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Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab. NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III–IVB p16-negative HNSCC or unfavourable stage I–III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m2 1 week before radiotherapy then 250 mg/m2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment. Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64–77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9–3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5–59·8) in the durvalumab group versus 63·7% (51·3–76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84–2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3–4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group). Our findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population. US National Cancer Institute and AstraZeneca.

Adults with cancer may perceive cannabis as beneficial for managing their cancer-related symptoms, but the evidence supporting its medical use is varied and inconclusive. This study characterized associations of cannabis use with cancer-related symptom trajectories. Participants were adults undergoing cancer treatment at the Stephenson Cancer Center (SCC; n  = 218) in Oklahoma; they were 71% female, 10% minoritized race, and 45% had stage III or IV cancer. Participants completed surveys at baseline and 2-, 4-, and 6-months post-baseline. Assessments queried about cannabis use behavior, physical and psychological distress via the Rotterdam Symptoms Checklist (RSCL), respiratory symptoms via the American Thoracic Society Questionnaire (ATSQ), and quality of life indices (physical and social functioning, pain interference, sleep quality, fatigue) via the Patient Reported Outcomes Measurement Information System (PROMIS-29). Cannabis use status was categorized based on self-reported past 30-day cannabis use at each assessment as non-use [no use at any assessment], occasional-use [use at 1–2 assessments], or consistent-use [use at 3–4 assessments]. Longitudinal hierarchical linear modeling evaluated associations of cannabis use status with average symptoms and symptom trajectories across all four assessments. One-third (33%) of participants reported past 30-day cannabis use at ≥ 1 assessment. Participants who reported cannabis use (occasional-use and consistent-use) had more severe symptoms overall across assessments. While most cancer symptom trajectories did not differ by cannabis use status, participants who reported consistent cannabis use uniquely showed worsening physical function over time. Cannabis use was associated with greater cancer-related symptom severity over time.

DNA-dependent protein kinase (DNA-PK) plays a crucial role in repair of DNA double-strand breaks by facilitating non-homologous end-joining. Inhibitors of DNA-PK have the potential to block DNA repair and enhance DNA-damaging agents. Peposertib (M3814) is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including ionizing radiation (IR) and topoisomerase II inhibitors. Here we evaluated the activity of peposertib (M3814) in combination with radiation in a mouse xenograft model of HPV-associated cervical cancer. Athymic nude female mice with established tumors derived from HeLa cells injected into the flank were treated with vehicle alone (n = 3), IR alone (n = 4), and peposertib (M38814) in combination with IR (M3814 + IR; n = 4). While IR alone was associated with a trend towards decreased tumor volume compared with untreated, only the M3814 + IR treatment arm was associated with consistent and significant reduction in tumor burden, which correlated with higher levels of γ-H2AX in tumor cells, a marker of double-strand DNA breaks. Our data support further clinical evaluation of the combination of peposertib (M38814) and IR in cervical cancer.

Transparent and precise endpoint definitions are a crucial aspect of clinical trial conduct and reporting, and are used to communicate the benefit of an intervention. Previous studies have identified inconsistencies in endpoint definitions across oncological clinical trials. Here, the Head and Neck Cancer International Group assessed endpoint definitions from phase 3 trials or trials considered practice-changing for patients with recurrent or metastatic mucosal head and neck squamous cell carcinoma, published between 2008 and 2021. We identify considerable and global heterogeneity in endpoint definitions, which undermines the interpretation of results and development of future studies. We show how fundamental components of even incontrovertible endpoints such as overall survival vary widely, highlighting an urgent need for increased rigour in reporting and harmonisation of endpoints.

Robust time-to-event endpoint definitions are crucial for the assessment of treatment effect and the clinical value of trial interventions. Here, the Head and Neck Cancer International Group investigated endpoint use in phase 3 trials and trials considered potentially practice-changing published between 2008 and 2021 in the curative-intent setting for patients with mucosal head and neck squamous cell carcinoma. Of the 92 trials reviewed, we show that all core components of endpoint reporting were heterogeneous, including definitions of common terms, such as overall survival and progression-free survival. Our report highlights the urgent need for harmonisation of fundamental components of clinical trial endpoints and the engagement of all stakeholders to ensure the transparent reporting of endpoint details.

Background Advanced squamous cell carcinoma (SCCa) of the oral cavity is often not amenable to curative-intent therapy due to tumor location, tumor size, or comorbidities. Case presentation A 51-year-old male patient with human immunodeficiency virus and on highly active antiretroviral therapy (HAART) presented with a cT4aN2c SCCa of the tongue. He received a preoperative single course of Quad-Shot radiation therapy to 14 Gy in 4 fractions followed by surgical resection. Patient had no residual carcinoma on surgical pathology and no evidence of disease on subsequent clinical and radiological exams. Conclusions To our knowledge, this is the first case of pathologic complete response for a patient on HAART following a single cycle of the Quad-Shot regimen for advanced oral cavity SCCa. Protease inhibitors in HAART can induce spontaneous tumor regression via inhibition of proteasome function and activation of apoptosis, and thus act as a cancer therapeutic. Graphical Abstract

Hepatopancreatobiliary surgery belongs to one of the most complex fields of general surgery. An intricate and vital anatomy is accompanied by difficult distinctions of tumors from fibrosis and inflammation; the identification of precise tumor margins; or small, even disappearing, lesions on currently available imaging. The routine implementation of ultrasound use shifted the possibilities in the operating room, yet more precision is necessary to achieve negative resection margins. Modalities utilizing fluorescent-compatible dyes have proven their role in hepatopancreatobiliary surgery, although this is not yet a routine practice, as there are many limitations. Modalities, such as photoacoustic imaging or 3D holograms, are emerging but are mostly limited to preclinical settings. There is a need to identify and develop an ideal contrast agent capable of differentiating between malignant and benign tissue and to report on the prognostic benefits of implemented intraoperative imaging in order to navigate clinical translation. This review focuses on existing and developing imaging modalities for intraoperative use, tailored to the needs of hepatopancreatobiliary cancers. We will also cover the application of these imaging techniques to theranostics to achieve combined diagnostic and therapeutic potential.

Background Primary squamous cell carcinoma of the thyroid is a very rare malignancy with aggressive growth and poor prognosis. There is currently no consensus for treatment modality, however, most patients with primary squamous cell carcinoma of the thyroid are treated with surgery and adjuvant chemoradiation. Case presentation We report a rare case of primary squamous cell carcinoma of the thyroid in a 68-year-old White male who underwent chemoradiation and palliative immunotherapy after declining surgery. He was treated with intensity-modulated radiation therapy to 70 Gy in 35 fractions, with concurrent carboplatin–paclitaxel and palliative pembrolizumab. Local thyroid disease recurrence occurred at 6 months post-chemoradiation, and the patient died at 16 months post-chemoradiation. Conclusions This is the first case report demonstrating the use of pembrolizumab as palliative therapy for primary squamous cell carcinoma of the thyroid. Our study also highlights the importance of chemoradiation in decreasing primary mass size and immunotherapy in preventing metastatic disease progression.

The US cancer survivor population is projected to hit 26M by 2040. Chemotherapy is an effective cancer treatment, but can diminish cancer survivors' quality of life-particularly cognitive function-through select pathophysiological processes, including immune system and antioxidant dysregulation. The resulting cytokine release can impair cerebrovascular function-likely contributing to chemotherapy-induced cognitive impairment (CICI; \"chemo-brain\"). Type 2 diabetes mellitus (T2DM)-a common cancer survivor comorbidity-shares underlying pathophysiology with CICI. Cancer survivors with T2DM might thus have a higher CICI risk than those without T2DM. Physical activity (PA) counteracts CICI's and T2DM's pathophysiology, but little to no research has been conducted assessing the impact of PA on this joint pathophysiology. To compare cerebrovascular and cognitive function as well as proinflammatory, cardiometabolic, epigenetic, and psychosocial outcomes between ancer survivors with and without T2DM pre- to postengagement in a 12-week technology-based PA program grounded in the Social Cognitive Theory. We hypothesize that cancer survivors with and without T2DM will demonstrate similar pre to poststudy improvements in psychosocial outcomes, but that changes in cerebrovascular and cardiometabolic outcomes, as well as PA engagement, will be greater for cancer survivors with T2DM. We also believe that each group will have distinct epigenetic profiles that will change pre to poststudy. We are conducting a 30-participant pilot study in cancer survivors with (n=15) and without (n=15) T2DM-all of whom report currently experiencing \"chemo-brain.\" To account for attrition, we are recruiting 38 cancer survivors from Oklahoma City, OK, and the surrounding area. Among the most important eligibility criteria are the self-report of cognitive difficulties following primary cancer treatment, being ≥18 years old, being within 3 years of primary cancer treatment, and not meeting nationally recommended PA guidelines. Participants receive 2 smartphone apps. One smartphone app provides health education and the ability to set goals and journal about their wellness journey. The other provides a workout program continually tailored to each participant via their communication with the study exercise physiologist, with resistance bands and a wearable device provided to support the program. At Baseline and Poststudy, we assess cerebrovascular function (transcranial doppler [TCD]), cognition (National Institutes of Health Toolbox), cardiometabolic outcomes (venipuncture), and epigenetics (saliva collection). Participants also wear accelerometers at Baseline and Poststudy to objectively assess PA, with Baseline, Midpoint, and Poststudy surveys assessing psychosocial outcomes. We will use t tests and chi-square tests to assess baseline differences and repeated-measures ANCOVA to assess changes over time. Participant recruitment started in March 2025, and we expect to recruit until late 2026. We will begin analyzing baseline data in 2026. Successful study completion will provide valuable insights into the remote delivery of PA-oriented supportive care for cancer survivors experiencing chemo-brain, as well as how T2DM and PA contribute to the mechanistic underpinnings of chemo-brain. ClinicalTrials.gov NCT06725953; https://clinicaltrials.gov/study/NCT06725953. DERR1-10.2196/79739.