagnosed and treated between 1982 and 2012 were eligible (n = 319, median follow-up 46 months). Clinical variables were extracted from a prospectively-maintained database. The performance of AJCC/UICC and MSK staging systems and a soft tissue sarcoma-specific nomogram were assessed. Results Four-year overall survival (OS), disease specific survival (DSS), and recurrence-free survival (RFS) were 72%, 76%, and 71%, respectively. AJCC/UICC and MSK staging systems accurately stratified outcomes (OS, DSS, and RFS; P

Background: Angiosarcomas (AS) are rare tumors of vascular origin with a variable behavior and overall poor prognosis. We sought to assess the outcomes of patients treated for metastatic disease. Methods: We performed a retrospective analysis of 119 patients treated for metastatic AS. Outcomes and efficacy measurements of the first and subsequent lines of treatment were analyzed. Results: Median age was 61 years, and the most frequent primary sites were chest wall/breast (31%), viscera (22%) and head/neck (20%). Seventy-three (61%) and 46 (39%) patients received ≥2 and ≥3 lines of therapy, respectively. The most commonly used agents included taxanes and anthracyclines. Median overall survival was 12.1 months. Median times to tumor progression were 3.5 months for first line, 3.7 months for second line and 2.7 months for third line. Among 48 patients evaluable per RECIST, the overall response rate to first line was 30% and Conclusion: Despite reasonable response rates in the first-line setting, benefit from systemic therapy is short-lived in metastatic AS, and outcomes are poor. Doxorubicin, liposomal doxorubicin and taxanes are reasonable and appropriate choices for monotherapy.

OBJECTIVE. The purpose of this study was to compare the diagnostic performance of 18F-FDG PET/CT and conventional imaging for staging and follow-up of pediatric osteosarcoma and skeletal Ewing sarcoma. MATERIALS AND METHODS. We calculated sensitivity, specificity, and accuracy of PET/CT and conventional imaging (CT, MRI, bone scanning) for sites of disease and number of lesions. Diagnostic benefit, defined as better characterization of lesions, was evaluated on a per-scan basis, comparing PET/CT and conventional imaging. RESULTS. A total of 412 lesions were characterized by imaging in 64 patients (20, osteosarcoma; 44, Ewing sarcoma). For osteosarcoma patients PET/CT was available only at follow-up, where it proved more accurate than conventional imaging for the detection of bone lesions (accuracy, 95% vs 67% for CT and 86% for MRI) and complementary to CT in evaluating lung nodules (sensitivity, 84% vs 94%; specificity, 79% vs 71%) with diagnostic benefit in 18% of examinations. In patients with Ewing sa...

Venous thromboembolism (VTE) is a common complication in cancer patients and anticoagulation (AC) remains the standard of care for treatment. Inferior vena cava (IVC) filters may also used to reduce the risk of pulmonary embolism, either alone or in addition to AC. Although widely used, data are limited on the safety and efficacy of IVC filters in cancer patients. We performed a retrospective review of outcomes after IVC filter insertion in a database of 1270 consecutive patients with cancer-associated pulmonary embolism (PE) at our institution between 2008 and 2009. Outcomes measured included rate of all recurrent VTE, recurrent PE, and overall survival within 12 months. 317 (25%) of the 1270 patients with PE had IVC filters placed within 30 days of the index PE event or prior to the index PE in the setting of prior DVT. Patients with IVC filters had markedly lower overall survival (7.3 months) than the non-IVC filter patients (13.2 months). Filter patients also had a lower rate of AC use at time of initial PE. There was a trend towards higher recurrent VTE in patients with IVC filters (11.9%) compared to non-filter patients (7.7%), but this was not significant (p = 0.086). The risk of recurrent PE was similar between the IVC filter cohort (3.5%) and non-filter group (3.5%, p = 0.99). Cancer patients receiving IVC filters had a similar risk of recurrent PE, but a trend towards more overall recurrent VTE. The filter patients had poorer overall survival, which may reflect a poorer cancer prognosis, and had greater contraindication to AC; therefore these patients likely had a higher inherent risk for recurrent VTE. A prospective study would be helpful for further clarification on the partial reduction in the recurrent PE risk by IVC filter placement in cancer patients.

While previously thought to be clinically indolent, recent data suggest significant late metastatic capacity of solitary fibrous tumors (SFTs). We define prognostic factors for recurrence and disease-specific death (DSD) in resected primary SFTs. Resected primary SFTs from 1982 to 2015 were identified from a prospective, single institutional database. Risk factors for local (LR) and distant recurrence (DR), and DSD were assessed using competing risk analysis. A total of 219 patients with median follow-up of 6.1 (0.1–22) years were included. Five- and 10-year cumulative DSD was 9 and 11%, respectively. Size greater than the median 8 cm, gender, location, and complete gross resection were significantly associated with DSD (p

OBJECTIVE To determine the prognostic significance of histologic type/subtype in a large series of patients with primary resected retroperitoneal sarcoma. BACKGROUND The histologic diversity and rarity of retroperitoneal sarcoma has hampered the ability to predict patient outcome. METHODS From a single-institution, prospective database, 675 patients treated surgically for primary, nonmetastatic retroperitoneal sarcoma during 1982 to 2010 were identified and histologic type/subtype was reviewed. Clinicopathologic variables were analyzed for association with disease-specific death (DSD), local recurrence (LR), and distant recurrence (DR). RESULTS Median follow-up for survivors was 7.5 years. The predominant histologies were well-differentiated liposarcoma, dedifferentiated liposarcoma, and leiomyosarcoma. Five-year cumulative incidence of DSD was 31%, and factors independently associated with DSD were R2 resection, resection of 3 or more contiguous organs, and histologic type. Five-year cumulative incidence for LR was 39% and for DR was 24%. R1 resection, age, tumor size, and histologic type were independently associated with LR; size, resection of 3 or more organs, and histologic type were independently associated with DR. Liposarcoma and leiomyosarcoma were associated with late recurrence and DSD (as long as 15 years from diagnosis). For solitary fibrous tumor, LR was uncommon (

Purpose The use of intensity-modulated radiation therapy (IMRT) in the treatment of soft tissue sarcoma (STS) of the extremity is increasing, but no large-scale direct comparison has been reported between conventional external-beam radiation therapy (EBRT) and IMRT. Methods Between January 1996 and December 2010, 319 consecutive adult patients with primary nonmetastatic extremity STS were treated with limb-sparing surgery and adjuvant radiotherapy (RT) at a single institution. Conventional EBRT was used in 154 patients and IMRT in 165 with similar dosing schedules. Median follow-up time for the cohort was 58 months. Results Treatment groups were comparable in terms of tumor location, histology, tumor size, depth, and use of chemotherapy. Patients treated with IMRT were older (P = .08), had more high-grade lesions (P = .05), close (< 1 mm) or positive margins (P = .04), preoperative radiation (P < .001), and nerve manipulation (P = .04). Median follow-up was 90 months for patients treated with conventional EBRT and 42 months for patients treated with IMRT. On multivariable analysis adjusting for patient age and tumor size, IMRT retained significance as an independent predictor of reduced LR (hazard ratio = 0.46; 95% CI, 0.24 to 0.89; P = .02). Conclusion Despite a preponderance of higher-risk features (especially close/positive margin) in the IMRT group, IMRT was associated with significantly reduced local recurrence compared with conventional EBRT for primary STS of the extremity.

Evaluation of myeloid-derived suppressor cells (MDSC), a cell type implicated in T-cell suppression, may inform immune status. However, a uniform methodology is necessary for prospective testing as a biomarker. We report the use of a computational algorithm-driven analysis of whole blood and cryopreserved samples for monocytic MDSC (m-MDSC) quantity that removes variables related to blood processing and user definitions. Applying these methods to samples from patients with melanoma identifies differing frequency distribution of m-MDSC relative to that in healthy donors. Patients with a pretreatment m-MDSC frequency outside a preliminary definition of healthy donor range (

Melanoma patients with palpable nodal disease in more than one basin have a worse prognosis than those with single-basin disease. Little is known about the outcome of patients with microscopically positive nodal disease in more than one basin, or how they are currently managed at tertiary referral centers. We identified 97 patients with positive sentinel lymph nodes (SLNs) in more than one lymph node basin from 1994 to 2010 from three tertiary care centers. Clinical and pathologic outcome variables were analyzed. Ninety-seven patients (72 men, 25 women) were identified with at least one positive SLN in at least two node basins. Most primary tumors were truncal (68, 70 %) followed by extremity (16, 17 %) and head/neck (13, 13 %). The median Breslow depth was 3.2 mm (range 0.8–12 mm), and 49 (51 %) were ulcerated. The most frequently involved nodal basins were the axilla (112, 57 %), neck (40, 20 %), and groin (24, 12 %). Seventy-seven percent (153 of 198) of all positive SLN basins underwent completion lymph node dissection (CLND). Most patients (54, 56 %) developed recurrent disease, with a median time to recurrence of 20 months. The majority of first recurrences were distant (42, 43 %), followed by regional nonnodal metastases (17, 18 %) and regional nodal metastases (16, 16 %). There was no significant difference in median overall survival between CLND versus no-CLND groups (45 vs. 30 months, respectively). Most melanoma patients with more than one SLN-positive basin are currently managed with CLND. Outcomes after CLND and no CLND are similarly poor; therefore, consideration of close nodal observation may be more appropriate.

The benefit of completion lymph node dissection (CLND) in melanoma patients with a positive sentinel lymph node (SLN) remains unknown.We identified patients with a positive SLN from 1994 to 2012. Patient and tumor characteristics, reasons for not undergoing CLND, patterns of recurrence, and melanoma-specific survival data were analyzed.Of 4,310 patients undergoing SLN biopsy (SLNB), 495 (11 %) had a positive SLN-167 (34 %) patients underwent nodal observation and 328 (66 %) had immediate CLND. Patients in the no-CLND group were older (66 vs. 56 years; p0.001) and more likely to have lower extremity lesions (57 vs. 42 %; p = 0.006). There were no differences in tumor thickness, Clark level of invasion, ulceration, or SLN tumor burden. Median follow-up was 23 and 80 months for the no-CLND and CLND groups, respectively, and median time to recurrence was similar at 9 and 12 months, respectively (p = 0.48). There was no difference in local and in transit recurrence rates between groups (16 %, no CLND, and 18 %, CLND; p = 0.48). Nodal disease as a site of first recurrence occurred in 15 % of patients in the no-CLND group and 6 % of CLND patients (p = 0.002). In contrast, systemic recurrences occurred in 8 % of no-CLND patients compared with 27 % of CLND patients (p0.001). While median recurrence-free survival was higher after CLND (34.5 vs. 20.9 months; p = 0.02), melanoma-specific survival was similar (not reached, no CLND vs. 110 months, CLND; p = 0.09).Immediate CLND after a positive SLNB is associated with fewer initial nodal basin recurrences but similar melanoma-specific survival. These results support ongoing equipoise in the Multicenter Selective Lymphadenectomy Trial II (MSLT-II).

Anti-G(D2) murine antibody 3F8 plus subcutaneously (sc) administered granulocyte-macrophage colony-stimulating factor (GM-CSF) was used against primary refractory neuroblastoma in metastatic osteomedullary sites. Large study size and long follow-up allowed assessment of prognostic factors in a multivariate analysis not reported with other anti-G(D2) antibodies. In a phase II trial, 79 patients without prior progressive disease were treated for persistent osteomedullary neuroblastoma documented by histology and/or metaiodobenzyl-guanidine (MIBG) scan. In the absence of human antimouse antibody, 3F8 + scGM-CSF cycles were repeated up to 24 months. Minimal residual disease (MRD) in bone marrow was measured by quantitative reverse transcription-polymerase chain reaction pre-enrollment and post-cycle #2, before initiation of 13-cis-retinoic acid. Study endpoints were: (i) progression-free survival (PFS) compared with the predecessor trial of 3F8 plus intravenously administered (iv) GM-CSF (26 patients) and (ii) impact of MRD on PFS. Using all 105 patients from the two consecutive 3F8 + GM-CSF trials, prognostic factors were analyzed by multivariate Cox regression model. Complete response rates to 3F8 + scGM-CSF were 87% by histology and 38% by MIBG. Five-year PFS was 24 ± 6%, which was significantly superior to 11 ± 7% with 3F8 + ivGM-CSF (p = 0.002). In the multivariate analysis, significantly better PFS was associated with R/R or H/R FCGR2A polymorphism, sc route of GM-CSF and early MRD response. MYCN amplification was not prognostic. Complement consumption was similar with either route of GM-CSF. Toxicities were manageable, allowing outpatient treatment. 3F8 + scGM-CSF is highly active against chemoresistant osteomedullary neuroblastoma. MRD response may be an indicator of tumor sensitivity to anti-G(D2) immunotherapy. Correlative studies highlight the antineoplastic potency of myeloid effectors.

To compare the features of bone metastases at computed tomography (CT) to tracer uptake at fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and fluorine 18 16β-fluoro-5-dihydrotestosterone (FDHT) PET and to determine associations between these imaging features and overall survival in men with castration-resistant prostate cancer.This is a retrospective study of 38 patients with castration-resistant prostate cancer. Two readers independently evaluated CT, FDG PET, and FDHT PET features of bone metastases. Associations between imaging findings and overall survival were determined by using univariate Cox proportional hazards regression.In 38 patients, reader 1 detected 881 lesions and reader 2 detected 867 lesions. Attenuation coefficients at CT correlated inversely with FDG (reader 1: r = -0.3007; P.001; reader 2: r = -0.3147; P.001) and FDHT (reader 1: r = -0.2680; P = .001; reader 2: r = -0.3656; P.001) uptake. The number of lesions on CT scans was significantly associated with overall survival (reader 1: hazard ratio [HR], 1.025; P = .05; reader 2: HR, 1.021; P = .04). The numbers of lesions on FDG and FDHT PET scans were significantly associated with overall survival for reader 1 (HR, 1.051-1.109; P.001) and reader 2 (HR, 1.026-1.082; P ≤ .009). Patients with higher FDHT uptake (lesion with the highest maximum standardized uptake value) had significantly shorter overall survival (reader 1: HR, 1.078; P = .02; reader 2: HR, 1.092; P = .02). FDG uptake intensity was not associated with overall survival (reader 1, P = .65; reader 2, P = .38).In patients with castration-resistant prostate cancer, numbers of bone lesions on CT, FDG PET, and FDHT PET scans and the intensity of FDHT uptake are significantly associated with overall survival.

The prognosis of signet ring cell (SRC) gastric adenocarcinoma is regarded as poor, although studies addressing outcomes in relation to non-SRC tumors are conflicting. Our objective was to compare the survival of SRC tumors with stage-matched intestinal-type tumors in a cohort of Western patients. Review of a prospectively maintained database identified 569 patients undergoing curative resection (R0) from 1990 to 2009. Patients were divided into three histologic groups on the basis of the Lauren classification: SRC (n = 210), intestinal well- or moderately differentiated (WMD, n = 242) disease, and intestinal poorly differentiated (PD, n = 117) disease. Patient demographics, clinicopathologic features, and postoperative outcomes were determined. Stage-stratified disease-specific mortality was calculated and multivariate analysis performed. When compared with WMD and PD tumors, SRC tumors were associated with younger age (63 years SRC vs. 71 years WMD and 72 years PD, p

Background Tumor-associated macrophages (TAMs) support growth in most human cancers, with the notable exception of colorectal adenocarcinoma, in which TAM infiltration of primary tumors is correlated with a better outcome. The importance of TAMs in colorectal liver metastases (CLM) is unknown. Methods Using a tissue microarray of CLM resected at their institution from 1998 to 2000, the authors quantified immune marker expression by immunohistochemistry (IHC) using Metamorph Image Analysis software. Findings showed that CD68, CD3, CD4, CD8, FoxP3, and MHC-I were correlated with overall survival (OS) and disease-free survival (DFS). Results Tumor cores from 158 patients were analyzed. The median follow-up period was 117 months for survivors (n = 39). The univariate analysis showed a significant positive association between DFS and CD4+ (p = 0.025) and CD68+ (p = 0.007). The findings showed a significant positive correlation of OS with CD4+ (p = 0.042), whereas the correlation with CD68+ was not significant (p = 0.17). Cutoffs were determined to dichotimize each marker for the highest log-rank statistic. Patients with CD4high had a median OS of 115 months and DFS of 41 months (p = 0.007 compared with 40 and 16 months, respectively, for patients with CD4low (p = 0.022). Patients with CD68high had a median OS of 50 months and a median DFS of 25 months (p = 0.67) compared with 43 and 15 months (p = 0.028). In the multivariate analysis of factors affecting DFS, high CD68 was associated with longer DFS (hazard ratio [HR], 0.63, 95% confidence interval [CI], 0.43-0.94; p = 0.02), independently of clinicopathologic variables and CD4. Conclusions High TAM infiltration in resected CLM is associated with better outcome, independently of known clinicopathologic and immune predictors. This suggests that TAM depletion, which is being tested clinically in other cancers, may be detrimental in CLM.

Background: Radiation-associated breast angiosarcoma (RT-AS) is an uncommon malignancy with an incidence of less than 1 % of all soft tissue sarcomas. The overall prognosis is quite dismal with high rates of recurrences and poor overall survival. There is an obvious paucity of data regarding clinical outcomes of patients with breast RT-AS. Methods: We identified all patients with RT-AS treated at the Memorial Sloan-Kettering Cancer Center between 1982–2011 and collected their correlative clinical information. Results: We identified 79 women with RT-AS with a median age of 68 (range 36–87). The median interval between radiation and development of RT-AS was 7 years (range 3–19). The median time to local and distant recurrence was 1.29 years (95 % CI 0.72–NA) and 2.48 years (95 % CI 1.29–NA), respectively. The median disease-specific survival was 2.97 years (95 % CI 2.21–NA). Independent predictors of worse disease-specific survival included age ⩾68 years (HR 3.11, 95 % CI 1.20–8.08, P=0.020) and deep tumors (HR 3.23, 95 % CI 1.02–10.21, P=0.046.) Conclusion: RT-AS has high local/distant recurrence rates, limited duration on standard chemotherapy and poor disease-specific survival.

In the analysis of time-to-event data, the problem of competing risks occurs when an individual may experience one, and only one, of m different types of events. The presence of competing risks complicates the analysis of time-to-event data, and standard survival analysis techniques such as Kaplan-Meier estimation, log-rank test and Cox modeling are not always appropriate and should be applied with caution. Fine and Gray developed a method for regression analysis that models the hazard that corresponds to the cumulative incidence function. This model is becoming widely used by clinical researchers and is now available in all the major software environments. Although model selection methods for Cox proportional hazards models have been developed, few methods exist for competing risks data. We have developed stepwise regression procedures, both forward and backward, based on AIC, BIC, and BICcr (a newly proposed criteria that is a modified BIC for competing risks data subject to right censoring) as selection criteria for the Fine and Gray model. We evaluated the performance of these model selection procedures in a large simulation study and found them to perform well. We also applied our procedures to assess the importance of bone mineral density in predicting the absolute risk of hip fracture in the Women's Health Initiative-Observational Study, where mortality was the competing risk. We have implemented our method as a freely available R package called crrstep.

Consolidation with allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides a survival benefit to patients with acute lymphoblastic leukemia (ALL). We have previously reported comparable survival and relapse rates after T cell–depleted (TCD) allo-HSCT compared with unmodified transplantations for acute myelogenous leukemia, myelodysplastic syndrome, and non-Hodgkin lymphoma with significantly decreased graft-versus-host disease (GVHD). We performed a 56-patient retrospective study to evaluate TCD allo-HSCT for the treatment of ALL after myeloablative total body irradiation–based therapy. The 2-year and 5-year overall survival rates for patients with ALL after TCD allo-HSCT were 0.39 (95% confidence interval [CI], 0.26-0.52) and 0.32 (95% CI, 0.19-0.44), respectively, and the 2-year and 5-year disease-free survival rates were 0.38 (95% CI, 0.25-0.50) and 0.32 (95% CI, 0.20-0.44). There was a trend toward improved survival of patients who underwent TCD allo-HSCT in first complete remission compared with those who did so in other remission states. The cumulative incidence of grade II-IV acute GVHD at 1 year was 0.20 (95% CI, 0.10-0.31), and no patients developed grade IV acute GVHD. The cumulative incidence of chronic GVHD in 41 evaluable patients at 2 and 5 years was 0.15 (95% CI, 0.04-0.26), and that of extensive chronic GVHD at 2 and 5 years was 0.05 (95% CI, 0-11.6). We demonstrate OS and DFS rates that compare favorably to unmodified allo-HSCT with lower rates of GVHD.

BackgroundThe response of rectal cancers to neoadjuvant chemoradiation (CRT) is variable, but tools to predict response remain lacking. We evaluated whether KRAS and TP53 mutations are associated with pathologic complete response (pCR) and lymph node metastasis after adjusting for neoadjuvant regimen.MethodsRetrospective analysis of 229 pretreatment biopsies from patients with stage II/III rectal cancer was performed. All patients received CRT. Patients received 0-8 cycles of FOLFOX either before or after CRT, but prior to surgical excision. A subset was analyzed to assess concordance between mutation calls by Sanger Sequencing and a next-generation assay.ResultsA total of 96 tumors (42%) had KRAS mutation, 150 had TP53 mutation (66%), and 59 (26%) had both. Following neoadjuvant therapy, 59 patients (26%) achieved pCR. Of 133 KRAS wild-type tumors, 45 (34%) had pCR, compared with 14 of 96 (15%) KRAS mutant tumors (p=.001). KRAS mutation remained independently associated with a lower pCR rate on multivariable analysis after adjusting for clinical stage, CRT-to-surgery interval and cycles of FOLFOX (OR 0.34; 95% CI 0.17-0.66, p&nbsp

// T. Peter Kingham 2, * , Hoang C.B. Nguyen 1, * , Jian Zheng 2 , Ioannis T. Konstantinidis 2 , Eran Sadot 2 , Jinru Shia 3 , Deborah Kuk 4 , Steven Zhang 1 , Leonard Saltz 5 , Michael I. D’Angelica 2 , William R. Jarnagin 2 , Hani Goodarzi 6, 7, 8 , Sohail F. Tavazoie 1, 5 1 Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA 2 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA 3 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 4 Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA 5 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA 6 Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA, USA 7 Department of Urology, University of California, San Francisco, San Francisco, CA, USA 8 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA * These authors contributed equally to this work Correspondence to: T. Peter Kingham, email: kinghamt@mskcc.org Hani Goodarzi, email: hani.goodarzi@ucsf.edu Sohail F. Tavazoie, email: stavazoie@mail.rockefeller.edu Keywords: microRNA, miR-203, colorectal liver metastasis, survival, resection Received: July 25, 2016 Accepted: November 14, 2016 Published: December 07, 2016 ABSTRACT Background: Resection of colorectal liver metastasis (CRLM) can be curative. Predicting which patients may benefit from resection, however, remains challenging. Some microRNAs (miRNAs) become deregulated in cancers and contribute to cancer progression. We hypothesized that miRNA expression can serve as a prognostic marker of survival after CRLM resection. Results: MiR-203 was significantly overexpressed in tumors of short-term survivors compared to long-term survivors. R1/R2 margin status and high clinical risk score (CRS) were also significantly associated with short-term survival (both p = 0.001). After adjusting for these variables, higher miR-203 expression remained an independent predictor of shorter survival ( p = 0.010). In the serum cohort, high CRS and KRAS mutation were significantly associated with short-term survival ( p = 0.005 and p = 0.026, respectively). After adjusting for CRS and KRAS status, short-term survivors were found to have significantly higher miR-203 levels ( p = 0.016 and p = 0.033, respectively). Materials and Methods: We employed next-generation sequencing of small-RNAs to profile miRNAs in solid tumors obtained from 38 patients who underwent hepatectomy for CRLM. To validate, quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was performed on 91 tumor samples and 46 preoperative serum samples. Conclusions: After CRLM resection, short-term survivors exhibited significantly higher miR-203 levels relative to long-term survivors. MiR-203 may serve as a prognostic biomarker and its prognostic capacity warrants further investigation.

Despite the success of monotherapies based on blockade of programmed cell death 1 (PD-1) in human melanoma, most patients do not experience durable clinical benefit. Pre-existing T-cell infiltration and/or the presence of PD-L1 in tumours may be used as indicators of clinical response; however, blood-based profiling to understand the mechanisms of PD-1 blockade has not been widely explored. Here we use immune profiling of peripheral blood from patients with stage IV melanoma before and after treatment with the PD-1-targeting antibody pembrolizumab and identify pharmacodynamic changes in circulating exhausted-phenotype CD8 T cells (Tex cells). Most of the patients demonstrated an immunological response to pembrolizumab. Clinical failure in many patients was not solely due to an inability to induce immune reinvigoration, but rather resulted from an imbalance between T-cell reinvigoration and tumour burden. The magnitude of reinvigoration of circulating Tex cells determined in relation to pretreatment tumour burden correlated with clinical response. By focused profiling of a mechanistically relevant circulating T-cell subpopulation calibrated to pretreatment disease burden, we identify a clinically accessible potential on-treatment predictor of response to PD-1 blockade.

BackgroundAge is a critical factor in outcome for patients with well-differentiated thyroid cancer. Currently, age 45 years is used as a cutoff in staging, although there is increasing evidence to suggest this may be too low. The aim of this study was to assess the potential for changing the cut point for the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) staging system from 45 years to 55 years based on a combined international patient cohort supplied by individual institutions.MethodsA total of 9484 patients were included from 10 institutions. Tumor (T), nodes (N), and metastasis (M) data and age were provided for each patient. The group was stratified by AJCC/UICC stage using age 45 years and age 55 years as cutoffs. The Kaplan-Meier method was used to calculate outcomes for disease-specific survival (DSS). Concordance probability estimates (CPE) were calculated to compare the degree of concordance for each model.ResultsUsing age 45 years as a cutoff, 10-year DSS rates for stage I-IV were 99.7%, 97.3%, 96.6%, and 76.3%, respectively. Using age 55 years as a cutoff, 10-year DSS rates for stage I-IV were 99.5%, 94.7%, 94.1%, and 67.6%, respectively. The change resulted in 12% of patients being downstaged, and the downstaged group had a 10-year DSS of 97.6%. The change resulted in an increase in CPE from 0.90 to 0.92.ConclusionsA change in the cutoff age in the current AJCC/UICC staging system from 45 years to 55 years would lead to a downstaging of 12% of patients, and would improve the statistical validity of the model. Such a change would be clinically relevant for thousands of patients worldwide by preventing overstaging of patients with low-risk disease while providing a more realistic estimate of prognosis for those who remain high risk.

In recent years, increasingly sophisticated tools have allowed for more complex robotic surgery. Robotic hepatectomy, however, is still in its infancy. Our goals were to examine the adoption of robotic hepatectomy and to compare outcomes between open and robotic liver resections. The robotic hepatectomy experience of 64 patients was compared to a modern case-matched series of 64 open hepatectomy patients at the same center. Matching was according to benign/malignant diagnosis and number of segments resected. Patient data were obtained retrospectively. The main outcomes and measures were operative time, estimated blood loss, conversion rate (robotic to open), Pringle maneuver use, single non-anatomic wedge resection rate, resection margin size, complication rates (infectious, hepatic, pulmonary, cardiac), hospital stay length, ICU stay length, readmission rate, and 90-day mortality rate. Sixty-four robotic hepatectomies were performed in 2010–2014. Forty-one percent were segmental and 34 % were wedge resections. There was a 6 % conversion rate, a 3 % 90-day mortality rate, and an 11 % morbidity rate. Compared to 64 matched patients who underwent open hepatectomy (2004–2012), there was a shorter median OR time (p = 0.02), lower median estimated blood loss (p

Despite their favorable prognosis, 10-20% of acute promyelocytic leukemia (APL) patients relapse. Reinduction therapy is often followed by autologous hematopoietic cell transplantation (auto-HCT). Arsenic trioxide (ATO) has become part of standard reinduction and is often followed by auto-HCT. Data on patients in CR2 were collected from two large transplant registries (Center for International Blood and Marrow Transplant Research (CIBMTR) and European Group for Blood and Marrow Transplant (EBMT)) and two specialty referral centers. The outcome of patients in CR2 who received only ATO-based therapy as reinduction was retrospectively compared with those who got an auto-HCT, with or without ATO. Prognostic factors included age, disease risk, extramedullary disease and duration of CR1. Of 207 evaluable patients, the median age was 31.5 years, 15.3% had extramedullary disease and median WBC at diagnosis was 4.8 × 10(9)/L. Sixty-seven patients received ATO alone and 140 underwent auto-HCT. The groups were comparable for age, gender, extramedullary disease, risk group and duration of CR1. At 5 years, overall survival (OS) was 42% and 78% for the ATO-only and auto-HCT groups, respectively (P

Background. Leiomyosarcomas (LMS) represent a heterogeneous subset of soft tissue sarcomas. Factors influencing prognosis for patients with metastatic extrauterine LMS (euLMS) are not well described. Limited data are available regarding responses to systemic therapy.Methods. We collected clinical and pathologic information for all patients with metastatic euLMS seen at Memorial Sloan Kettering Cancer Center between 1989 and 2012. Objective responses to first-line therapy were analyzed for a subset of patients with available baseline and on-treatment imaging using RECIST 1.1.Results. 215 patients with metastatic euLMS had a median overall survival (OS) of 2.6 years from the time of metastasis. Older age, male sex, and ≥3 initial sites of metastasis were associated with worse OS on multivariate analysis. Objective response rate (ORR) inN=113was 19% overall and 25%, 26%, and 25% for gemcitabine, gemcitabine plus docetaxel, and anthracycline-alkylator combinations. Patients whose tumors objectively responded to first-line therapy had a lower risk of death versus those who did not (Hazard Ratio 0.46; 95% CI: 0.26–0.79,p=0.005).Conclusions. Anthracycline- and gemcitabine-based regimens have similar activity in this cohort of euLMS. Prognostic factors for OS include older age, male sex, and ≥3 initial sites.

UNLABELLED Study Type--Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Radiation Therapy for prostate cancer can increase the risk for the development of second cancers after treatment. This study highlights the fact that such second cancers within the pelvis do occur but are not as common as previously reported. In this report we also note that even among patients who develop second cancers, if detected earlier, the majority are alive 5 years after the diagnosis. OBJECTIVE • To report on the incidence of secondary malignancy (SM) development after external beam radiotherapy (EBRT) and brachytherapy (BT) for prostate cancer and to compare this with a cohort contemporaneously treated with radical prostatectomy (RP). MATERIALS AND METHODS • Between 1998 and 2001, 2658 patients with localized prostate cancer were treated with RP (n = 1348), EBRT (n = 897) or BT (n = 413). • Using the RP cohort as a control we compared the incidence of SMs, such as rectal or bladder cancers noted within the pelvis, and the incidence of extrapelvic SMs. RESULTS • The 10-year SM-free survival for the RP, BT and EBRT cohorts were 89%, 87%, and 83%, respectively (RP vs EBRT, P = 0.002; RP vs BT, P = 0.37). • The 10-year likelihoods for bladder or colorectal cancer SM development in the RP, BT and EBRT groups were 3%, 2% and 4%, respectively (P = 0.29). • Multivariate analysis of predictors for development of all SMs showed that older age (P = 0.01) and history of smoking (P < 0.001) were significant predictors for the development of a SM, while treatment intervention was not found to be a significant variable. • Among 243 patients who developed a SM, the 5-year likelihood of SM-related mortality among patients with SMs in the EBRT and BT groups was 43.7% and 15.6%, respectively, compared with 26.3% in the RP cohort; P = 0.052). CONCLUSIONS • The incidence of SM after radiotherapy was not significantly different from that after RP when adjusted for patient age and smoking history. • The incidence of bladder and rectal cancers was low for both EBRT- and BT-treated patients. • Among patients who developed a SM, the likelihood of mortality related to the SM was not significantly different among the treatment cohorts.

Background Subtypes of melanoma, such as mucosal, uveal, and acral, are believed to result in worse prognoses than nonacral cutaneous melanoma. After a diagnosis of distant metastatic disease, however, the overall survival of patients with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma has not been directly compared. Materials and methods We conducted a single-center, retrospective analysis of 3,454 patients with melanoma diagnosed with distant metastases from 2000 to 2013, identified from a prospectively maintained database. We examined melanoma subtype, date of diagnosis of distant metastases, age at diagnosis of metastasis, gender, and site of melanoma metastases. Results Of the 3,454 patients (237 with mucosal, 286 with uveal, 2,292 with nonacral cutaneous, 105 with acral cutaneous, and 534 with unknown primary melanoma), 2,594 died. The median follow-up was 46.1 months. The median overall survival for those with mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma was 9.1, 13.4, 11.4, 11.7, and 10.4 months, respectively. Patients with uveal melanoma, cutaneous melanoma (acral and nonacral), and unknown primary melanoma had similar survival, but patients with mucosal melanoma had worse survival. Patients diagnosed with metastatic melanoma in 2006-2010 and 2011-2013 had better overall survival than patients diagnosed in 2000-2005. In a multivariate model, patients with mucosal melanoma had inferior overall survival compared with patients with the other four subtypes. Conclusion Additional research and advocacy are needed for patients with mucosal melanoma because of their shorter overall survival in the metastatic setting. Despite distinct tumor biology, the survival was similar for those with metastatic uveal melanoma, acral, nonacral cutaneous, and unknown primary melanoma. Implications for practice Uveal, acral, and mucosal melanoma are assumed to result in a worse prognosis than nonacral cutaneous melanoma or unknown primary melanoma. No studies, however, have been conducted assessing the overall survival of patients with these melanoma subtypes starting at the time of distant metastatic disease. The present study found that patients with uveal, acral, nonacral cutaneous, and unknown primary melanoma have similar overall survival after distant metastases have been diagnosed. These findings provide information for oncologists to reconsider previously held assumptions and appropriately counsel patients. Patients with mucosal melanoma have worse overall survival and are thus a group in need of specific research and advocacy.