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BACKGROUND: The current standard of care of screening and referring patients for treatment for symptoms, such as depression, pain, and fatigue, is not effective. This trial aimed to test the efficacy of an integrated screening and novel stepped collaborative care intervention versus standard of care for patients with cancer and at least one of the following symptoms: depression, pain, or fatigue. METHODS: This randomised, parallel, phase 3 trial was conducted in 29 oncology outpatient clinics associated with the UPMC Hillman Cancer Center in the USA. Patients (aged ≥21 years) with any cancer type and clinical levels of depression, pain, or fatigue (or all of these) were eligible. Eligible family caregivers were aged 21 years or older and providing care to a patient diagnosed with cancer who consented for this study. Patients were randomly assigned (1:1) to stepped collaborative care or standard of care using a central, permuted block design (sizes of 2, 4, and 6) stratified by sex and prognostic status. The biostatistician, oncologists, and outcome assessors were masked to treatment assignment. Stepped collaborative care was once-weekly cognitive behavioural therapy for 50-60 min from a care coordinator via telemedicine (eg, telephone or videoconferencing). Pharmacotherapy for symptoms might be initiated or changed if recommended by the treatment team or preferred by the patient. Standard of care was screening and referral to a health-care provider for treatment of symptoms. The primary outcome was health-related quality of life in patients at 6 months. Maintenance of the treatment benefits was assessed at 12 months. Participants included in the primary analysis were per intention to treat, which included patients missing one or both follow-up assessments. This trial was registered with ClinicalTrials.gov (NCT02939755). FINDINGS: Between Dec 5, 2016, and April 8, 2021, 459 patients and 190 family caregivers were enrolled. 222 patients were assigned to standard of care and 237 to stepped collaborative care. Of 459 patients, 201 (44%) were male and 258 (56%) were female. Patients in the stepped collaborative care group had a greater 0-6-month improvement in health-related quality of life than patients in the standard-of-care group (p=0·013, effect size 0·09). Health-related quality of life was maintained for the stepped collaborative care group (p=0·74, effect size 0·01). Patients in the stepped collaborative care group had greater 0-6-month improvements than the standard-of-care group in emotional (p=0·012), functional (p=0·042), and physical (p=0·033) wellbeing. No adverse events were reported by patients in either group and deaths were considered unrelated to the study. INTERPRETATION: An integrated screening and novel stepped collaborative care intervention, compared with the current standard of care, is recommended to improve health-related quality of life. The findings of this study will advance the implementation of guideline concordant care (screening and treatment) and has the potential to shift the practice of screening and treatment paradigm nationwide, improving outcomes for patients diagnosed with cancer. FUNDING: US National Cancer Institute.
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Cuidadores , Neoplasias , Feminino , Humanos , Masculino , Fadiga , Neoplasias/diagnóstico , Neoplasias/terapia , Dor , Qualidade de Vida , Resultado do Tratamento , Adulto Jovem , AdultoRESUMO
Combining immunotherapies with distinct mechanisms of action has the potential to overcome treatment resistance and improve outcomes. The inducible T-cell co-stimulator (ICOS) agonist feladilimab is directed at enhancing T-cell activation and function, thereby promoting an antitumor response. INDUCE-2 (NCT03693612) was a Phase I/II, open-label, two-part study evaluating the anti-ICOS agonist feladilimab in combination with the anti-CTLA-4 antibody tremelimumab in patients with select advanced solid tumors. Objectives of Part 1 were to determine the safety, tolerability, and recommended phase 2 dose (RP2D) of feladilimab in combination with tremelimumab. In Part 2, the antitumor activity of the combination (administered at the RP2D determined in Part 1) was to be assessed in patients with relapsed/refractory head and neck squamous cell carcinoma. Primary endpoints included the rates of dose-limiting toxicities (DLTs), adverse events (AEs), AEs of special interest, and serious AEs. Secondary endpoints included overall response rate, while biomarker assessment was exploratory. A total of 26 patients were enrolled, 18 (69%) of whom had completed the study at end date. One patient, in the highest dose group (24/225 mg feladilimab/tremelimumab), experienced a DLT 18 days after the first dose of study treatment. All patients experienced at least one AE; AEs led to treatment discontinuation in four (15%) patients. Partial response was observed in one patient. Feladilimab in combination with tremelimumab was well-tolerated but showed limited efficacy. Based on the totality of data from Part 1, it was decided not to continue with Part 2.
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Anticorpos Monoclonais Humanizados , Neoplasias de Cabeça e Pescoço , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , ImunoterapiaRESUMO
INTRODUCTION: We retrospectively studied young patients with head and neck squamous cell carcinoma (HNSCC) to identify factors associated with disease-specific survival (DSS). METHODS: Patient and tumor characteristics of patients aged ≤45 who received treatments for non-metastatic HNSCC were collected to identify factors associated with DSS. Proportional hazards regression was applied separately for surgical and non-surgical patients. RESULTS: 230 patients were included. Surgical and non-surgical patients had similar DSS. Higher pathologic stages, positive margins, perineural invasion (PNI), extranodal extension and negative HPV status were associated with worse DSS for surgical patients and negative HPV status for non-surgical patients. In the multivariate analysis, pathologic stages, positive margins, and PNI were associated with worse DSS in surgical patients. CONCLUSION: Pathologic stages, positive margins, and PNI are independently associated with worse DSS in young surgical HNSCC patients. PNI is a uniquely strong prognostic factor for young patients.
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BACKGROUND: The objectives of this study were to examine benefits and consequences of the COVID-19 pandemic for patients diagnosed with cancer and their family caregivers. METHODS: A 23-item questionnaire assessing COVID-19-related issues, the Patient Health Questionnaire-2, Generalized Anxiety Disorder-2, Pittsburgh Sleep Quality Index, and the Perceived Stress Scale (PSS)-4 were administered to patients diagnosed with cancer and their family caregivers. RESULTS: Of the 161 patients and 78 caregivers who participated, 38.1% and 32.8 were male, 95% and 84.6% Caucasian, and the mean age was 66 and 64.6 years, respectively. A total of 16.5% and 15.2% reported depressive symptoms, 18.4% and 19% reported anxiety; 35.5% and 26.6% reported poor sleep quality, and 66% and 63.3% scored one standard deviation above the norms for the PSS, respectively. Predictors of poorer patient- and caregiver-reported outcomes included greater loneliness, worry about self or family being infected by the COVID-19, and worsening relationships with family. The fear of COVID-19 led to 20.8% of patients and 24.4% of family caregivers cancelling medical appointments, procedures, and treatments. A total of 52.5% of patients and 53.2% caregivers reported that the pandemic led to benefit finding but these changes were not associated with any of the measured patient- or caregiver-related outcomes. CONCLUSIONS: Psychological functioning for patients and caregivers was similar to that of pre-pandemic levels, however the decrease in health care utilization secondary to fear of COVID-19 was notable. While there were many negative effects of the pandemic, the majority of patients and caregivers reported some benefit to the pandemic.
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COVID-19 , Neoplasias , Ansiedade/epidemiologia , Ansiedade/psicologia , COVID-19/epidemiologia , Cuidadores/psicologia , Estudos Transversais , Depressão/epidemiologia , Depressão/psicologia , Feminino , Humanos , Masculino , Neoplasias/terapia , Pandemias , SARS-CoV-2RESUMO
BACKGROUND: Risk stratification for patients with differentiated thyroid cancer (DTC) is based primarily on pathologic tumor characteristics. Accurate preoperative prognostication could allow for more informed initial surgical recommendations, particularly among patients at a higher risk for distant metastasis (DM). The objective of this study was to characterize the genetic profile of DTC with DM and to validate a molecular-based risk stratification. METHODS: A case-control study design was used to analyze patients who had DTC with DM (n = 62) and a propensity matched cohort of patients who had DTC without DM after at least 5 years of follow-up using the ThyroSeq version 3 targeted next-generation sequencing assay. The results were classified into high-risk, intermediate-risk, and low-risk of aggressive disease. RESULTS: Most patients who had DTC with DM (66%) had a late-hit mutation in TERT, TP53, or PIK3CA. After propensity matching by age, tumor size, and sex, the high-risk molecular profile had strong association with DM (high-risk vs intermediate-risk: odds ratio, 25.1; 95% CI, 3.07-204.4; P < .001; high-risk vs low-risk: odds ratio, 122.5; 95% CI, 14.5-1038.4; P < .001). Overall, molecular risk categories were associated with DM risk, with a concordance index of 0.836 (95% CI, 0.759-0.913), which remained consistent after internal validation. Within the range of 5% to 10% of DM observed in DTC, the expected probability of DM would be 0.2% to 0.4% for the low-risk molecular profile, 4.7% to 9.4% for the intermediate-risk molecular profile, and 19.3% to 33.5% for the high-risk molecular profile. CONCLUSIONS: In this matched case-control study, genetic profiling using an available molecular assay provided accurate and robust risk stratification for DM in patients with DTC. The availability of preoperative prognostication may allow tailoring treatment for patients with DTC.
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Adenocarcinoma , Neoplasias da Glândula Tireoide , Adenocarcinoma/genética , Adenocarcinoma/patologia , Estudos de Casos e Controles , Humanos , Mutação , Medição de Risco , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologiaRESUMO
Human papillomavirus (HPV), one of the most common sexually transmitted diseases worldwide, has an established role in the pathogenesis of genital malignancies such as cervical cancer. The virus has also been implicated in the oncogenesis of nongenital cancers including head and neck malignancies (specifically oropharyngeal cancers) as well as anal cancer. There is less clarity regarding its role in lung and esophageal cancers. Worldwide, the incidence and prevalence of HPV-associated oropharyngeal cancer has been increasing over time. These patients have improved outcomes compared with those with HPV-negative oropharyngeal cancers, and there is continued interest in designing treatments specifically for this HPV-positive subgroup. Clinicians continue to gain an understanding of HPV in anal cancers and the risk factors associated with infection and progression to malignancy. This has potential implications for the eventual screening of high-risk groups. While HPV vaccination is currently approved for the prevention of cervical cancer, it also has potential in the prevention of all HPV-associated malignancies. In this review, current understanding of the role of HPV in nongenital cancers is discussed, as well as future implications for treatment and prevention.
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Neoplasias/virologia , Papillomaviridae/imunologia , Doenças Virais Sexualmente Transmissíveis/virologia , Neoplasias do Ânus/imunologia , Neoplasias do Ânus/prevenção & controle , Neoplasias do Ânus/virologia , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/prevenção & controle , Neoplasias Esofágicas/virologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/prevenção & controle , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/prevenção & controle , Neoplasias Pulmonares/virologia , Neoplasias/imunologia , Neoplasias/prevenção & controle , Vacinas contra Papillomavirus , Prevalência , Prognóstico , Fatores de Risco , Doenças Virais Sexualmente Transmissíveis/imunologia , Doenças Virais Sexualmente Transmissíveis/prevenção & controleRESUMO
OPINION STATEMENT: The demographics of head and neck cancer (HNC) survivors are changing, contributing to a growing number of survivors and a greater length of survivorship. Curative treatment involves intense multimodal therapy, which contributes to both short-term toxicities and long-term treatment-related effects. Delivering high-quality, relevant cancer survivorship care is a growing national priority. Various survivorship models and tools, such as survivorship care plans, have been utilized in an attempt to enhance care and optimize outcomes. However, an essential, yet understudied, component of high-quality survivorship care is the identification and management of late and long-term treatment-related effects. In this article, we will describe the current advancements in survivorship care as well as the research related to late and long-term treatment effects. While there is a growing body of literature that describes the prevalence of treatment-related effects and their impact on quality of life, more work is needed. Research that investigates the interplay of these complex treatment effects, the biological mechanisms that contribute to their variability, and interventions designed to mitigate them are desperately needed. While de-intensification offers the potential to alleviate these effects for future survivors, we need clinically meaningful assessment tools and therapies to provide the survivors we evaluate and treat daily. Targeted patient-reported outcomes and objective measures validated through clinical research are needed to help us systematically identify and treat late and long-term effects. In order to tailor and optimize the care we provide to our HNC survivors, we will need to leverage these tools as well as the expertise of all members of our multidisciplinary survivorship teams.
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Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/mortalidade , Animais , Sobreviventes de Câncer , Humanos , Medidas de Resultados Relatados pelo Paciente , Qualidade da Assistência à Saúde , Qualidade de Vida , SobrevivênciaRESUMO
BACKGROUND: To characterize the expression of co-signaling molecules PD-L1, PD-1, and B7-H3 in cutaneous squamous cell carcinoma (cSCC) by immune status. METHODS: We retrospectively analyzed 66 cases of cSCC treated with surgical resection from 2012 to 2015. Immunostained tumor sections were analyzed for percent of tumor cells expressing PD-L1 (Tum-PD-L1%), B7-H3 (Tum-B7-H3%), density of peri and intratumoral CD8 T cells (CD8 density), proportion of CD8 T cells expressing PD-1 (CD8-PD-1%) and of tumor-infiltrating immune cells (TII) expressing PD-L1 (TII-PD-L1%). RESULTS: Of 66 cases, 42 were immunocompetent, 24 immunosuppressed (13 organ transplant, 8 HIV+, 3 other). Defining positive expression at > 5%, 26% of tumors were positive for PD-L1, 85% for B7-H3, 80% had CD8 T cells that expressed PD-1 and 55% had TII that expressed PD-L1. Tum-B7-H3% was significantly higher (median 60 vs. 28%, p = 0.025) in immunocompetent vs. immunosuppressed patients, including when factoring in cause of immunosuppression. No significant difference in Tum-PD-L1%, TII-PD-L1%, CD8 density, or CD8-PD-1% was observed. Tumors from HIV+ patients lacked PD-L1 expression, and had lower B7-H3% (median 2.5 vs. 60%, p = 0.007), and higher CD8 density (median 75% vs. 40%, p = 0.04) compared to immunocompetent patients. Higher tumor grade (Rs = 0.34, p = 0.006) and LVI (Rs = 0.61, p < 0.001) were both associated with higher Tum-PD-L1%. CONCLUSION: cSCC showed expression of PD-L1 on tumor in 26% of cases, and high tumor B7-H3 expression (85%) and PD-1 expression on CD8 TILs (80%). Tumor B7-H3 expression was significantly higher in immunocompetent vs. immunosuppressed patients, largely driven by very low expression in HIV+ patients.
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Antígenos B7/metabolismo , Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Imunocompetência/imunologia , Hospedeiro Imunocomprometido/imunologia , Terapia de Imunossupressão , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologiaRESUMO
OPINION STATEMENT: In head and neck cancer, we continue to work towards a more personalized approach to treatment of patients, where analysis of a patient's tumor guides targeting of molecular or immunologic pathways. Critically important to this pursuit is a better understanding of the direct biologic effect of a drug or combination on the tumor microenvironment in humans, as well as biomarker discovery. These goals are consistent with the primary purpose of a "window of opportunity" trial and while conduct of these trials requires a careful balance of benefits and potential risks, to date these trials have been both feasible and safe in HNSCC in the curative intent setting. In the era of immunotherapy, with countless possible combinations and ongoing clinical trials, window trials are even more important for informing clinical trial design and appropriate combination therapy, and ultimately a more personalized approach to our patients that leads to improvement in outcomes.
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Terapia Combinada/métodos , Imunoterapia/métodos , Terapia de Alvo Molecular/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Humanos , Fatores Imunológicos/uso terapêuticoRESUMO
BACKGROUND: We conducted a phase I dose escalation study to evaluate the safety and immunologic response to peptide immunomodulatory vaccines GL-0810 (HPV16) and GL-0817 (MAGE-A3) in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively. METHODS: Three dose levels (500, 1,000, and 1,500 µg) of GL-0810 or GL-0817 with adjuvants Montanide (1.2 ml) and GM-CSF (100 µg/m2) were administered subcutaneously q2 weeks for a total of four vaccinations in HPV16 and MAGE-A3-positive RM-SCCHN patients, respectively. RESULTS: Nine and seven patients were enrolled in the HPV16 and MAGE-A3 cohorts, respectively. No dose-limiting toxicities were observed, and toxicity was predominantly local and grade 1 (erythema, pain, and itching at the injection site). In those patients who received all four vaccinations, 80 % (4/5) of the HPV16 cohort and 67 % (4/6) of the MAGE-A3 cohort developed antigen-specific T cell and antibody responses to the vaccine. Significant concordance between T cell and antibody responses was observed for both groups. No clear dose-response correlation was seen. All patients progressed by RECIST at first repeat imaging, except for one patient in the MAGE-A3 500 µg cohort who had stable disease for 10.5 months. The median PFS and OS for the MAGE-A3 cohorts were 79 and 183 days, respectively, and for the HPV16 cohort 80 and 196 days, respectively. CONCLUSIONS: GL-0810 and GL-0817 were well tolerated in patients with RM-SCCHN with T cell and antibody responses observed in the majority of patients who received all four vaccinations.
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Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Papillomavirus Humano 16/imunologia , Fatores Imunológicos/administração & dosagem , Proteínas de Neoplasias/imunologia , Vacinas de Subunidades Antigênicas/administração & dosagem , Adulto , Idoso , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/imunologia , Estudos de Coortes , Progressão da Doença , Relação Dose-Resposta Imunológica , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/administração & dosagem , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Fatores Imunológicos/imunologia , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço , Vacinas de Subunidades Antigênicas/imunologiaRESUMO
BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy arising in immunocompromised patients such as solid organ transplant recipients. In addition to an abundance in number, the morbidity and mortality of these tumors in this patient population exceeds that of immune competent individuals. Here, we used whole exome and bulk RNA sequencing to analyze mutation profiles between tumors arising in immunocompetent and immunosuppressed patients. METHODS: DNA and RNA extracted from twenty formalin-fixed, paraffin embedded tumors and adjacent skin was sequenced. Bioinformatic analysis revealed tumor mutational burden, mutational signatures, microsatellite instability, and aberrant signaling pathways. RESULTS: Similar median tumor mutational burden was found in both the tumors from the immunocompetent and the immunosuppressed cohorts. Mutation signature analysis revealed UVR signatures and evidence of azathioprine exposure. 50% of tumors from the immunosuppressed patients have mutations consistent with microsatellite instability, yet mismatch repair protein expression was preserved in the samples analyzed. Additionally, frequently mutated genes in this cohort belong to the extracellular matrix receptor interaction and calcium signaling pathways, suggesting these may be targets for future treatments of this disease. CONCLUSIONS: This study utilizes whole exome and bulk RNA sequencing to identify difference between cSCC arising in immunosuppressed and immunocompetent patients using the patient's photo exposed, but histologically normal appearing skin as the "germline" comparison. We demonstrate an enrichment in microsatellite instability in the tumors from immunosuppressed patients and differences in oxidative phosphorylation and epithelial-mesenchymal transition which may be targets for therapeutic intervention based on identification of mutations.
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Carcinoma de Células Escamosas , Neoplasias Cutâneas , Humanos , Carcinoma de Células Escamosas/patologia , Neoplasias Cutâneas/patologia , Instabilidade de Microssatélites , Hospedeiro Imunocomprometido , Genômica , Perfilação da Expressão GênicaRESUMO
BACKGROUND: We retrospectively evaluated radiomics as a predictor of the tumor microenvironment (TME) and efficacy with anti-PD-1 mAb (IO) in R/M HNSCC. METHODS: Radiomic feature extraction was performed on pre-treatment CT scans segmented using 3D slicer v4.10.2 and key features were selected using LASSO regularization method to build classification models with XGBoost algorithm by incorporating cross-validation techniques to calculate accuracy, sensitivity, and specificity. Outcome measures evaluated were disease control rate (DCR) by RECIST 1.1, PFS, and OS and hypoxia and CD8 T cells in the TME. RESULTS: Radiomics features predicted DCR with accuracy, sensitivity, and specificity of 76%, 73%, and 83%, for OS 77%, 86%, 70%, PFS 82%, 75%, 89%, and in the TME, for high hypoxia 80%, 88%, and 72% and high CD8 T cells 91%, 83%, and 100%, respectively. CONCLUSION: Radiomics accurately predicted the efficacy of IO and features of the TME in R/M HNSCC. Further study in a larger patient population is warranted.
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BACKGROUND: Sinonasal malignancies (SNMs) frequently present with orbital invasion. Orbital exenteration (OE) can lead to significant morbidity. Induction chemotherapy (IC) is a promising treatment alternative that may allow for orbit preserving (OP) treatments without compromising patient survival. This systematic review was conducted to synthesize the published data on SNM patients with orbital invasion who underwent IC, including tumor response, orbital outcomes, and survival. METHODS: The study protocol was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Databases Embase, Cochrane, Medline, and Scopus, from inception to July 17, 2023, were searched. RESULTS: Nineteen studies were included, encompassing 305 SNM patients with orbital invasion treated with IC. Fourteen studies reported an overall IC response rate (positive response defined as complete or partial tumor volume reduction) of 77.2%. Among included studies, OE rates after IC ranged from 0 to 40%. Three studies reported a high rate of posttreatment functional orbital preservation (89.8-96.0%). Five studies specifically reported that 62.5% (60 out of 96) of patients were downgraded from planned OE to OP treatment following IC. Three studies reported a significant overall survival (OS) improvement in IC responders versus IC nonresponders. Following IC, 5-year OS ranged from 44.2 to 55.5%. Patients with olfactory neuroblastoma demonstrated the highest IC response rate and lowest OE rate (100 and 0%, respectively) versus those with sinonasal undifferentiated carcinomas (68.4 and 0%) or squamous cell carcinomas (76.7 and 16%). CONCLUSIONS: For select patients, IC may allow for OP in locally advanced SNMs with orbital involvement.
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Quimioterapia de Indução , Neoplasias Orbitárias , Neoplasias dos Seios Paranasais , Humanos , Neoplasias dos Seios Paranasais/tratamento farmacológico , Neoplasias dos Seios Paranasais/patologia , Neoplasias Orbitárias/tratamento farmacológico , Neoplasias Orbitárias/patologia , Invasividade Neoplásica , Resultado do Tratamento , Órbita/patologiaRESUMO
OBJECTIVES: Currently, no systemic treatments are approved for patients with recurrent and/or metastatic (R/M) adenoid cystic carcinoma (ACC). PRT543, a protein arginine methyltransferase 5 inhibitor that downregulates NOTCH1 and MYB signalling in tumours, is a potential candidate for R/M ACC treatment. We report the safety, tolerability and preliminary efficacy of PRT543 in a dose-expansion cohort of patients with R/M ACC. MATERIALS AND METHODS: This phase I multicentre, open-label, sequential-cohort, dose-escalation and dose-expansion study (NCT03886831) enrolled patients with advanced solid tumours and select haematologic malignancies. Dose-escalation study design and results were reported previously. In the dose expansion, patients with R/M ACC received recommended phase II doses of 35 or 45 mg PRT543 orally on days 1-5 of each week. Primary objectives were to establish the safety and tolerability of PRT543. Secondary objectives included efficacy. RESULTS: Between February 2019 and May 2022, 56 patients with ACC were enrolled across 23 US sites and received either 35 mg (n = 28) or 45 mg (n = 28) of PRT543. Overall, 23% of patients experienced a grade 3 treatment-related adverse event, most commonly anaemia (16%) and thrombocytopaenia (9%). No grade 4/5 treatment-emergent adverse events were reported. Median progression-free survival was 5.9 months (95% CI: 3.8-8.3). The clinical benefit rate was 57% (95% CI: 43-70). Overall response rate (per Response Evaluation Criteria in Solid Tumours v1.1) was 2%, with 70% of patients having stable disease. CONCLUSION: In this analysis, PRT543 was tolerable, and the observed efficacy was limited in patients with R/M ACC.
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Carcinoma Adenoide Cístico , Humanos , Carcinoma Adenoide Cístico/tratamento farmacológico , Proteína-Arginina N-Metiltransferases , Recidiva Local de Neoplasia , Intervalo Livre de ProgressãoRESUMO
Prior studies have investigated patients' characteristics, treatments, and outcomes for older adults with myelodysplastic syndromes, but most failed to distinguish chronic myelomonocytic leukemia. Recognizing potentially important differences between the diseases, we undertook a population-based comparison of baseline characteristics, treatments, and outcomes between older adults with chronic myelomonocytic leukemia and myelodysplastic syndromes. The patients' data were obtained from Surveillance Epidemiology and End Results registry data from 2001-2005, linked to Medicare claims. Baseline characteristics, treatment (red blood cell transfusions, hematopoietic growth factors, hypomethylating agents, chemotherapy or transplantation), progression to acute myeloid leukemia, and overall survival were compared using bivariate techniques. Multivariate logistic regression estimated differences in treatments received. Cox proportional hazard models estimated the effects of chronic myelomonocytic leukemia relative to myelodysplastic syndromes on progression-free survival. A larger proportion of patients with chronic myelomonocytic leukemia (n=792), compared to patients with myelodysplastic syndromes (n=7,385), failed to receive any treatment (25% versus 15%; P<0.0001), or only received red blood cell transfusions (19.8% versus 16.7%; P=0.037). A larger percentage of patients with chronic myelomonocytic leukemia progressed to acute myeloid leukemia (42.6% versus 15.5%, respectively; P<0.0001), with shorter time to progression. Chronic myelomonocytic leukemia patients had a shorter median survival (13.3 versus 23.3 months; P<0.0001) and lower 3-year survival rate (19% versus 36%; P<0.0001). Adjusted estimates, controlling for baseline characteristics and selected treatments, indicate that chronic myelomonocytic leukemia was associated with an increased risk of progression to acute myeloid leukemia or death (HR 2.22; P<0.0001), compared to myelodysplastic syndromes. In conclusion, chronic myelomonocytic leukemia is less frequently treated in older adults and is associated with worse outcomes, even after controlling for the patients' baseline characteristics and selected treatments. Our data suggest the need for continued evaluation of the biological differences between these diseases and clinical trials targeting chronic myelomonocytic leukemia.
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Leucemia Mieloide/terapia , Leucemia Mielomonocítica Crônica/terapia , Síndromes Mielodisplásicas/terapia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Tratamento Farmacológico/métodos , Transfusão de Eritrócitos/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide/patologia , Leucemia Mielomonocítica Crônica/patologia , Modelos Logísticos , Masculino , Medicare/estatística & dados numéricos , Pessoa de Meia-Idade , Análise Multivariada , Síndromes Mielodisplásicas/patologia , Avaliação de Resultados da Assistência ao Paciente , Prognóstico , Modelos de Riscos Proporcionais , Programa de SEER/estatística & dados numéricos , Estados UnidosRESUMO
Targeted immunotherapy has improved patient survival in head and neck squamous cell carcinoma (HNSCC), but less than 20% of patients produce a durable response to these treatments. Thus, new immunotherapies that consider all key players of the complex HNSCC tumour microenvironment (TME) are necessary to further enhance tumour-specific T cell responses in patients. HNSCC is an ideal tumour type in which to evaluate immune and non-immune cell differences because of two distinct TME aetiologies (human papillomavirus (HPV)-positive and HPV-negative disease), multiple anatomic sites for tumour growth, and clear distinctions between patients with locally advanced disease and those with recurrent and/or metastatic disease. Recent technological and scientific advancements have provided a more complete picture of all cellular constituents within this complex TME and have evaluated the interplay of both immune and non-immune cells within HNSCC. Here, we include a comprehensive analysis of the complete ecosystem of the HNSCC TME, performed utilizing data-rich resources such as The Cancer Genome Atlas, and cutting-edge techniques, such as single-cell RNA sequencing, high-dimensional flow cytometry and spatial multispectral imaging, to generate improved treatment strategies for this diverse disease.
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Antineoplásicos Imunológicos , Neoplasias de Cabeça e Pescoço , Imunomodulação , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral , Humanos , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/terapia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Microambiente Tumoral/imunologia , Antineoplásicos Imunológicos/imunologia , Antineoplásicos Imunológicos/uso terapêuticoRESUMO
OBJECTIVE: In the setting of similar outcomes, quality of life (QOL) measures can be utilized to compare treatment modalities in head and neck squamous cell carcinoma (HNSCC). We evaluate QOL and symptoms in patients treated for primary, second primary, and recurrent HNSCC. STUDY DESIGN: Retrospective cohort study. SETTING: Head and neck cancer survivorship clinic. METHODS: We identified patients seen between 2016 and 2019. QOL and symptoms were assessed with the University of Washington Quality of Life (UW-QOL) questionnaire, 10-item Eating Assessment Tool, 8-item Patient Health Questionnaire, 7-item Generalized Anxiety Disorder, and Neck Disability Index. Regression analysis was utilized to explore associations and compare QOL outcomes. RESULTS: Our cohort comprised 662 patients: 546 with primary HNSCC, 34 with second primary HNSCC, and 82 with recurrent HNSCC. Multimodality therapy was associated with lower UW-QOL Physical Subscale (UW-QOL-PS) vs single modality: chemoradiation therapy (-12.17 [95% CI, -16.57 to -7.78]) and surgery + postadjuvant treatment (-12.11 [-16.06 to -8.16]). Multimodality therapy was also associated with lower UW-QOL Social-Emotional Subscale (UW-QOL-SS): chemoradiation therapy (-6.70 [-11.41 to -1.99]) and surgery + postadjuvant treatment (-7.41 [-11.63 to -3.19]). Recurrence (-14.42 [-18.80 to -10.04]) and second primary (-11.15 [-17.71 to -4.59]) demonstrated lower UW-QOL-PS vs primary. Radiation for recurrence or second primary had worse UW-QOL-PS (-10.43 [-19.27 to -1.59]) and UW-QOL-SS (-10.58 [-18.76 to -1.54]) and higher Eating Assessment Tool (6.08 [1.39-10.77]) than surgery alone. Surgery + postadjuvant treatment showed worse UW-QOL-PS (-12.65 [-23.76 to -1.54]) and UW-QOL-SS (-12.20 [-22.38 to -2.03]). CONCLUSION: Multimodality therapy, particularly with recurrent and second primary HNSCC, is more likely to contribute to diminished QOL and symptoms. This important consideration should play a role in framing informed discussions with patients regarding treatment.
Assuntos
Neoplasias de Cabeça e Pescoço , Qualidade de Vida , Humanos , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Recidiva Local de Neoplasia/terapia , Neoplasias de Cabeça e Pescoço/terapia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: A position statement put forth by the American Head and Neck Society (AHNS) was constructed to provide evidence-based treatment recommendations for PD-1 inhibitor use in advanced cutaneous squamous cell carcinoma (cSCC). Secondarily, we sought to identify knowledge gaps warranting further investigation. METHODS: A literature search utilizing key terms: cutaneous squamous cell carcinoma, cutaneous cancer, checkpoint inhibitors, systemic therapy, Program Cell Death, PD-1 (PubMed, Cochrane, and Google Scholar) was carried out to generate evidence-based statements. The statements were distributed among the AHNS membership. Delphi methodology was applied to identify statements achieving 70% or greater consensus among the leadership team. RESULTS: Twenty-six position statements achieved consensus. Knowledge gaps for future research included: impact of immunosuppression on cSCC staging and associated treatment; role of PD-1 inhibitors in immunosuppressed patients. CONCLUSION: This comprehensive position statement put forth by the AHNS represents majority consensus by practicing head and neck surgeons throughout the country.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Cutâneas , Humanos , Estados Unidos , Carcinoma de Células Escamosas/patologia , Neoplasias Cutâneas/patologia , Inibidores de Checkpoint Imunológico , Consenso , Neoplasias de Cabeça e Pescoço/tratamento farmacológicoRESUMO
OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) causes severe pain and opioids, the mainstay of pain management, may have immunomodulatory effects. We evaluated the effect of opioids on immunotherapy efficacy in recurrent/metastatic (R/M) HNSCC patients. MATERIALS AND METHODS: In a retrospective study of 66 R/M HNSCC patients from 2015 to 2020, opioid dosage, calculated as mean morphine milligram equivalent per day, was assessed on the day of anti-PD-1 monoclonal antibody (mAb) treatment and most recent prior visit. Intratumoral T cells were evaluated by single cell RNAseq and immunohistochemistry prior to treatment. Univariable and multivariable Cox proportional hazards and logistic regression models were used to estimate the association between opioid usage, progression-free survival (PFS), overall survival (OS), disease control rate. RESULTS: Patients were 79% male, 35% oropharynx, 35% oral cavity, 40% locoregional recurrence, and 56% platinum failure. Higher opioid dosage by continuous variable was significantly associated with lower PFS (p = 0.016) and OS (p < 0.001). In multivariable analysis, including platinum failure status and PD-L1, higher opioids were associated with lower OS. Opioid usage by categorical variable was associated with significantly lower intratumoral CD8+ T cells. Opioid receptor, OPRM1, expression was identified in intratumoral and circulating T cells. CONCLUSIONS: In our study cohort of anti-PD-1 mAb treatment in R/M HNSCC patients, higher opioids were associated with significantly lower PFS and OS and lower CD8+ T cells in the tumor microenvironment. To our knowledge, this is the first analysis in R/M HNSCC patients and further research into the clinical and biologic effect of opioids is warranted.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Humanos , Masculino , Feminino , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Analgésicos Opioides/uso terapêutico , Linfócitos T CD8-Positivos/metabolismo , Estudos Retrospectivos , Platina/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/etiologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Imunoterapia/efeitos adversos , Recidiva Local de Neoplasia/patologia , Microambiente TumoralRESUMO
OBJECTIVES: The aims of the study were to (1) describe types of pain in cancer patients, (2) examine the predictors and consequences of pain, (3) investigate the association between type of pain and survival, and (4) examine potential biological mediators of pain and survival. METHODS: This was a secondary analysis of baseline data from patients diagnosed with cancer. Patients answered questionnaires that assessed sociodemographic characteristics, pain, depression, sleep, and fatigue. Blood was collected and cytokine assays were performed. Analysis of variance, Kaplan-Meier, and Cox regression survival analyses were used to test the aims. RESULTS: Of the 779 patients diagnosed with cancer, the mean age was 63.5 years, 57.8% male, and 90.6% White. Of those who reported pain (total 70.3%), 46.5% stated their pain was cancer-related while 53.5% stated their pain was non-cancer-related. While both cancer and non-cancer-related pain was associated with depressive symptoms, fatigue, and sleep duration, those with cancer-related pain had significantly higher rates of depressive symptoms (F(1,516) = 21.217, p < 0.001) and fatigue (F(1,516) = 30.973, p < 0.001) but not poorer sleep (F(1,497) = 0.597, p = 0.440). After adjusting for sociodemographic, disease-related characteristics, depression, sleep duration, and morphine milligram equivalent, patient reports of cancer-related pain were significantly associated with poorer survival (HR = 0.646, 95% CI = 0.459-0.910, p = 0.012) compared to those with non-cancer-related pain, which was not associated with survival (HR = 1.022, 95% CI = 0.737-1.418, p = 0.896). Cytokines did not significantly mediate the link between pain and survival. CONCLUSION: While nearly half of the pain reported was cancer-related, both types of pain resulted in greater symptom burden, but only cancer-related pain was associated with survival.