Oncologist最新文献

Melanoma of unknown primary (MUP) is a rare subtype of melanoma, with its low incidence posing challenges for clinical management. This systematic review integrates recent advances in MUP research, with a focus on pathogenesis, molecular characteristics, and therapeutic strategies. The proposed pathogenesis involves spontaneous regression of the primary lesion, potentially driven by sequential immune responses mediated by T cells and natural killer cells. At the molecular level, whole-exome/genome analyses reveal that MUP and cutaneous melanoma share a highly concordant UV damage-driven mutational landscape; nevertheless, MUP exhibits distinct genomic alterations, including recurrent mutations in the telomerase reverse transcriptase promoter, protein phosphatase 6 catalytic subunit, and isocitrate dehydrogenase 1. Current therapeutic approaches are similar to those for advanced melanoma, encompassing surgery, immune checkpoint inhibitors (ICIs), and targeted therapies. While ICIs have demonstrated significant improvements in survival, the clinical efficacy of targeted therapies in MUP remains to be fully established. By consolidating current knowledge, this review provides insights to guide diagnosis, treatment, and future research in MUP.

Background: People living with HIV (PWH) have an increased risk of developing aggressive skin cancers, yet they have been largely excluded from immune checkpoint inhibitor (ICI) trials. Consequently, evidence on the safety and efficacy of ICIs in this population remains scarce, particularly for the nivolumab plus ipilimumab (NIVO+IPI) combination.

Methods: This multicentre, real-world study included PWH treated with ICIs for melanoma or non-melanoma skin cancers. The objective was to evaluate patient characteristics, treatment management, and clinical outcomes across the different skin cancer types.

Results: Among the 54 patients, 89% were male, and 92.6% had a suppressed HIV viral load. Melanoma was the most frequent tumour (35/54, 64.8%), followed by cutaneous squamous cell carcinoma (12/54, 22.2%), Kaposi sarcoma (4/54, 7.4%), basal cell carcinoma (2/54, 3.7%), and one Merkel cell carcinoma. Anti-PD-1/PD-L1 monotherapy was given as first-line treatment in 81.5% (44/54). Immune-related adverse events (irAEs) occurred in 42.6% (23/54), with a median onset of 43.5 days (IQR, 20.5-126). The maximum toxicity grade was 1/2 in 39% (21/54), grade ≥ 3 in 13% (7/54). Seventeen melanoma patients received NIVO+IPI. Among them, 64.7% (11/17) experienced irAEs, including grade ≥ 3 events in 30% (5/17). Objective response rates were 43% (9/21) in melanoma, 58% (7/12) in cSCC, and 75% (3/4) in Kaposi sarcoma.

Conclusions: PWH treated with ICIs for skin cancer demonstrated favourable outcomes, with a notably reassuring safety profile of NIVO+IPI. These findings support managing well-controlled PWH similarly to the general population and highlight the importance of including this population across all settings of skin cancer trials.

Background: It has been hypothesized that sequencing antigen-directed immunotherapy with immune checkpoint inhibitors could prime a tumor for immune response to immune checkpoint inhibitors.

Methods: This study (NCT03072160) was designed to evaluate two cohorts of patients with medullary thyroid cancer, a cancer that is not known to have therapeutic responses to immune checkpoint inhibitors. One cohort included patients with previous immunotherapy (GI-6207, an experimental therapeutic cancer targeting carcinoembryonic antigen), and a second cohort included patients with no previous history of GI-6207. All patients were treated with standard of care dosing of pembrolizumab, 200 mg every 3 weeks for up to 2 years. Patients were followed with imaging every 3 months. Peripheral blood mononuclear cells (PBMCs) were evaluated at 3 months for immune responses.

Results: 17 patients were enrolled on this study. Among the 13 patients with previous immunotherapy (GI-6207), the median age was 52.4 years. Among the 4 patients with no previous immunotherapy the median age was 58.8 years. No patients in either cohort had evidence of therapeutic response. No patients had confirmed 50% declines in either serum carcinoembryonic antigen or calcitonin. No radiographic responses were observed. There was no evidence of immune impact of pembrolizumab in analysis of PBMCs. Given the lack of responses in the previous immunotherapy cohort, the study was closed early. No new safety signals were observed.

Conclusions: This study did not support the hypothesis that sequencing immunotherapy with an immune checkpoint inhibitor could enhance the clinical activity of the immune checkpoint, which has not demonstrated independent activity in that disease previously.

Introduction: Metastatic uveal melanoma (MUM) has a poor prognosis, but hepatic arterial infusion chemotherapy (HAIC) may improve outcomes in patients with hepatic metastases. To identify reliable prognostic factors for patient stratification and treatment allocation, we analyzed the clinical and imaging data from a large single-center cohort using machine learning (ML) models.

Methods: Pre- and post-first treatment clinical data of 235 patients with MUM treated with HAIC between 2009 and 2019 were retrospectively analyzed using Cox regression to identify prognostic factors for overall survival (OS) and time to change treatment strategy (TTCS). Furthermore, ML models were trained on clinical and computed tomography (CT) data for endpoint prediction.

Results: Pre-treatment multi-variate analysis identified elevated lactate dehydrogenase (LDH) (OS: 6.5 vs. 16.4 months, hazard ratio [HR]) = 1.87, P = 0.006) and gamma-glutamyl transpeptidase (GGT) (OS: 7.6 vs. 16.4 months, HR = 1.67, P = 0.012) as prognostic factors for inferior OS. Decreased albumin (TTCS: 1.3 vs. 6.1 months, HR = 6.26, P < 0.001) and elevated LDH (TTCS: 2.9 vs. 7.6 months, HR = 1.72, P = 0.011) and alanine aminotransferase (ALT) (TTCS: 3.7 vs. 6.4 months, HR = 1.65, P = 0.004) predicted shorter TTCS. Scoring enhanced the power of the prognosticators for OS and TTCS. Post-first treatment multi-variate analysis emphasized the importance of inflammation management and liver protection. ML models incorporating radiomics features from baseline CT imaging were not superior to models based on pre-treatment clinical data alone.

Conclusion: We identified independent but synergistic prognostic factors for outcome stratification to guide treatment decisions and optimize patient management. ML-based radiomics features did not significantly enhance prognostic performance.

Background: Trastuzumab deruxtecan (T-DXd), an approved human epidermal growth factor receptor 2 (HER2)-directed antibody-drug conjugate, may cause treatment-emergent adverse events (TEAEs), most commonly gastrointestinal and hematologic TEAEs. This pooled analysis evaluated TEAEs across 2 doses of T-DXd in patients with different cancers to support safe and effective real-world use.

Patients and methods: Data were pooled from 9 phase I-III clinical trials (DS8201-A-J101; DESTINY-Breast01/02/03/04; DESTINY-Lung01/02; DESTINY-Gastric01/02) of T-DXd 5.4 or 6.4 mg/kg every 3 weeks in patients (N = 1678) with metastatic breast, gastric, or lung cancer with varying HER2 expression or HER2 mutation status. Nausea, vomiting, neutropenia, fatigue, and interstitial lung disease (ILD) were evaluated for time to onset and dose-related outcomes. Antiemetic analysis was limited before a 2020 protocol change recommending prophylaxis.

Results: Common TEAEs (in ≥20%) were fatigue, nausea, vomiting, neutropenia, anemia, and thrombocytopenia; mostly grade 1 or 2. TEAEs leading to dose reduction, drug interruption, and discontinuation with T-DXd were 22.6%, 42.8%, and 17.7% (5.4 mg/kg), and 29.7%, 47.6%, and 16.6% (6.4 mg/kg), respectively. Neutropenia, nausea, and fatigue occurred in 34.6%, 74.6%, and 56.5% of patients (5.4 mg/kg) and 49.3%, 65.5%, and 52.8% (6.4 mg/kg). Adjudicated drug-related ILD occurred in 12.0% and 10.9%, respectively.

Conclusion: Gastrointestinal and hematologic TEAEs were most common, with nausea, neutropenia, and fatigue most commonly reported. ILD/pneumonitis occurred in ∼11%-12% of patients, with severe cases infrequent. Most TEAEs were low grade, though dose modifications highlight the need for proactive TEAE management, particularly in older patients and those with renal impairment.

Glioneuronal tumors are rare CNS neoplasms that can exhibit overlapping histological features with embryonal tumors, posing diagnostic and therapeutic challenges. We report a case of a 19-year-old Tunisian woman with a large right frontal tumor and contralateral extension. Initial partial resection suggested CNS neuroblastoma, and the patient underwent chemoradiotherapy with temporary disease control. Upon progression, a second partial resection was followed by DNA methylation profiling, which reclassified the tumor as a glioneuronal tumor with ATRX alteration, kinase fusion, and anaplastic features (GTAKA), harboring a KANK1::NTRK2 fusion. Entrectinib therapy was initiated, leading to a complete radiological response at 14 months, with marked clinical improvement and no serious adverse effects. This case highlights the essential role of DNA methylation profiling in resolving diagnostic ambiguity and guiding targeted treatment in CNS tumors. It further supports the potential efficacy of entrectinib in NTRK fusion-positive glioneuronal tumors.

Background: The emergence of neoadjuvant immunotherapy has improved outcomes for hepatocellular carcinoma (HCC) patients, yet early postoperative recurrence remains a critical challenge. This study aimed to identify clinicopathological and immune microenvironment features associated with recurrence-free survival (RFS) and develop a predictive model for early recurrence in HCC patients undergoing neoadjuvant anti-PD-1 antibody therapy.

Materials and methods: Clinicopathological characteristics and immune microenvironment profiles were analyzed in 70 HCC patients treated with neoadjuvant anti-PD-1 antibody and 20 patients receiving transarterial chemoembolization (TACE). Key variables, including microvascular invasion (MVI), tumor capsule integrity, and immune cell infiltration, were evaluated. Statistical analyses included multivariate Cox regression, Kaplan-Meier survival analysis, and nomogram construction with internal validation to predict recurrence risk.

Results: Foam cell response and tumor-infiltrating lymphocytes (TILs) were strongly linked to favorable immunotherapy responses. Patients without MVI, those with intact tumor capsules, and those exhibiting high CD4+ T cell density in central tumor regions demonstrated significantly prolonged RFS. A nomogram integrating these three factors achieved robust predictive accuracy for early recurrence stratifying patients into distinct risk groups.

Conclusions: This study highlights MVI absence, tumor capsule integrity, and CD4+ T cell infiltration as key predictors of RFS in HCC patients receiving neoadjuvant immunotherapy. The proposed nomogram provides a clinically actionable tool for early recurrence risk assessment, enabling personalized postoperative monitoring and adjuvant therapy strategies to improve survival outcomes.

Background: Adjuvant 5-FU monotherapy was previously the standard treatment for stage II/III rectal cancer. This study compared adjuvant FOLFIRI, FOLFOX, and 5-FU/LV.

Methods: Eligible patients had T3-T4 N0 or Tany N1-3 rectal adenocarcinoma ≤12 cm from the anal verge and received pre-operative or postoperative 5-FU chemoradiotherapy (CRT). Patients were randomized to adjuvant FOLFIRI (8 cycles), FOLFOX (8 cycles), or 5-FU/LV weekly (6/8 weeks; 3 cycles). The trial planned to enroll 3,150 patients but was closed early following activation of an alternative adjuvant rectal cancer study including bevacizumab (E5204). The primary endpoint was overall survival (OS); secondary endpoints included disease-free survival (DFS), sphincter preservation, tolerability, and quality of life (QOL).

Results: The trial enrolled 225 patients (179 randomized) before early closure. Grade 3/4 toxicity occurred in 59%, with neutropenia, leukopenia, and diarrhea being the most common. At a median follow-up of 9.7 years, no significant OS or DFS differences were observed. The rate of sphincter preservation was numerically higher with FOLFIRI and FOLFOX versus 5-FU/LV, but the difference was not statistically significant.

Conclusion: FOLFOX and FOLFIRI can be safely administered after CRT in rectal cancer patients safely with expected toxicities. Due to early trial closure and small sample size, the survival analysis was underpowered to detect a significant difference between regimens.

Clinicaltrials.gov identifier: NCT00068692.

Background: Zambia has the third highest cervical cancer incidence rate globally, and it remains the leading cause of cancer-related death among women. We explored the experiences of Zambian women who accessed cervical cancer screening and precancer treatment services to understand factors influencing care-seeking and access across urban, peri-urban, and rural settings.

Methods: In 2020, we conducted eight focus group discussions with women living with and without Human Immunodeficiency Virus (HIV) who underwent cervical cancer screening between 2016 and 2020. To explore their care journey, participants were grouped by screening outcome-those with cervical precancerous lesions and those without. We also conducted 18 in-depth interviews with healthcare workers providing antiretroviral treatment, cervical cancer screening, or precancer treatment at government health facilities. Transcripts were coded and analyzed using thematic analysis.

Results: Care-seeking unfolded across five stages: recognition of need to screen, hesitation and consultation, screening, result interpretation, and treatment. Women were generally knowledgeable about cervical cancer and sought screening promptly, though some delayed due to fear. Social networks and interactions with healthcare workers facilitated screening, while logistical and financial barriers, along with delays in histopathology services particularly in rural areas, hindered access to timely diagnosis and treatment.

Conclusion: Improving cervical cancer screening and precancer treatment in Zambia requires addressing systemic inefficiencies by strengthening laboratory capacity, decentralizing diagnostics, and training healthcare workers to provide respectful, consistent counselling. Expanding community engagement to counter misinformation, leveraging social networks, and providing financial protection are also critical to ensuring timely, equitable, and reassuring care.

Mutations in the adenomatous polyposis coli (APC) gene are frequent in colorectal cancer (CRC), whereas epidermal growth factor receptor (EGFR) mutations, particularly the L858R variant, are exceedingly rare. Their coexistence in CRC is rare and poorly described in the literature and poses diagnostic and therapeutic challenges. We describe a 69-year-old man with a history of resected CRC who presented with a lung mass and adrenal lesions, initially suspected as metastatic non-small cell lung cancer (NSCLC). Biopsy revealed poorly differentiated carcinoma with immunohistochemistry suggestive of gastrointestinal origin. Due to doubts regarding the primary site, It was decided to start systemic treatment with mFOLFIRINOX while awaiting NGS. After 7 cycles, a partial radiologic and clinical response was observed. Next-generation sequencing (NGS) became available and identified an EGFR L858R mutation, favoring NSCLC. Chemotherapy was paused and the patient was treated with gefitinib. Rapid disease progression ensued, with new brain metastases. Expanded NGS subsequently revealed concurrent APC and TP53 pathogenic variants, confirming the diagnosis of metastatic CRC harboring co-occurring with EGFR and APC mutations. The patient died 10 months after diagnosis. This case underscores the critical role of comprehensive molecular profiling via NGS in accurately diagnosing complex oncologic presentations. To our knowledge, this is the first case report of APC and EGFR L858R co-mutation in colorectal cancer. For this patient, the misclassification delayed the use of more appropriate therapies for CRC, which may have impacted clinical outcomes.