Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Melanoma staging: Evidence-based changes in the American Joint Committee on Cancer eighth edition cancer staging manual.

Answer questions and earn CME/CNE To update the melanoma staging system of the American Joint Committee on Cancer (AJCC) a large database was assembled comprising >46,000 patients from 10 centers worldwide with stages I, II, and III melanoma diagnosed since 1998. Based on analyses of this new database, the existing seventh edition AJCC stage IV database, and contemporary clinical trial data, the AJCC Melanoma Expert Panel introduced several important changes to the Tumor, Nodes, Metastasis (TNM) classification and stage grouping criteria. Key changes in the eighth edition AJCC Cancer Staging Manual include: 1) tumor thickness measurements to be recorded to the nearest 0.1 mm, not 0.01 mm; 2) definitions of T1a and T1b are revised (T1a, <0.8 mm without ulceration; T1b, 0.8-1.0 mm with or without ulceration or <0.8 mm with ulceration), with mitotic rate no longer a T category criterion; 3) pathological (but not clinical) stage IA is revised to include T1b N0 M0 (formerly pathologic stage IB); 4) the N category descriptors "microscopic" and "macroscopic" for regional node metastasis are redefined as "clinically occult" and "clinically apparent"; 5) prognostic stage III groupings are based on N category criteria and T category criteria (ie, primary tumor thickness and ulceration) and increased from 3 to 4 subgroups (stages IIIA-IIID); 6) definitions of N subcategories are revised, with the presence of microsatellites, satellites, or in-transit metastases now categorized as N1c, N2c, or N3c based on the number of tumor-involved regional lymph nodes, if any; 7) descriptors are added to each M1 subcategory designation for lactate dehydrogenase (LDH) level (LDH elevation no longer upstages to M1c); and 8) a new M1d designation is added for central nervous system metastases. This evidence-based revision of the AJCC melanoma staging system will guide patient treatment, provide better prognostic estimates, and refine stratification of patients entering clinical trials. CA Cancer J Clin 2017;67:472-492. © 2017 American Cancer Society.

American Joint Committee on Cancer acceptance criteria for inclusion of risk models for individualized prognosis in the practice of precision medicine.

The American Joint Committee on Cancer (AJCC) has increasingly recognized the need for more personalized probabilistic predictions than those delivered by ordinal staging systems, particularly through the use of accurate risk models or calculators. However, judging the quality and acceptability of a risk model is complex. The AJCC Precision Medicine Core conducted a 2-day meeting to discuss characteristics necessary for a quality risk model in cancer patients. More specifically, the committee established inclusion and exclusion criteria necessary for a risk model to potentially be endorsed by the AJCC. This committee reviewed and discussed relevant literature before creating a checklist unique to this need of AJCC risk model endorsement. The committee identified 13 inclusion and 3 exclusion criteria for AJCC risk model endorsement in cancer. The emphasis centered on performance metrics, implementation clarity, and clinical relevance. The facilitation of personalized probabilistic predictions for cancer patients holds tremendous promise, and these criteria will hopefully greatly accelerate this process. Moreover, these criteria might be useful for a general audience when trying to judge the potential applicability of a published risk model in any clinical domain. CA Cancer J Clin 2016;66:370-374. © 2016 American Cancer Society.

High-Flow Nasal Cannula Therapy for Exertional Dyspnea in Patients with Cancer: A Pilot Randomized Clinical Trial.

BACKGROUND: Exertional dyspnea is common in patients with cancer and limits their function. The impact of high-flow nasal cannula on exertional dyspnea in nonhypoxemic patients is unclear. In this double-blind, parallel-group, randomized trial, we assessed the effect of flow rate (high vs. low) and gas (oxygen vs. air) on exertional dyspnea in nonhypoxemic patients with cancer. PATIENTS AND METHODS: Patients with cancer with oxygen saturation >90% at rest and exertion completed incremental and constant work (80% maximal) cycle ergometry while breathing low-flow air at 2 L/minute. They were then randomized to receive high-flow oxygen, high-flow air, low-flow oxygen, or low-flow air while performing symptom-limited endurance cycle ergometry at 80% maximal. The primary outcome was modified 0-10 Borg dyspnea intensity scale at isotime. Secondary outcomes included dyspnea unpleasantness, exercise time, and adverse events. RESULTS: Seventy-four patients were enrolled, and 44 completed the study (mean age 63; 41% female). Compared with low-flow air at baseline, dyspnea intensity was significantly lower at isotime with high-flow oxygen (mean change, -1.1; 95% confidence interval [CI], -2.1, -0.12) and low-flow oxygen (-1.83; 95% CI, -2.7, -0.9), but not high-flow air (-0.2; 95% CI, -0.97, 0.6) or low-flow air (-0.5; 95% CI, -1.3, 0.4). Compared with low-flow air, high-flow oxygen also resulted in significantly longer exercise time (difference + 2.5 minutes, p = .009), but not low-flow oxygen (+0.39 minutes, p = .65) or high-flow air (+0.63 minutes, p = .48). The interventions were well tolerated without significant adverse effects. CONCLUSION: Our preliminary findings support that high-flow oxygen improved both exertional dyspnea and exercise duration in nonhypoxemic patients with cancer. (ClinicalTrials.gov ID: NCT02357134). IMPLICATIONS FOR PRACTICE: In this four-arm, double-blind, randomized clinical trial examining the role of high-flow nasal cannula on exertional dyspnea in patients with cancer without hypoxemia, high-flow oxygen, but not high-flow air, resulted in significantly lower dyspnea scores and longer exercise time. High-flow oxygen delivered by high-flow nasal cannula devices may improve clinically relevant outcomes even in patients without hypoxemia.

Combination Therapy of Physical Activity and Dexamethasone for Cancer-Related Fatigue: A Phase II Randomized Double-Blind Controlled Trial.

BACKGROUND: Despite the high frequency of cancer-related fatigue (CRF) and its debilitating effects on the quality of life of patients with advanced cancer, there are limited treatment options available. Treatments including physical activity (PA) or dexamethasone (Dex) improve CRF; however, they have lower adherence rates (PA) or long-term adverse effects (Dex). The aim of this study was to determine the feasibility of and preliminary results for the combination of PA and Dex in improving CRF. METHODS: In this phase II randomized controlled trial, patients with advanced cancer and CRF scores of ≥4/10 on the Edmonton Symptom Assessment Scale were eligible. Patients were randomized to standardized PA for 4 weeks with either 4 mg of Dex (LoDex arm) or 8 mg of Dex (HiDex arm) twice a day for 7 days. Feasibility and change in the Functional Assessment of Cancer Illness Therapy-Fatigue subscale (FACIT-F) from baseline to day 8 and day 29 (primary outcome) were assessed. Secondary outcomes included changes in fatigue dimensions (FACIT-General, Patient-Reported Outcomes Measurement Information System [PROMIS]-Fatigue). RESULTS: A total of 60 of 67 (90%) patients were evaluable. All patients were adherent to study medication. We found that 84% and 65% of patients in the LoDex arm and 96% and 68% of patients in the HiDex arm were adherent to aerobic and resistance exercise, respectively. The FACIT-F effect size in the LoDex arm was 0.90 (P<.001) and 0.92 (P<.001) and the effect size in the HiDex arm was 0.86 and 1.03 (P<.001 for both) at days 8 and 29, respectively. We found significant improvements in the Functional Assessment of Cancer Therapy-Physical (P≤.013) and the PROMIS-Fatigue (P≤.003) at days 8 and 29 in both arms. Mixed-model analysis showed a significant improvement in the FACIT-F scores at day 8 (P<.001), day 15 (P<.001), and day 29 (P=.002). Changes in the FACIT-F scores were not significantly different between patients in the 2 arms (P=.86). CONCLUSIONS: Our study found that the combination therapy of PA with Dex was feasible and resulted in the improvement of CRF. The improvement was seen for up to 3 weeks after the discontinuation of Dex. Further larger studies are justified. CLINICALTRIALS: gov identifier: NCT02491632.

Central nervous system miliary metastasis in breast cancer: a case series analysis and proposed identification criteria of a rare metastasis subtype.

BACKGROUND: CNS miliary metastasis (MiM) is poorly recognised in breast and other malignancies. Given its rarity, little epidemiologic, radiographic and clinical data are known. Although usually identified on neuroimaging, criteria for radiographic diagnosis do not exist. In this analysis, we establish its presence in breast cancer and identify factors contributing to outcome. METHODS: We identified 546 female patients with brain metastasis from breast cancer between 2000 and 2015. Radiographic criteria were established through review of neuroimages by a senior Neuroradiologist, and defined as: (1) ≥20 lesions per image on ≥2 non-contiguous MRI images or ≥10 lesions per image on ≥2 non-contiguous CT images, and (2) bilateral lesions located in both the supratentorial and infratentorial compartments. RESULTS: Twenty-one MiM cases were identified (3.8%). Number and anatomical distribution of metastases best identified MiM, while lesion size did not. Ten patients were diagnosed with MiM as initial CNS metastasis; 11 developed MiM following known CNS metastasis. Breast cancer subtype did not influence MiM development before or after other CNS metastasis. CONCLUSIONS: This is the first study to propose radiographic criteria for MiM diagnosis. Additional analysis is needed to verify data, but our results may enable a standardised approach for future MiM research.

Pre-clinical animal models are poor predictors of human toxicities in phase 1 oncology clinical trials.

BACKGROUND: Our objective was to determine the correlation between preclinical toxicity found in animal models (mouse, rat, dog and monkey) and clinical toxicity reported in patients participating in Phase 1 oncology clinical trials. METHODS: We obtained from two major early-Phase clinical trial centres, preclinical toxicities from investigational brochures and clinical toxicities from published Phase 1 trials for 108 drugs, including small molecules, biologics and conjugates. Toxicities were categorised according to Common Terminology Criteria for Adverse Events version 4.0. Human toxicities were also categorised based on their reported clinical grade (severity). Positive predictive values (PPV) and negative predictive values (NPV) were calculated to determine the probability that clinical studies would/would not show a particular toxicity category given that it was seen in preclinical toxicology analysis. Statistical analyses also included kappa statistics, and Matthews (MCC) and Spearman correlation coefficients. RESULTS: Overall, animal toxicity did not show strong correlation with human toxicity, with a median PPV of 0.65 and NPV of 0.50. Similar results were obtained based on kappa statistics and MCC. CONCLUSIONS: There is an urgent need to assess more novel approaches to the type and conduct of preclinical toxicity studies in an effort to provide better predictive value for human investigation.

Quantitative hormone receptor (HR) expression and gene expression analysis in HR+ inflammatory breast cancer (IBC) vs non-IBC.

BACKGROUND: The purpose of this study was to determine the prognostic role of hormone receptor (HR) on inflammatory breast cancer (IBC) to elucidate its aggressive biological behavior. METHODS: We evaluated the expression of estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemical staining and determined the predictive and prognostic role of HR expression on 189 patients with HR+/HER2- IBC and 677 patients with HR+/HER2- stage III non-IBC. Furthermore, we performed gene expression (GE) analyses on 137 patients with HR+/HER2- IBC and 252 patients with HR+/HER2- non-IBC to detect genes that are specifically overexpressed in IBC. RESULTS: The expression of ER% was significantly associated with longer distant disease-free survival and overall survival. However, there was no significant relationship between ER% and neoadjuvant chemotherapy outcome. In the GE study, 84 genes were identified as significantly distinguishing HR+ IBC from non-IBC. Among the top 15 canonical pathways expressed in IBC, the ERK/MAPK, PDGF, insulin receptor, and IL-7 signaling pathways were associated with the ER signaling pathway. Upregulation of the MYC gene was observed in three of these four pathways. Furthermore, HR+/HER2- IBC had significantly higher MYC amplification, and the genetic alteration was associated with poor survival outcome. CONCLUSIONS: Higher ER expression was significantly associated with improved survival in both HR+/HER2- IBC and HR+/HER2- stage III non-IBC patients. HR+/HER2- IBC had several activated pathways with MYC upregulation, and the genetic alteration was associated with poor survival outcome. The results indicate that MYC may be a key gene for understanding the biology of HR+/HER2- IBC.

Modified FOLFIRINOX in pancreatic cancer patients Age 75 or older.

BACKGROUND: Although FOLFIRINOX (5-Fluorouracil + leucovorin + irinotecan + oxaliplatin) is now the standard of care for patients (pts) with metastatic pancreatic cancer (PC) based on the 2011 study by Conroy et al. which demonstrated improved median overall survival (mOS), pts > 75 yrs old were excluded from this study. The purpose of this study was to assess the safety and efficacy of modified FOLFIRINOX (mFOLFIRINOX) in this population. METHODS: We retrospectively analyzed unresectable PC pts, age ≥ 75, treated with mFOLFIRINOX at MD Anderson from 2011 to 2017. Primary outcome was rate of grade 3 or 4 hematologic toxicity (HT). RESULTS: 24 pts were included. Grade 3 or 4 HT occurred in 11 pts 6 pts required hospitalization for any toxicity, and 10 stopped mFOLFIRINOX due to toxicity. The most frequently used starting doses of infusional 5-FU, irinotecan and oxaliplatin were 2400, 150 and 75 mg/m2, respectively. Median PFS was 3.7 months (95% CI: 3.0-5.7) with a median OS of 11.6 months (95% CI: 6.14-15.7). For first line pts, median PFS and OS were 5.1 (95% CI: 2.0-12.8) and 12.2 months (95% CI: 4.8-30.8), respectively. CONCLUSIONS: In this single-center retrospective analysis of unresectable PC pts age 75 or older given mFOLFIRINOX, toxicities and survival outcomes were similar to those reported in the initial study. These data indicate that the use of modified dosing FOLFIRINOX in advanced PC pts older than 75 appears to maintain similar toxicity and efficacy when compared to younger pts.

The role of magnetic resonance imaging in patients with palpable breast abnormalities and negative mammographic and sonographic findings.

OBJECTIVE OR PURPOSE OF STUDY: The objective of this retrospective study was to determine the frequency of positive findings on breast magnetic resonance imaging (MRI) in patients with palpable breast abnormalities in the setting of negative mammographic and sonographic evaluations. MATERIALS, METHODS, AND PROCEDURES: Consecutive patients undergoing breast MRI for palpable abnormalities from January 1, 2005 to December 31, 2015 were identified for this retrospective study. Those with preceding imaging (mammograms or ultrasounds) demonstrating positive findings related to the palpable abnormalities were excluded. The location and the duration of the symptoms, the type and the location of the abnormal MRI findings, and their relationships to the symptoms were recorded. Clinical and imaging follow-up as well as the type and the resultant biopsies were recorded. Patients with less than two years of imaging or clinical follow-up were excluded from the study. RESULTS: 22 004 women presented with palpable abnormalities at one breast imaging center between January 1, 2005 and December 31, 2015. Nine thousand and three hundred and thirty-four patients had negative or benign findings on mammography, ultrasound, or mammography plus ultrasound. Thirty-one patients underwent MRI with the complaint of palpable abnormalities despite negative or benign mammographic and/or sonographic findings. Their age range was between 32 and 74 years, and their mean age was 49 years. Of those who had MRI, twenty-one patients had negative MRI findings. Six patients had negative concordant results for the palpable abnormalities and benign incidental findings. Three patients had benign concordant results for the palpable abnormalities, and one patient had incidental atypia. Twenty-eight patients had negative MRI results in the area of the palpable abnormality, and none of these patients underwent biopsy. Of the 31 cases, four patients (13%) underwent additional examinations (three second-look ultrasounds and one bone scan) after MRI. Five patients (16%) underwent MRI-guided biopsies, two patients (6%) underwent ultrasound-guided biopsies, and one patient (3%) had an excision. All biopsies showed benign results. The Gail risk score was calculated for 22 of them and the mean 5-year risk was 1.64 and the mean lifetime risk was 12.51. CONCLUSION: Breast MRI to evaluate palpable abnormalities after negative mammography and ultrasound results in a low yield for malignancy. The majority of patients (67.7%) had negative MRI examinations, and there were no malignancies detected. Our findings lead us to believe that there are no data to encourage the use of MRI in patients with palpable abnormalities and negative mammographic and/or ultrasound studies.

Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma.

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

Minimally Invasive Cordotomy for Refractory Cancer Pain: A Randomized Controlled Trial.

BACKGROUND: Up to 30% of patients with cancer continue to suffer from pain despite aggressive supportive care. The present study aimed to determine whether cordotomy can improve cancer pain refractory to interdisciplinary palliative care. MATERIALS AND METHODS: In this randomized controlled trial, we recruited patients with refractory unilateral somatic pain, defined as a pain intensity (PI) ≥4, after more than three palliative care evaluations. Patients were randomized to percutaneous computed tomography-guided cordotomy or continued interdisciplinary palliative care. The primary outcome was 33% improvement in PI at 1 week after cordotomy or study enrollment as measured by the Edmonton Symptom Assessment Scale. RESULTS: Sixteen patients were enrolled (nine female, median age 58 years). Six of seven patients (85.7%) randomized to cordotomy experienced >33% reduction in PI (median preprocedure PI = 7, range 6-10; 1 week after cordotomy median PI = 1, range 0-6; p = .022). Zero of nine patients randomized to palliative care achieved a 33% reduction in PI. Seven patients (77.8%) randomized to palliative care elected to undergo cordotomy after 1 week. All of these patients experienced >33% reduction in PI (median preprocedure PI = 8, range 4-10; 1 week after cordotomy median PI = 0, range 0-1; p = .022). No patients were withdrawn from the study because of adverse effects of the intervention. CONCLUSION: These data support the use of cordotomy for pain refractory to optimal palliative care. The findings of this study justify a large-scale randomized controlled trial of percutaneous cordotomy. IMPLICATIONS FOR PRACTICE: This prospective clinical trial was designed to determine the improvement in pain intensity in patients randomized to either undergo cordotomy or comprehensive palliative care for medically refractory cancer pain. This study shows that cordotomy is effective in reducing pain for medically refractory cancer pain, and these results can be used to design a large-scale comparative randomized controlled trial that could provide the evidence needed to include cordotomy as a treatment modality in the guidelines for cancer pain management.

Lapatinib activity in metastatic human epidermal growth factor receptor 2-positive breast cancers that received prior therapy with trastuzumab, pertuzumab, and/or ado-trastuzumab emtansine (T-DM1).

PURPOSE: Lapatinib (L) is approved in combination with capecitabine or letrozole for patients with trastuzumab-resistant HER2-positive metastatic breast cancer (MBC). However, there is no efficacy data of L in patients who received prior pertuzumab (P) and ado-trastuzumab emtansine (T-DM1), now included as standard first- and second-line therapies, respectively. The goal of this study was to assess the efficacy of L in a contemporary patient population that received prior P and/or T-DM1. METHODS: We identified patients with HER2-positive MBC who received L (n = 520) between 2003 and 2017 at MD Anderson Cancer Center and selected a target cohort who received L after prior P or T-DM1 (n = 43) with the remaining included in the comparison cohort (n = 477). We evaluated outcome measures including clinical benefit rate (CBR), best tumor response (BTR), duration on L, and time to progression (TTP). Survival analyses used Kaplan-Meier statistics. RESULTS: CBR was 28% (95% CI 10-32) for the target cohort and 40% (95% CI 36-45) for the comparison cohort. The median duration on L was 5 months (95% CI 3.0-9.0) in the target cohort and 6.7 months (5.9-8.0) in the comparison cohort. In both cohorts, the median time to progression (TTP) and overall survival (OS) were longer in patients with de novo metastatic disease compared to patients with disease recurrence. CONCLUSION: L-based therapy is an active therapeutic option and remains a viable option for HER2 + MBC after prior trastuzumab, P and/or T-DM1.

Risk of Distant Metastasis in Parathyroid Carcinoma and Its Effect on Survival: A Retrospective Review from a High-Volume Center.

BACKGROUND: Development of distant metastases (DM) is associated with markedly decreased survival in parathyroid carcinoma (PC). We sought to identify factors associated with development of DM and to quantify the effect that development of DM had on overall survival (OS). METHODS: Patients with surgically resected local/regional PC treated or surveilled at a tertiary-referral cancer hospital from 1980 to 2017 were included. We assessed the association between biochemical and clinicopathologic factors (preoperative parathyroid hormone (PTH) levels, sex, race, age, preoperative serum calcium levels, serum calcium levels at 6 months postop, tumor size, and extent of resection) with the development of DM. We also assessed the effect of development of DM on OS. RESULTS: Seventy-five patients with PC were assessed; 17 (22.7%) developed DM at a median follow-up of 77 months. The cumulative incidence of DM in the cohort was 20, 30, and 38% at 5, 10, and 20 years respectively. Tumor size > 3.2 cm based on recursive partitioning analysis was the only significant predictor for development of DM (hazard ratio (HR) = 3.51; 95% confidence interval [CI] 1.04-11.91; p = 0.04). Median OS for the entire cohort was 17 years compared with 40 months for the cohort who developed DM. The HR for death after distant metastasis was 9.6 (95% CI 4.2-22.3; p < 0.0001). CONCLUSIONS: Development of distant metastasis during surveillance is associated with decreased OS, including late recurrences. Primary tumor size should be considered in future interval surveillance and development of treatment algorithms.

Efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal patients with metastatic, hormone receptor-positive, HER2-negative breast cancer: a phase II study.

Background Increased adiposity is thought to result in worse clinical outcomes in patients with breast cancer through increased estrogen production, hyperinsulinemia, insulin resistance, and activation of the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway. Thus, we hypothesized that the addition of metformin to everolimus and exemestane, could lead to better outcomes in overweight and obese patients with metastatic, hormone receptor-positive, HER2-negative breast cancer. We conducted a phase II trial to evaluate the efficacy and safety of the combination of metformin, everolimus and exemestane in overweight and obese postmenopausal women with metastatic, hormone receptor-positive, HER2-negative breast cancer. Methods Twenty-two patients with a body mass index ≥25 kg/m2 were treated with metformin 1000 mg twice daily, everolimus 10 mg daily and exemestane 25 mg daily. Median progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results Median PFS and OS were 6.3 months (95% confidence interval [CI]: 3.8-11.3 months) and 28.8 months (95% CI: 17.5-59.7 months), respectively. Five patients had a partial response and 7 had stable disease for ≥24 weeks yielding a clinical benefit rate of 54.5%. Compared with overweight patients, obese patients had an improved PFS on univariable (p = 0.015) but not multivariable analysis (p = 0.215). Thirty-two percent of patients experienced a grade 3 treatment-related adverse event (TRAE). There were no grade 4 TRAEs and 7 patients experienced a grade 3 TRAE. Conclusion The combination of metformin, everolimus and exemestane was safe and had moderate clinical benefit in overweight and obese with patients metastatic, hormone receptor-positive, HER2-negative breast cancer.

Correction to: Volumetric response of progressing post-SRS lesions treated with laser interstitial thermal therapy.

The original article was published with an incorrect protocol number. The correct protocol number is DR07-0585.

Cancer-Related Internet Use and Its Association With Patient Decision Making and Trust in Physicians Among Patients in an Early Drug Development Clinic: A Questionnaire-Based Cross-Sectional Observational Study.

BACKGROUND: The role of cancer-related internet use on the patient-physician relationship has not been adequately explored among patients who are cancer-related internet users (CIUs) in early-phase clinical trial clinics. OBJECTIVE: We examined the association between cancer-related internet use and the patient-physician relationship and decision making among CIUs in an early drug development clinic. METHODS: Of 291 Phase I clinic patients who completed a questionnaire on internet use, 179 were CIUs. Generations were defined by the year of patient's birth: "millennials" (after 1990) and "Generation X/Y" (1965-1990) grouped as "Millennials or Generation X/Y"; "Baby Boomers" (1946-1964); and "Greatest or Silent Generation" (1945 and earlier). Statistical analyses included the Wilcoxon matched-pairs signed-rank test and the Mann-Whitney U test. RESULTS: CIUs were 52% (94/179) female, 44% (78/179) were older than 60 years, and 60% (108/179) had household incomes exceeding US $60,000. The sources of information on cancer and clinical trials included physicians (171/179, 96%), the internet (159/179, 89%), and other clinical trial personnel (121/179, 68%). For the overall sample and each generation, the median values for trust in referring and Phase I clinical trial physicians among early drug development clinic CIUs were 5 on a 0-5 scale, with 5 indicating "complete trust." CIUs' trust in their referring (5) and phase 1 (5) physicians was higher than CIUs' trust in Web-based cancer-related information (3; P<.001 for both). CIUs who reported visiting the National Cancer Institute (NCI) website, NCI.org, to learn about cancer reported higher levels of trust in Web-based cancer-related information than CIUs who did not use the NCI website (P=.02). Approximately half of CIUs discussed internet information with their doctor. Only 14% (23/165) of CIUs had asked their physician to recommend cancer-related websites, and 24% (35/144) of CIUs reported at least occasional conflict between their physician's advice and Web-based information. CONCLUSIONS: Despite the plethora of websites related to cancer and cancer clinical trials, patients in early-phase clinical trial settings trust their physicians more than Web-based information. Cancer-related organizations should provide regularly updated links to trustworthy websites with cancer and clinical trial information for patients and providers and educate providers on reliable cancer websites so that they can better direct their patients to appropriate internet content.

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.

BACKGROUND: Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy. METHODS: This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study. FINDINGS: The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66-0·90] for progression-free survival and 0·74 [0·58-0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57-0·91] for progression-free survival and 0·60 [0·45-0·79] for overall survival) and immunotherapy (HR 0·75 [0·56-1·00] and 0·64 [0·47-0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65-1·17, pinteraction=0·61] for progression-free survival and 1·03 [0·80-1·34, pinteraction=0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40-0·70]), but no associations observed in women (HR 0·85 [0·61-1·18, pinteraction=0·03]). INTERPRETATION: Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations. FUNDING: ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.

Effect of neoadjuvant chemotherapy regimen on relapse-free survival among patients with breast cancer achieving a pathologic complete response: an early step in the de-escalation of neoadjuvant chemotherapy.

BACKGROUND: Patients with breast cancer who have a pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) have improved survival. We hypothesize that once pCR has been achieved, there is no difference in subsequent postsurgical recurrence-free survival (RFS), whichever NACT regimen is used. METHODS: Data from patients with breast cancer who achieved pCR after NACT between 1996 and 2011 were reviewed. RFS was estimated by the Kaplan-Meier method, and differences between groups were assessed using log-rank testing. Cox proportional hazards regression analysis adjusted for age, menopausal status, stage, grade, tumor subtype, and adjuvant endocrine HER2-targeted radiation treatment. RESULTS: Among 721 patients who achieved pCR after NACT, 157 (21.8%) were hormone receptor-positive (HR), 310 (43.3%) were HER2-amplified, and 236 (32.7%) were triple-negative; 292 (40.5%) were stage IIA, 153 (21.2%) were stage IIB, 78 (10.8%) were stage IIIA, 66 (9.2%) were stage IIIB, and 132 (18.3%) were stage IIIC. Most patients (367 [50.9%]) had been treated with adriamycin-based chemotherapy plus taxane (A + T), 56 (7.8%) without taxane (A no T), 227 (31.5%) with HER2-targeted therapy, and 71 (9.8%) provider choice. Median follow-up was 7.1 years. Adjuvant chemotherapy was employed in 196 (27%) patients, adjuvant endocrine in 261 (36%), and adjuvant radiation in the majority (559 [77.5%]). There was no statistically significant difference in RFS by NACT group. Adjusted RFS hazard ratios, comparing each treatment with the reference group A + T, were 1.25 (95% CI 0.47-3.35) for A no T, 0.90 (95% CI 0.37-2.20) for HER2-targeted therapy, and 1.28 (95% CI 0.55-2.98) for provider choice. CONCLUSIONS: These data suggest that postsurgical RFS is not significantly influenced by the choice of NACT or cancer subtype among patients achieving pCR.

The minimal clinically important difference of the Richmond Agitation-Sedation Scale in patients with cancer with agitated delirium.

BACKGROUND: The Richmond Agitation-Sedation Scale (RASS) is commonly used to assess psychomotor activity; however, to the authors' knowledge, its minimal clinically important difference (MCID) has not been determined to date. The objective of the current study was to identify the MCID for RASS using 2 anchor-based approaches. METHODS: The current study was a secondary analysis of a randomized controlled trial to compare the effect of lorazepam versus placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium. The primary outcome was change in RASS (10-point numeric rating scale ranging from -5 [unarousable] to +4 [combative]) from baseline to 8 hours after treatment administration. The sensitivity-specificity and within-patient change methods were used to identify the MCID, with the anchor being patient comfort after the study intervention as perceived by caregivers and nurses. RESULTS: A total of 90 patients were randomized and 58 (64%) received the study medication for restlessness/agitation (mean baseline RASS, 1.6). A total of 23 caregivers (61%) and 23 nurses (55%) perceived that the patient was more comfortable after treatment. Using the sensitivity-specificity method, the optimal RASS reduction was ≥4 points according to both caregivers (sensitivity of 61% and specificity of 80%; area under the curve, 0.71) and nurses (sensitivity of 73% and specificity of 84%; area under the curve, 0.78). The RASS cutoff value based on the within-patient change method was similar (-4.2 for caregivers and -4.0 for nurses). CONCLUSIONS: For patients with persistent restlessness/agitation, a reduction of ≥4 points in RASS was considered to be the MCID for both nurses and caregivers. These preliminary findings may have implications for sample size calculation and the interpretation of treatment effect in future delirium trials. Cancer 2018;124:2246-52. © 2018 American Cancer Society.