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1.
Clin Cancer Res ; 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33509808

RESUMO

PURPOSE: Cutaneous and unknown primary melanomas frequently harbor alterations that activate the Mitogen Activated Protein Kinase (MAPK) pathway. Whether MAPK driver detection beyond BRAF V600 is clinically relevant in the checkpoint inhibitor era is unknown. METHODS: Patients with melanoma were prospectivelyofferedtumor sequencingof 341-468 genes. Oncogenic alterations in 28 RTK-RAS-MAPK pathway genes were used to construct MAPK driver groups. Time to treatment failure(TTF)was determinedfor patients who received frontline PD-1 monotherapy,nivolumab plus ipilimumab,or subsequentgenomically matched targeted therapies.A Cox proportional hazards model was constructed for TTF using driver group and clinical variables. RESULTS: 670 of 696 sequenced melanomas (96%) harbored an oncogenic RTK-RAS-MAPK pathway alteration; 33% had {greater than or equal to}1 driver. Nine driver groups varied by clinical presentation and mutational burden. TTF of PD-1 monotherapy (N=181) varied by driver, with worse outcomes for NRAS Q61 and BRAF V600 versus NF1 or other alterations (median 4.2, 7.5, 22 and not reached;p<0.0001). Driver group remained significant independent of TMB and clinical features. TTF did not vary by driver for nivolumab plus ipilimumab (N=141). Among 172 patients with BRAF V600 wild-type melanoma who progressed on checkpoint blockade, 27 were treated with genomically matched therapy, and 8 (30%) derived clinical benefit lasting {greater than or equal to}6 months. CONCLUSION: Targeted capture multigene sequencingcan detect oncogenicRTK-RAS-MAPK pathway alterations in almost allcutaneous and unknown primary melanomas. Time to treatment failure of PD-1 monotherapy varies by mechanism of ERK activation.Oncogenic kinase fusionscan be successfully targetedin immune checkpointinhibitor-refractory melanoma.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33507480

RESUMO

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect in cancer survivors. This study aimed to assess the characteristics of quantitative sensory testing (QST) and its correlation with patient-reported outcomes (PROs) in cancer patients with and without CIPN. METHODS: We conducted a cross-sectional analysis using baseline data from two clinical trials in solid tumor cancer survivors with no CIPN symptoms rated < 2 on a 0-10 Numerical Rating Scale (NRS) or moderate-to-severe CIPN rated ≥ 4 on the NRS. We collected PROs (NRS, Neuropathic Pain Scale, and Functional Assessment of Cancer Therapy-Gynecologic Oncology Group/Neurotoxicity subscale at baseline. QST [Tactile Threshold (TT), Vibration Threshold (VT), Thermal Threshold (THT)] measurements were used to assess sensory fiber function; they were compared between patients with and without CIPN using Wilcoxon rank-sum tests. We used Spearman correlation coefficients to estimate associations between PROs and QST in all patients. RESULTS: Among 116 participants with CIPN (median NRS 5.00) and 10 participants without CIPN (median NRS 0.00), the median (interquartile range) TT was 3.84 (3.47, 4.12) and 3.53 (3.00, 3.84) in feet, respectively (p = 0.043). The median VT was 17.90 (9.42, 26.95) and 7.73 (5.94, 11.11) in feet, respectively (p = 0.001). Thermal cool threshold was 30.00 °C (28.90, 30.57) and 30.67 °C (30.57, 30.93), respectively (p = 0.007). Correlation coefficients between PROs and QST measures ranged between 0.02 and 0.50 in absolute magnitude. CONCLUSION: Patients with moderate-to-severe CIPN had significantly impaired tactile, vibratory, and thermal thresholds compared to patients without CIPN. QST correlates with PROs, suggesting CIPN symptom severity may correspond to sensory fiber functionality. QST may be incorporated into future CIPN research.

4.
JCO Oncol Pract ; : OP2000832, 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33332173
5.
JNCI Cancer Spectr ; 4(6): pkaa048, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33225208

RESUMO

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect that worsens quality of life and increases the risk of falls in cancer survivors. Evidence of yoga's safety and efficacy in treating CIPN is lacking. Methods: In a randomized controlled study, we assigned breast and gynecological cancer survivors with persistent moderate-to-severe CIPN pain, numbness, or tingling with a score of 4 or greater (0-10 numeric rating scale [NRS]) for at least 3 months after chemotherapy to 8 weeks of usual care or yoga focused on breathwork and musculoskeletal conditioning. Primary endpoint was treatment arm differences for NRS, and secondary endpoints were Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity subscale (FACT/GOG-Ntx), and Functional Reach Test after week 8. We tested treatment arm differences for each outcome measure using linear mixed models with treatment-by-time interactions. All statistical tests were two-sided. Results: We randomly assigned 41 participants into yoga (n = 21) or usual care (n = 20). At week 8, mean NRS pain decreased by 1.95 points (95% confidence interval [CI] = -3.20 to -0.70) in yoga vs 0.65 (95% CI = -1.81 to 0.51) in usual care (P = .14). FACT/GOG-Ntx improved by 4.25 (95% CI = 2.29 to 6.20) in yoga vs 1.36 (95% CI = -0.47 to 3.19) in usual care (P = .035). Functional reach, an objective functional measure predicting the risk of falls, improved by 7.14 cm (95% CI = 3.68 to 10.59) in yoga and decreased by 1.65 cm (95% CI = -5.00 to 1.72) in usual care (P = .001). Four grade 1 adverse events were observed in the yoga arm. Conclusion: Among breast and gynecological cancer survivors with moderate-to-severe CIPN, yoga was safe and showed promising efficacy in improving CIPN symptoms.

6.
JCO Clin Cancer Inform ; 4: 691-699, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32755461

RESUMO

PURPOSE: As data-sharing projects become increasingly frequent, so does the need to map data elements between multiple classification systems. A generic, robust, shareable architecture will result in increased efficiency and transparency of the mapping process, while upholding the integrity of the data. MATERIALS AND METHODS: The American Association for Cancer Research's Genomics Evidence Neoplasia Information Exchange (GENIE) collects clinical and genomic data for precision cancer medicine. As part of its commitment to open science, GENIE has partnered with the National Cancer Institute's Genomic Data Commons (GDC) as a secondary repository. After initial efforts to submit data from GENIE to GDC failed, we realized the need for a solution to allow for the iterative mapping of data elements between dynamic classification systems. We developed the Linked Entity Attribute Pair (LEAP) database framework to store and manage the term mappings used to submit data from GENIE to GDC. RESULTS: After creating and populating the LEAP framework, we identified 195 mappings from GENIE to GDC requiring remediation and observed a 28% reduction in effort to resolve these issues, as well as a reduction in inadvertent errors. These results led to a decrease in the time to map between OncoTree, the cancer type ontology used by GENIE, and International Classification of Disease for Oncology, 3rd Edition, used by GDC, from several months to less than 1 week. CONCLUSION: The LEAP framework provides a streamlined mapping process among various classification systems and allows for reusability so that efforts to create or adjust mappings are straightforward. The ability of the framework to track changes over time streamlines the process to map data elements across various dynamic classification systems.

7.
J Neurosurg ; : 1-12, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32619972

RESUMO

OBJECTIVE: The utility and safety of intraoperative MRI (iMRI) for resection of pituitary adenomas is not clearly established in the context of advances in endoscopic approaches. The goal in this study was to evaluate the safety and efficacy of iMRI for pituitary adenoma resection, with endoscopic transsphenoidal (ETS) versus microscopic transsphenoidal (MTS) approaches. METHODS: Radiographic and clinical outcomes of all pituitary adenomas resected using iMRI between 2008 and 2017 at a single institution were retrospectively evaluated. RESULTS: Of 212 tumors treated, 131 (62%) underwent further resection based on iMRI findings, resulting in a significant increase in gross-total resection on postoperative MRI compared with iMRI (p = 0.0001) in both ETS and MTS groups. iMRI increased rates of gross-total resection for cavernous sinus invasion Knosp grades 1 and 2, but not in Knosp ≥ 3 across treatment groups (p < 0.0001). The extent of resection on postoperative MRI was significantly correlated with increased progression-free survival (p < 0.0001). Initial hormone remission off medical therapy was achieved in 64%, with a significantly higher rate of remission in tumors resected via the ETS approach (81%) compared with the MTS approach (55%) (p = 0.02). The rate of persistent new hormone deficit was low at 8%, including a 2.8% rate of permanent diabetes insipidus, and 45% of patients had improvement in preoperative hormone deficit following surgery. Serious postoperative complications including CSF leaks requiring reoperation were rare at 1%, with no postoperative infections. CONCLUSIONS: These results suggest that iMRI is a safe and effective method of increasing the extent of resection for pituitary adenomas while preserving hormone function. When paired with the endoscope, iMRI may offer the ability to tailor more aggressive removal of tumors while optimizing pituitary function, resulting in high rates of secretory hormone remission. Secretory tumors and adenomas with Knosp grade < 3 cavernous sinus invasion may benefit most from the use of iMRI.

8.
Medicine (Baltimore) ; 99(21): e20085, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481275

RESUMO

INTRODUCTION: Chronic pain is a leading cause of disability and remains under-treated in nearly half of patients with cancer. The opioid crisis has highlighted an urgent public health need for effective nonpharmacological pain management. Electroacupuncture (EA) and Battlefield Acupuncture (BFA) represent nonpharmacological modalities used in clinical practice to manage pain; however, their effectiveness has not been rigorously evaluated in oncology settings. METHODS: We describe the design of a 3-arm, parallel, single-center, multisite randomized controlled trial that investigates EA and BFA versus usual-care wait-list control (WLC) for chronic musculoskeletal pain among 360 patients with diverse cancer types across various stages. The primary aim is to compare effects of EA and BFA versus WLC on pain, physical function, and co-morbid symptoms. The secondary aim is to examine the interaction between patient outcome expectancy and acupuncture modality (EA vs BFA) on pain reduction. The tertiary aim is to evaluate the association between genetic polymorphisms and responses to acupuncture. Patients will be randomized in a 2:2:1 ratio to EA:BFA:WLC. Acupuncture groups will receive weekly treatments over 10 weeks. WLC will receive usual care over the same evaluation period as the acupuncture groups. The primary endpoint will be the change in average pain intensity score from baseline to week 12. We will collect validated patient-reported outcomes and blood/saliva samples at multiple timepoints over 24 weeks. DISCUSSION: Our findings will advance nonpharmacological pain management in oncology and inform personalized treatment approaches that integrate individuals' expectations and genetic biomarkers to deliver "precision" acupuncture to cancer patients with chronic pain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02979574.


Assuntos
Terapia por Acupuntura/métodos , Sobreviventes de Câncer , Dor Crônica/terapia , Dor Musculoesquelética/terapia , Manejo da Dor/métodos , Adulto , Humanos , Medição da Dor/métodos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto
10.
Ann Clin Transl Neurol ; 7(4): 429-436, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32293798

RESUMO

PURPOSE: Malignant glioma (MG) is the most deadly primary brain cancer. Signaling though the PI3K/AKT/mTOR axis is activated in most MGs and therefore a potential therapeutic target. The mTOR inhibitor temsirolimus and the AKT inhibitor perifosine are each well-tolerated as single agents but with limited activity reclinical data demonstrate synergistic anti-tumor effects from combined treatment. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs to determine safety and a recommended phase II dose. METHODS: Adults with recurrent MG, Karnofsky Performance Status ≥ 60 were enrolled, with no limit on the number of prior therapies. Temsirolimus dose was escalated using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. Perifosine was fixed as a 600 mg load on day 1 followed by 100 mg nightly (single agent MTD) until dose level 7 when the load increased to 900 mg. RESULTS: We treated 35 patients with with glioblastoma (17) or other MGs (18; including nine anaplastic astrocytoma, nine anaplastic oligodendroglioma, one anaplastic oligoastrocytoma, and two low grade astrocytomas with radiographic transformation to MG). We observed five dose-limiting toxicities (DLTs): one at dose level 3 (50mg temsirolimus), then two at dose level 7 expansion (170 mg temsirolimus), and then two more at dose level 6 expansion (170 mg temsirolimus). DLTs included thrombocytopenia (n = 3), intracerebral hemorrhage (n = 1) and lung infection (n = 1). CONCLUSION: Combining the mTOR inhibitor temsirolimus dosed at 115 mg weekly and the AKT inhibitor perifosine dosed at 100 mg daily (following 600 mg load) is tolerable in heavily pretreated adults with recurrent MGs.

11.
Clin Cancer Res ; 26(13): 3193-3201, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32205463

RESUMO

PURPOSE: Preclinical data suggest that radiotherapy (RT) is beneficial in combination with immune checkpoint blockade. Clinical trials have explored RT with single-agent immune checkpoint blockade, but no trials have reported RT with the combination of nivolumab and ipilimumab. PATIENTS AND METHODS: We conducted a phase 1 study of patients with stage IV melanoma receiving nivolumab and ipilimumab with two different dose-fractionation schemes of RT. Patients had at least one melanoma metastasis that would benefit from palliative RT and one metastasis that would not be irradiated. Nivolumab 1 mg/kg + ipilimumab 3 mg/kg and extracranial RT with a dose of 30 Gy in 10 fractions was administered in Cohort A, and then 27 Gy in 3 fractions was administered in Cohort B. The primary outcome was safety. RESULTS: Twenty patients were treated (10 in each cohort). The rates of treatment-related grade 3-4 adverse events in Cohort A and B were 40% and 30%, respectively. There were no grade ≥3 adverse events attributed to RT. Patients responded to treatment outside of the irradiated volume (Cohort A 5/10; Cohort B 1/9). No evaluable patients had progression of irradiated metastases. Immunologic changes were seen in the peripheral blood with increases in T-cell receptor diversity in some responding patients. CONCLUSIONS: RT with nivolumab and ipilimumab was safe compared with historical data of nivolumab and ipilimumab alone. Immunologic effects were observed in the peripheral blood. Randomized studies are ongoing to assess whether RT increases the efficacy of nivolumab and ipilimumab.

12.
Leuk Lymphoma ; 61(6): 1406-1417, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32090658

RESUMO

Research examining the experience of informal caregivers (ICs) for patients with rare cancers is limited. This was a mixed-methods pilot study of 14 ICs for patients with Erdheim-Chester disease (ECD), an ultra-rare neoplasm. Participants were predominantly female and over half provided at least 60% of their loved one's care. Participants completed measures of the impact of caregiving, caregiver burden, unmet needs, quality of life, anxiety, and depression. Participants reported substantial impact of caregiving, including limiting (50%) or discontinuing (21%) paid employment, and exhausting financial savings (43%). ICs reported a moderate level of burden with five (38%) reporting risk for burnout. While participants reported anxiety (64%) and depression (14%), their overall quality of life was favorable. Semi-structured interviews highlighted factors related to the distress and isolation of navigating a rare cancer. ECD ICs report burden and distress shaped by the experience of providing care for a patient with a rare cancer.

13.
J Clin Oncol ; 38(15): 1655-1663, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32053428

RESUMO

PURPOSE: To analyze long-term outcomes after treatment discontinuation of anti-programmed death-1 (anti-PD-1) therapy in a cohort of patients with melanoma with the longest follow-up yet available to our knowledge, including a majority of patients treated outside of a clinical trial. We also assessed efficacy of retreatment with anti-PD-1 therapy with or without ipilimumab in relapsing patients. METHODS: We retrospectively analyzed all patients with nonuveal, unresectable stage III/IV melanoma treated with single-agent anti-PD-1 therapy at Memorial Sloan Kettering from 2009-2018 who had discontinued treatment and had at least 3 months of follow-up after discontinuation (n = 396). Overall survival for patients with complete response (CR) was calculated from time of CR. Time to treatment failure for patients with CR was time from CR to the next melanoma treatment or death. RESULTS: CRs were seen in 102 of 396 patients (25.8%). The median number of months of treatment after CR was zero (range, stopped before CR to 26 months after CR). With a median follow-up of 21.1 months from time of CR in patients who did not relapse, the probability of being alive and not needing additional melanoma therapy at 3 years was 72.1%. There was no significant association between treatment duration and relapse risk. In multivariable analysis, CR was associated with M1b disease and cutaneous versus mucosal or acral primaries. Among the 78 patients (of 396) retreated after disease progression, response was seen in 5 of 34 retreated patients with single-agent anti-PD-1 therapy and 11 of 44 patients escalated to anti-PD-1 plus ipilimumab. CONCLUSION: In our cohort, most patients discontinued treatment at the time of CR. Most CRs were durable but the probability of treatment failure was 27% at 3 years. Responses to retreatment were infrequent. The optimal duration of treatment after CR is not yet established.

14.
Cancer Med ; 9(5): 1648-1660, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31918457

RESUMO

BACKGROUND: While public reporting of surgical outcomes for noncancer conditions is common, cancer surgeries have generally been excluded. This is true despite numerous studies showing outcomes to differ between hospitals based on their characteristics. Our objective was to assess whether three prerequisites for quality assessment and reporting are present for 30-day mortality after cancer surgery: low burden for timely reporting, hospital variation, and potential for public health gains. STUDY DESIGN: We used Fee-for-Service (FFS) Medicare claims to examine the extent of variation in 30-day cancer surgical mortality between 3860 US hospitals. We included 340 489 surgeries for 12 cancer types for FFS Medicare beneficiaries aged ≥66 years, 2011-2013. Hierarchical mixed-effects logistic regression models adjusted for patient and hospital characteristics and with a random hospital effect were fit to obtain hospital-specific risk-standardized mortality rates (RSMRs) and 99% confidence intervals (CI). We calculated a hospital odds ratio to describe the difference in mortality risk for a hospital above vs below average quality and estimated the potential mortality reduction. RESULTS: The median number of cancer surgeries per hospital was 34. The median RSMR overall was 2.41% (99% CI 2.28%, 2.66%). In aggregate and for most cancers, variation between hospitals exceeded that due to differences in patient and hospital characteristics. For individual cancers, relative differences exceeded 20% in mortality risk between patients undergoing surgery at a hospital below vs above average quality, with the potential for an estimated 500 deaths prevented annually given hypothetical improvements. CONCLUSION: Quality measurement and reporting of 30-day mortality for cancer surgery is worthy of consideration.

15.
Neuro Oncol ; 22(7): 979-992, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-31950179

RESUMO

BACKGROUND: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm characterized by recurrent alterations in the MAPK (mitogen-activating protein kinase) pathway. The existing literature about the neuro-oncological spectrum of ECD is limited. METHODS: We present retrospective clinical, radiographic, pathologic, molecular, and treatment data from 30 patients with ECD neurohistiocytic involvement treated at a tertiary center. RESULTS: Median age was 52 years (range, 7-77), and 20 (67%) patients were male. Presenting symptoms included ataxia in 19 patients (63%), dysarthria in 14 (47%), diabetes insipidus in 12 (40%), cognitive impairment in 10 (33%), and bulbar affect in 9 (30%). Neurosurgical biopsy specimens in 8 patients demonstrated varied morphologic findings often uncharacteristic of typical ECD lesions. Molecular analysis revealed mutations in BRAF (18 patients), MAP2K1 (5), RAS isoforms (2), and 2 fusions involving BRAF and ALK. Conventional therapies (corticosteroids, immunosuppressants, interferon-alpha [IFN-α], cytotoxic chemotherapy) led to partial radiographic response in 8/40 patients (20%) by MRI with no complete responses, partial metabolic response in 4/16 (25%), and complete metabolic response in 1/16 (6%) by 18F-fluorodeoxyglucose (FDG)-PET scan. In comparison, targeted (kinase inhibitor) therapies yielded partial radiographic response in 10/27 (37%) and complete radiographic response in 14/27 (52%) by MRI, and partial metabolic response in 6/25 (24%) and complete metabolic response in 17/25 (68%) by FDG-PET scan. CONCLUSIONS: These data highlight underrecognized symptomatology, heterogeneous neuropathology, and robust responses to targeted therapies across the mutational spectrum in ECD patients with neurological involvement, particularly when conventional therapies have failed.

16.
Cancer ; 126(1): 76-85, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31584709

RESUMO

BACKGROUND: An elevated neutrophil-to-lymphocyte ratio (NLR) is associated with poor survival in patients with cancer, including those who receive immunotherapies. The authors sought to investigate NLR as a biomarker of treatment outcomes in patients with melanoma who were treated with PD-1 inhibition. METHODS: Patients undergoing initial treatment with PD-1 inhibitor monotherapy for stage IV melanoma at a single center from 2012 to 2015 were included. Clinical characteristics and the NLR at baseline and before subsequent treatment cycles were collected. The time to treatment failure (TTF) and overall survival (OS) were evaluated using Kaplan-Meier and landmark analyses. RESULTS: Among 224 study patients, 63 (28%) had a baseline NLR ≥5. The baseline NLR was significantly associated with Eastern Cooperative Oncology Group performance status and the number of involved metastatic sites. With a median follow-up of 39 months in survivors, a baseline NLR ≥5 was independently associated with shorter OS (hazard ratio, 2.0; 95% CI, 1.3-2.9) and TTF (hazard ratio, 1.7; 95% CI, 1.2-2.4). An NLR increase ≥30% during the first 2 cycles of treatment was associated with worse OS (median, 47 vs 13.5 months; P < .001) and a trend toward shorter TTF (12.8 vs 5.9 months; P = .05). A combined baseline NLR ≥5 and an NLR increase ≥30% identified a small cohort with markedly shortened OS (median, 5.8 months) and TTF (median, 1.8 months). CONCLUSIONS: Elevated baseline NLR and an increased NLR early during treatment are prognostic for TTF and OS in patients who have melanoma treated with PD-1 inhibitor monotherapy. Combined, these biomarkers can widely risk-stratify patients for treatment failure and survival.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Melanoma/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Linfócitos/efeitos dos fármacos , Masculino , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neutrófilos/efeitos dos fármacos , Receptor de Morte Celular Programada 1/imunologia
17.
Ann Surg Oncol ; 27(4): 1180-1188, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31848819

RESUMO

INTRODUCTION: Checkpoint inhibitors have improved outcomes in metastatic melanoma, with 4-year overall survival (OS) of 46% for anti-PD-1 alone or 53% in combination with anti-CTLA-4. However, the median progression free survival is 6.9 and 11.5 months, respectively. Many who progress have gone on to alternative treatments, including surgery, yet the outcome of patients selected for surgery after checkpoint blockade remains unclear. METHODS: Patients who were treated with checkpoint blockade from 2003 to 2017, followed by metastasectomy, were identified from a prospectively maintained institutional melanoma database. Response to immunotherapy was assessed at the time of surgery. Patients were categorized as having responding, isolated progressing, or multiple progressing lesions. RESULTS: Of the 237 total patients identified, 208 (88%) had stage IV disease, and 29 (12%) had unresectable stage III disease at the start of immunotherapy. Median OS following first resection was 21 months. Median follow-up among survivors was 23 months. Complete resection at the first operation (n = 87, 37%) was associated with improved survival compared with patients with incomplete resection (n = 150, 63%) [median OS not reached (NR) vs. 10.8 months, respectively; 95% CI: 7.3, 14.8; p < 0.0001]. Patients resected for an isolated progressing or responding tumor had a longer median survival compared with those with multiple progressing lesions (NR vs. 7.8 months, 95% CI: 6.2, 11.2; p < 0.0001). CONCLUSIONS: Patients selected for surgical resection following checkpoint blockade have a relatively favorable survival, especially if they had a response to immunotherapy and undergo complete resection of isolated progressing or responding disease.

18.
J Neurooncol ; 146(1): 163-170, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31823165

RESUMO

PURPOSE: Understanding the molecular landscape of glioblastoma (GBM) is increasingly important in the age of targeted therapy. O-6-Methylguanine-DNA methyltransferase (MGMT) promoter methylation and EGFR amplification are markers that may play a role in prognostication, treatment, and/or clinical trial eligibility. Quantification of MGMT and EGFR protein expression may offer an alternative strategy towards understanding GBM. Here, we quantify baseline expression of MGMT and EGFR protein in newly diagnosed GBM samples using mass spectrometry. We correlate findings with MGMT methylation and EGFR amplification statuses and survival. METHODS: We retrospectively identified adult patients with newly diagnosed resected GBM. MGMT and EGFR protein expression were quantified using a selected reaction monitoring mass spectrometry assay. Protein levels were correlated with MGMT methylation and EGFR amplification and survival data. RESULTS: We found a statistically significant association between MGMT protein expression and promoter methylation status (p = 0.02) as well as between EGFR protein expression and EGFR amplification (p < 0.0001). EGFR protein expression and amplification were more tightly associated than MGMT protein expression and methylation. Only MGMT promoter methylation was statistically significantly associated with progression-free and overall survival. CONCLUSIONS: Unlike EGFR protein expression and EGFR amplification which are strongly associated, only a weak association was seen between MGMT protein expression and promoter methylation. Quantification of MGMT protein expression was inferior to MGMT methylation for prognostication in GBM. Discordance was observed between EGFR amplification and EGFR protein expression; additional study is warranted to determine whether EGFR protein expression is a better biomarker than EGFR amplification for clinical decisions and trial enrollment.


Assuntos
Neoplasias Encefálicas/mortalidade , Quimiorradioterapia/mortalidade , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Glioblastoma/mortalidade , Proteínas Supressoras de Tumor/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/uso terapêutico , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Terapia Combinada , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Seguimentos , Glioblastoma/metabolismo , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Regiões Promotoras Genéticas , Estudos Retrospectivos , Taxa de Sobrevida , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/genética
19.
Melanoma Res ; 30(1): 71-75, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31425479

RESUMO

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. Data included patients (n = 1136) treated in the two randomized, controlled phase III studies MDX010-20 and CA184-024. ALC was measured at pretreatment baseline and every 3 weeks for up to 12 weeks, before each dose of ipilimumab. Cox proportional hazards models were used to estimate and test associations between ALC measures and overall survival (OS). 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. 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 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.

20.
J Eval Clin Pract ; 26(1): 66-71, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31069903

RESUMO

RATIONAL, AIMS, AND OBJECTIVES: While public reports of hospital-level surgical quality measures are becoming increasingly common in health care, a comprehensive national assessment of surgical quality across multiple cancer sites has yet to be developed. Fee-for-service (FFS) Medicare claims present a potential resource from which to measure outcomes following cancer surgery given the national scope of patients and providers. However, due to the administrative nature of the data, clinical cancer information such as stage is not recorded. Leveraging the Surveillance, Epidemiology, and End Results (SEER) registry linked to FFS Medicare claims to analyse outcomes for patients whom we ultimately know stage information, we determined whether Medicare claims are suitable for measuring provider quality following cancer surgery by assessing the extent to which the lack of stage information modifies assessments of provider performance. METHODS: We identified patients aged 66 and older undergoing cancer surgery between 2011 and 2013 from SEER-Medicare. We compared the changes in the risk-standardized rates (RSRs), decile rankings, and c-statistics with and without risk adjustment for cancer stage for three measures of hospital performance: 30-day mortality, surgical complications, and unplanned readmissions. RESULTS: The RSR changed by at most 11.4% for mortality and by less than 4% for complications and readmissions, indicating that measures of hospital performance were stable with and without adjustment for stage. The relative performance of hospitals was also stable, as demonstrated by fewer than 20% of hospitals changing decile rank. The c-statistic declined by less than 2% across all measures, indicating that model fit was not substantially worsened without this information. CONCLUSION: These findings support the use of FFS Medicare claims for hospital-level analyses of short-term outcomes following cancer surgery. Quality reporting based on these analyses can be used to help patients choose among hospitals and for evaluating policies to improve surgical cancer care.

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