In 2017, the Netherlands introduced primary human papillomavirus (HPV)-based screening with cytology triage, which increased colposcopy referrals and low-grade lesions detected. In 2022, HPV16/18 genotyping was added for women with borderline/low-grade cytology. Triage with HPV genotyping may better balance screening benefits, harms, and costs. Therefore, we evaluated the cost-effectiveness of 19 triage strategies based on net monetary benefit (NMB) at cost-effectiveness thresholds of €20,000 and €50,000/quality-adjusted life-year (QALY), with the highest NMB indicating the most cost-effective strategy. Triage tests included 16/18 genotyping, 7-type (16/18/31/33/45/52/58) genotyping, and cytology (high-grade squamous intraepithelial lesions [HSIL]: moderate/severe, atypical squamous cells of undetermined significance [ASC-US]/low-grade squamous intraepithelial lesions [LSIL]: borderline/low-grade, negative for intraepithelial lesion or malignancy [NILM]: normal). Effects on cancer incidence and mortality were obtained by combining POBASCAM trial data with nationwide screening and cancer registries. Time since the onset of high-grade lesion (cervical intraepithelial neoplasia [grade 2/3] [CIN2/3]) at baseline of the Population-based Screening Study Amsterdam trial cannot be estimated from the data and was varied between 0 and 10 years. At a €20,000/QALY threshold, immediate referral for HSIL and 16/18-positive ASC-US/LSIL, and repeat cytology for 16/18-negative ASC-US/LSIL and 7-types positive NILM had the highest NMB (€214.1 to €309.3/woman gained compared to referring all HPV-positive women). At a €50,000/QALY threshold, immediate referral for all 16/18-positives and/or HSIL, and repeat cytology for 16/18-negative ASC-US/LSIL and 7-types positive NILM had the highest NMB if time since onset of CIN2/3 was greater than 2 years. Cytology combined with HPV16/18 and extended genotyping is cost-effective for triage of HPV-positives. Immediate colposcopy referral of all HPV16/18-positives is cost-effective at a €50,000/QALY threshold.

There is limited data regarding the rare and aggressive colorectal neuroendocrine carcinoma (CR-NEC). In this large prospective study, molecular-clinical characteristics and treatment outcomes following palliative chemotherapy are reported for 163 metastatic CR-NEC patients, with a comparison to a population-based prospective cohort of 263 metastatic colorectal adenocarcinoma (CR-AC) patients. Eighty-three percent of CR-NEC received first-line platinum-etoposide, while 98% of CR-AC patients received first-line fluorouracil-based chemotherapy. Disease control rate across all first-line regimens in CR-NEC and CR-AC was 43% vs. 74%, immediate progressive disease 46% vs. 15%, progression-free survival 2.4 months (m) (95% CI 2.1-3.3) vs. 7.7 m (95% CI 6.9-8.5), and overall survival 6.7 m (95% CI 5.6-8.8) vs. 16.8 m (95% CI 13.7-20.3), all, p < .001. CR-NEC more often had synchronous metastases, worse performance status, and symptom burden at treatment initiation than CR-AC (all, p < .001). Two-year survival was 9% vs. 37% in CR-NEC and CR-AC (p < .001). BRAF mutations were frequent in CR-NEC and CR-AC (26% vs. 20%, p = .153) and associated with shorter OS in CR-NEC and CR-AC (p = .025 and p = .003). KRAS mutations were less frequent in CR-NEC than CR-AC (34% vs. 45%, p = .041), but only associated with shorter OS in rectal NEC (p = .04). The frequencies of APC and TP53 mutations were similar between the cohorts and did not impact survival. Metastatic CR-NEC and CR-AC are clinically distinct, with NEC demonstrating more aggressive features, limited treatment effect, and worse prognosis. Although they share important driver mutations, the underlying reason for their marked clinical differences remains unclear.

Immunotherapy with checkpoint inhibitors targeting the PD1/PD-L1 and CTLA4 pathways has limited activity in patients with microsatellite stable (MSS) colorectal adenocarcinoma (CRC). In a prior study, the combination of cetuximab and pembrolizumab failed to improve outcomes for patients with advanced RAS wild-type (RASwt) CRC. In this post hoc secondary analysis, we show that the cetuximab and pembrolizumab-treated patients with TP53 mutant (p53mt) tumors had significantly higher progression-free survival (PFS) and a decrease in tumor burden compared to patients with TP53 wild-type (p53wt) tumors but no difference in overall survival compared to patients with p53wt tumors. The gene set enrichment analysis showed a uniform upregulation of multiple metabolic and immune gene sets, including NK-mediated immunity and IL-12 pathway, while the IL6 pathway was downregulated. There were no overlapping transcriptional alterations between the p53mt and p53wt groups with treatment that remain constant despite the therapeutic intervention. Functional overlap with treatment in both groups in the proliferative, immune, and metabolic pathways were identified. In the baseline tumor samples, the number of PD-L1+ tumor cells was significantly higher in p53mt tumors while the number of OX40-/AE1_AE3-/PD-L1- non-tumor cells, positive for either LAG3, CTLA4 or TIM3, was significantly higher in p53wt tumors. In conclusion, TP53 status was prognostic of improved PFS with cetuximab plus pembrolizumab in RASwt CRC. Future studies evaluating immune-oncology agents in patients with MSS, RASwt CRC should include TP53 as an integrated biomarker and evaluate its performance as a positive predictive biomarker (ClinicalTrials.gov NCT02713373).

Population-based cancer registry (PBCR) of Bhutan was established in Jigme Dorji Wangchuk National Referral Hospital (JDWNRH) in 2014 with the support of the Ministry of Health (Bhutan) and IARC Regional Hub, Tata Memorial Centre (TMC), Mumbai, India. This PBCR provides nationwide coverage (0.7 million population). We aim to present the cancer patterns in Bhutan for the years 2014-2022 using PBCR data. Trained registry staff collect cancer patient information by visiting various sources such as hospitals and diagnostic facilities. Data is entered into CanReg5 software. Data quality and consistency are checked by the IARC Regional Hub-TMC, Mumbai. The age-specific rate and age-adjusted rate were calculated using CanReg5 software. In the 9-year period (2014-2022), the PBCR registered 5906 incidence cancer cases, of which 2659 (45%) were males and 3247 (55%) were females. The age-adjusted incidence rate for males and females was 88.3 and 113.2 per 100,000 population, respectively. Age-adjusted mortality rates for males and females were 42.7 and 44.6 per 100,000 population, respectively. The leading cancer sites among males are stomach, esophagus, liver, lung, and rectum, and for females, cervix uteri, stomach, breast, lung, and thyroid. Cancer registry will play a pivotal role in boosting and monitoring screening program initiatives in Bhutan. Through effective linkages, it will build a robust database providing a cancer profile of the Bhutanese population which can be employed to devise effective cancer control activities in Bhutan.

Early life exposure to pesticides, in particular through pesticides drift in residents nearby agricultural crops, is suspected to increase testicular germ cell tumors (TGCT) risk. We conducted a hospital-based case-control study of 472 TGCT cases and 683 matched controls aged 18-45 years in France and estimated adult TGCT risk associated with agricultural surfaces around residence as a surrogate for environmental exposure to agricultural pesticides at time of birth. Surface of arable lands, orchards and vineyards in 500 m buffer around the participants' residential address at birth was assessed using geographic information system (GIS) methods and software semi-automatic processing of historical aerial images. Odds ratios (OR) for TGCT (overall and by histological subtype) and 95% confidence intervals (CI) were estimated using conditional logistic regression. No increased risk of TGCT was observed for presence of arable lands (OR = 1.14, CI = 0.86-1.52), vineyards (OR = 0.88, CI = 0.56-1.36) and agricultural surfaces overall (OR = 1.13, CI = 0.84-1.51) in 500 m buffer around residence at birth. Presence of orchards (prevalence: 8.7%) was associated with a modest increase in TGCT risk (OR = 1.51, 95% CI = 0.99-2.32), slightly stronger for seminoma (OR = 1.78, 1.07-2.97) and in participants conceived or in their first trimester after conception during spring-summer (OR = 1.70, 1.03-2.82). In conclusion, the study found no overall association between adult TGCT risk and agricultural crops around residence at birth, except for the presence of orchards, with a possible increase in seminoma risks, as well as TGCT risk in participants for whom the first trimester after conception fell into spring-summer.

The objective of this systematic review was to identify the evidence of testicular cancer risk for people with intersex conditions. This assessment is hoped to help refine risk stratification tools for assessing gonadal malignancy risk and guide the development of more robust evidence-based management strategies. The literature was searched in Ovid MEDLINE, Embase, and Cumulative Index of Nursing and Allied Health using a search string developed by a multidisciplinary team. The protocol was registered at Prospective Register of Systematic Reviews as CRD42021231313. A total of 3608 articles were found. After selection, 301 publications were included (1215 individuals). The results identified significant evidence that pre-pubertal gonadectomy may be linked to lower rates of malignant gonadal changes for patients with partial gonadal dysgenesis, Turner's syndrome with Y-chromosome material, complete androgen insensitivity, partial androgen insensitivity, and patients with ovotestis/es. The evidence was not significant for patients with complete gonadal dysgenesis, Klinefelter syndrome, nor WT1-related syndromes. Specific cancer outcomes were unable to be assessed due to small sample sizes and thus it is unknown if clinically significant cancer outcomes are meaningfully altered by pre-pubertal gonadectomy. Importantly, the quality of data on the topic of gonadal malignancy in intersex patients with testicular tissue was determined to be poor overall. The quality was relatively more robust regarding the conditions of Complete Androgen Insensitivity, Klinefelter syndrome, and patients with ovotestis/es. More high-quality research is needed to draw specific conclusions on the risks and benefits of performing pre-pubertal gonadectomy for intersex patients. When counseling these patients, clinicians should be transparent regarding the paucity of data supporting pre-pubertal gonadectomy.

Concurrent chemoradiotherapy is the standard treatment for inoperable, locally advanced esophageal cancer. However, older patients often have reduced tolerance to radiotherapy and concurrent intravenous chemotherapy due to declining physical function and multiple comorbidities. This prospective, single-center, phase II study assessed the efficacy and safety of nimotuzumab, an epidermal growth factor receptor antagonist, combined with concurrent radiotherapy and S-1 in patients 75 years and older. A total of 56 patients were enrolled, with the primary endpoint being progression-free survival (PFS), while secondary endpoints included overall survival (OS), objective response rate, disease control rate, treatment-related adverse events, nutritional indicators, and quality of life (QOL). Most nutritional indicators remained stable after treatment. As of June 2024, the median follow-up duration was 24.1 months (8.8-34.1). Eleven patients achieved complete response, 39 achieved partial response, five had stable disease, and one experienced progressive disease. The median PFS was 25.3 months (95% CI, 16.5-34.1), while the median OS was 28.2 months (95% CI, 24.1-32.3). Most adverse events were grade 1-2 (85.7%). Among survivors, 45.5% reported high satisfaction with their QOL, and 84.8% did not experience weight loss. This combination therapy demonstrated promising efficacy and safety, suggesting it may be a viable treatment option for this patient population.

Nivolumab plus ipilimumab has demonstrated activity after anti-PD-1 failure in advanced melanoma, but its effectiveness in later lines and as rechallenge remains unclear. We aimed to characterize outcomes of nivolumab/ipilimumab administered in the third line or beyond. Using the Danish Metastatic Melanoma Database (DAMMED), we identified patients with metastatic melanoma (excluding uveal melanoma) treated with nivolumab/ipilimumab after at least two prior lines of therapy, including adjuvant treatment, between 2017 and 2024. Baseline characteristics, prior treatments, and clinical outcomes were collected. Seventy-three patients were included (median age 57.8 years), of whom 47.9% had brain metastases. Most had progressed on anti-PD-1-based therapy (93.2%); 32.9% had prior exposure to anti-CTLA-4, and 84.9% had received BRAF/MEK inhibitors. Nivolumab/ipilimumab was administered as third-line therapy in 71.2%. After a median follow-up of 27.6 months, the overall response rate was 23.3% (12.5% with prior anti-CTLA-4 exposure vs. 28.6% without). Median duration of response was 19.4 months (95% CI, 14.5-NR). Median PFS was 2.7 months (95% CI, 2.4-5.7) and median OS was 9.6 months (95% CI, 6.5-20.1). In conclusion, in heavily pretreated melanoma, nivolumab/ipilimumab induces durable responses in a minority of patients, with reduced efficacy after prior anti-CTLA-4 exposure.