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Purpose: Accuracy in the diagnosis of HPV-associated oropharyngeal carcinoma (OPSCC) of a rapid, low-cost lateral flow immunochromatographic assay for detecting E6 oncoprotein of HPV-16 and HPV-18 was previously evaluated in a small pilot study. This cross-sectional study aimed to assess on a large case series the sensitivity and specificity of E6 oncoprotein as a diagnostic marker for HPV-associated carcinogenesis in OPSCC., Methods: 137 consecutive patients with histologically confirmed OPSCC were enrolled in two hospitals in Northeast Italy. HPV status was determined by PCR for HPV DNA and p16 INK4a immunohistochemistry on primary tumor biopsies. An OPSCC was defined as HPV-associated when double positive for high-risk HPV-DNA and p16 INK4a overexpression in primary lesion. Cytological samples from primary tumors and metastatic lymph nodes were obtained and tested for HPV16/18 E6 oncoproteins using the lateral flow immunochromatographic assay, which requires between 90 and 120 min to provide a result. Diagnostic performances were calculated as percentage with confidence intervals (CI)., Results: Of the 137 OPSCC cases, 68 (49.6%) were HPV-associated, testing positive for both high-risk HPV-DNA and p16 INK4a , with HPV16 predominating (82.4%). An average waiting time of 22 days was observed to obtain the results of p16 INK4a and HPV-DNA after primary lesions biopsy. In patients with HPV16/18-associated OPSCC, the HPV16/18 E6 oncoprotein was detected in 59 out of 60 cytological samples from the primary lesion (sensitivity: 98.3%; 95% CI: 91.1-100%) and in 45 out of 51 cytological samples from lymph node metastases (sensitivity: 88.2%; 95% CI: 76.1-95.6%). The E6 oncoprotein assay showed a specificity of 100% in both primary tumors and lymph node metastases., Conclusion: The low-cost lateral flow immunochromatographic assay for detecting HPV16/18 E6 oncoproteins confirmed high accuracy for identifying HPV-associated OPSCC, particularly in primary tumors, suggesting its potential as a valuable diagnostic tool in clinical practice. Its rapid diagnostic capability could significantly accelerate the process of treatment decision-making, enhancing the timely management of patients., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Inflammatory factors released during severe coronavirus disease-19 (COVID-19) caused by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are known to influence drug exposure, but data on the effect of mild infection are few. Here we describe for the first time an increase in plasma imatinib and norimatinib concentrations observed in a series of 5 patients treated with imatinib for gastrointestinal stromal tumor (GIST) after mild COVID-19., Methods: The patients were undergoing routine therapeutic drug monitoring (TDM) and pharmacogenetic (PGx) analyses of polymorphisms in genes involved in imatinib metabolism and transport ( CYP3A4 , CYP3A5 , ABCB1 , and ABCG2 ) when SARS-CoV-2 infection occurred. Imatinib and its active metabolite norimatinib concentrations were determined at C trough using a validated LC-MS/MS method. PGx analyses were performed by KASP genotyping assays on a Real-Time PCR system. All patients received imatinib 400 mg/day. Case 1 was prospectively monitored. Cases 2-5 were identified retrospectively., Results: On average, imatinib C trough increased significantly by 70% during COVID-19, whereas norimatinib showed a 44% increase compared with pre-COVID-19 levels. Elevated plasma imatinib concentrations persisted up to 6 months after infection remission. In 3 cases, this increase reflected the occurrence or worsening of imatinib side effects., Conclusion: This case-series highlights the clinical impact of SARS-CoV-2 infection on the management of patients with GIST treated with imatinib., Competing Interests: Author FP has received honoraria from Amgen - Astrazeneca - Daiichi Sankyo - Celgene - Eisai - Eli Lilly- - Exact Sciences- Gilead - Ipsen - Italfarmaco - Menarini- MSD - Novartis - Pierre Fabre - Pfizer - Roche - Seagen - Takeda - Viatris. Author FP is currently receiving research funding from Astrazeneca, EISAI, Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Gagno, Posocco, Orleni, Cecchin, Fumagalli, Guardascione, Buonadonna, Polesel, Puglisi, Toffoli and Cecchin.)

HPV-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) are recognized as distinct entities. There remains uncertainty surrounding the causal effects of smoking and alcohol on the development of these two cancer types. Here we perform multivariable Mendelian randomization (MR) to evaluate the causal effects of smoking and alcohol on the risk of HPV-positive and HPV-negative HNSCC in 3431 cases and 3469 controls. Lifetime smoking exposure, as measured by the Comprehensive Smoking Index (CSI), is associated with increased risk of both HPV-negative HNSCC (OR = 3.03, 95%CI:1.75-5.24, P = 7.00E-05) and HPV-positive HNSCC (OR = 2.73, 95%CI:1.39-5.36, P = 0.003). Drinks Per Week is also linked with increased risk of both HPV-negative HNSCC (OR = 7.72, 95%CI:3.63-16.4, P = 1.00E-07) and HPV-positive HNSCC (OR = 2.66, 95%CI:1.06-6.68, P = 0.038). Smoking and alcohol independently increase the risk of both HPV-positive and HPV-negative HNSCC. These findings have important implications for understanding the modifying risk factors between HNSCC subtypes., (© 2024. The Author(s).)

Background: Head and neck cancer (HNC) incidence is on the rise, often diagnosed at late stage and associated with poor prognoses. Risk prediction tools have a potential role in prevention and early detection., Methods: The IARC-ARCAGE European case-control study was used as the model development dataset. A clinical HNC risk prediction model using behavioral and demographic predictors was developed via multivariable logistic regression analyses. The model was then externally validated in the UK Biobank cohort. Model performance was tested using discrimination and calibration metrics., Results: 1926 HNC cases and 2043 controls were used for the development of the model. The development dataset model including sociodemographic, smoking, and alcohol variables had moderate discrimination, with an area under curve (AUC) value of 0.75 (95% CI, 0.74-0.77); the calibration slope (0.75) and tests were suggestive of good calibration. 384 616 UK Biobank participants (with 1177 HNC cases) were available for external validation of the model. Upon external validation, the model had an AUC of 0.62 (95% CI, 0.61-0.64)., Conclusion: We developed and externally validated a HNC risk prediction model using the ARCAGE and UK Biobank studies, respectively. This model had moderate performance in the development population and acceptable performance in the validation dataset. Demographics and risk behaviors are strong predictors of HNC, and this model may be a helpful tool in primary dental care settings to promote prevention and determine recall intervals for dental examination. Future addition of HPV serology or genetic factors could further enhance individual risk prediction., (© 2024 The Author(s). Head & Neck published by Wiley Periodicals LLC.)

Purpose: This retrospective cohort study aims to evaluate the clinical, oncological, and functional outcomes of transoral non-robotic surgery for oropharyngeal squamous cell carcinoma (OPSCC)., Materials and Methods: Data from 131 patients with surgically treated OPSCC (2010-2022) were analyzed. Patients who underwent exclusively transoral surgery were included in the study. The surgeries were performed under microscopic or endoscopic guidance and either a CO 2 laser or an ultrasound/radiofrequency scalpel was used as a cutting instrument, depending on the characteristics and location of the tumor. Functional outcomes were assessed in terms of length of hospital stay, tracheostomy rate, duration of feeding tube dependency and complications. Survival outcomes were assessed in terms of overall survival (OS), disease-free survival (DFS) and disease-specific survival (DSS)., Results: Of 74 included patients, transoral surgery demonstrated safety with no major complications. Tracheotomy was performed in 51.4 % of cases, and was maintained for a median of 10 days. Complete swallowing recovery was restored in 97.3 % of cases, after a median of 5 days. The median length of hospital stay was 12 days. At 5 years, OS was 68.2 %, PFS was 58.2 % and DSS was 83.6 %., Conclusion: The study confirms the safety and efficacy of a transoral approach for OPSCC. Having the capability to utilize and access a variety of tools provides the opportunity to tailor the technique to the individual patient and specific circumstances., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The present study challenges the appropriateness of considering invasion of the palatoglossus muscle (PGM) as a criterion for staging oropharyngeal squamous cell carcinoma (OPSCC) as T4., Study Design: Retrospective observational study., Setting: Tertiary University Hospital., Methods: This retrospective study included nonmetastatic OPSCC patients treated with curative intent at the University of Trieste, Italy from 2015 to 2021. Patients were categorized into 4 groups: (1) tumors classified as T1-T2 by both International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC)-TNM; (2) T1-T2 tumors upgraded to T4 solely by UICC due to oropharyngeal PGM infiltration; (3) T1-T2 tumors upgraded to T4 by both UICC and AJCC due to oral PGM infiltration; (4) tumors classified as T3-T4 by both UICC and AJCC. Kaplan-Meier analysis estimated overall survival (OS) and disease-free survival (DFS). Multivariable Cox models, adjusted for clinical factors, assessed the impact of palatoglossus invasion on outcomes over 5 years., Results: A total of 121 consecutive patients with primary OPSCC were included (median [interquartile range] age 65 years [58-74]; 63% male). While patients with upgraded T4 category due to infiltration of the oral portion of the PGM exhibited a prognosis superimposable on that of other patients with advanced stage disease, those with upgraded T4 category due to infiltration of the oropharyngeal portion of the PGM displayed OS and DFS comparable to T1-T2 patients., Conclusion: Our findings highlight that invasion of the oropharyngeal portion of the PGM may not be a suitable criterion for staging OPSCC as T4. Further research involving larger and independent patient cohorts is strongly encouraged to corroborate these observations., (© 2024 The Author(s). Otolaryngology–Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Objectives: Treatment of metastatic colorectal cancer (mCRC) includes resection of liver metastases (LM), however, no validated biomarker identifies patients most likely to benefit from this procedure. This meta-analysis aimed to assess the impact of the most relevant molecular alterations in cancer-related genes of CRC (i.e., RAS, BRAF, SMAD4, PIK3CA) as prognostic markers of survival and disease recurrence in patients with mCRC surgically treated by LM resection., Methods: A systematic literature review was performed to identify studies reporting data regarding survival and/or recurrence in patients that underwent complete liver resection for CRC LM, stratified according to RAS, BRAF, PIK3CA, and SMAD4 mutational status. Hazard ratios (HRs) from multivariate analyses were pooled in the meta-analysis and various adjustment strategies for confounding factors were combined. The search was conducted in numerous databases, including MEDLINE (PubMed), Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) (EBSCO host), and WHO Global Index Medicus, through March 18th, 2022. Meta-analyses, editorials, letters to the editor, case reports, studies on other primary cancers, studies with primary metastatic sites other than the liver, studies lacking specific oncological outcome variables or genetic data, non-English language studies, and studies omitting residual disease data from liver metastasectomy were excluded. The remaining 47 studies were summarized in a descriptive table which outlines the key characteristics of each study and final results were graphically presented., Results: RAS mutation status was negatively associated with overall survival (OS) (HR, 1.68; 95% CI, 1.54-1.84) and recurrence free survival (RFS) (HR, 1.46; 95% CI, 1.33-1.61). A negative association was also found for BRAF regarding OS (HR, 2.64; 95% CI, 2.15-3.24) and RFS (HR, 1.89; 95% CI, 1.32-2.73) and SMAD4 regarding OS (HR, 1.93; 95% CI, 1.56-2.38) and RFS (HR, 1.95; 95% CI, 1.31-2.91). For PIK3CA only three studies were eligible and no significant association with either OS or RFS could be highlighted., Conclusion: RAS, BRAF, and SMAD4 are negatively associated with OS and RFS in patients undergoing curative liver metastasectomy from colorectal cancer. No conclusion can be drawn for PIK3CA due to the limited literature availability. These data support the integration of RAS, BRAF, and SMAD4 mutational status in the surgical decision-making for colorectal liver metastasis. Nevertheless, we have to consider several limitations, the major ones being the pooling of results from studies that evaluated patient outcomes as either disease-free survival (DFS) or RFS; the inclusion of patients with minimal residual disease and unconsidered potential confounding factors, such as variability in resectability definitions, chemotherapy use, and a potential interaction between biological markers and pre- and post-resection pharmacological treatments., Competing Interests: The authors declare that they have no conflicts of interest to report regarding the present study., (© 2024 The Authors.)

Purpose: The choice of surgical approach for floor of the mouth (FOM) cancer, particularly for intermediate-stage tumors (cT2-cT3), remains controversial. This study aims to evaluate a method considering mylohyoid muscle (MM) invasion as a determinant for surgical approach selection, utilizing magnetic resonance imaging (MRI) preoperatively and frozen section (FS) analysis intraoperatively., Methods: This observational retrospective cohort study analyzed patients undergoing surgical resection of cT2 and cT3 FOM squamous cell carcinoma (SCC) between January 2013 and June 2023. MM infiltration assessed by preoperative MRI determined the surgical approach: clear infiltration led to compartmental surgery (CS), while doubtful or absent infiltration led to transoral surgery (TOS). Conversion from TOS to CS occurred intraoperatively based on macroscopic evidence or positive FS. Data collected included demographic, clinical, surgical, and pathological variables. Survival analysis was conducted using Kaplan-Meier method., Results: Among 44 patients included, majority had cT2 tumors (59.1%). MM resection was necessary in 22.7% of cases. Overall survival (OS) and progression-free survival (PFS) did not significantly differ between TOS and CS groups. Radiological depth of invasion (rDOI) < 10 mm is correlated with MM preservation in 89% of cases, while rDOI > 10 mm is correlated with MM resection only in 23.8% of cases. Pathological depth of invasion (pDOI) discrepancies were observed in the two groups: in CS group is shown a higher pDOI (> 10 mm) confirmation (90%). Surgical complications and functional outcomes differed between TOS and CS groups., Conclusion: Considering MM invasion for surgical approach selection in cT2-cT3 FOM tumors appears oncologically safe, with better functional outcomes in muscle preservation. Preoperative MRI for MM assessment combined with intraoperative FS analysis provides reliable guidance for surgical decision-making., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib represents an effective strategy for treatment of chronic lymphocytic leukemia (CLL), nevertheless about 30% of patients eventually undergo disease progression. Here we investigated by flow cytometry the long-term modulation of the CLL CXCR4 dim /CD5 bright proliferative fraction (PF), its correlation with therapeutic outcome and emergence of ibrutinib resistance. By longitudinal tracking, the PF, initially suppressed by ibrutinib, reappeared upon early disease progression, without association with lymphocyte count or serum beta-2-microglobulin. Somatic mutations of BTK/PLCG2, detected in 57% of progressing cases, were significantly enriched in PF with a 3-fold greater allele frequency than the non-PF fraction, suggesting a BTK/PLCG2-mutated reservoir resident within the proliferative compartments. PF increase was also present in BTK/PLCG2-unmutated cases at progression, indicating that PF evaluation could represent a marker of CLL progression under ibrutinib. Furthermore, we evidence different transcriptomic profiles of PF at progression in cases with or without BTK/PLCG2 mutations, suggestive of a reactivation of B-cell receptor signaling or the emergence of bypass signaling through MYC and/or Toll-Like-Receptor-9. Clinically, longitudinal monitoring of the CXCR4 dim /CD5 bright PF by flow cytometry may provide a simple tool helping to intercept CLL progression under ibrutinib therapy., (© 2024. The Author(s).)

Background: Pancreatic cancer risk has been associated with increased serum cholesterol level, which is in turn partially influenced by diet. This study aimed at evaluating the association between pancreatic cancer risk and the adherence to a plant-based cholesterol-lowering diet., Methods: Data were derived from an Italian case-control study including 258 pancreatic cancer patients and 551 controls. The cholesterol-lowering diet score was based on seven components: high intakes of (i) non-cellulosic polysaccharides (a proxy of viscous fibers), (ii) monounsaturated fatty acids, (iii) legumes, and (iv) seeds/corn oils (a proxy of phytosterols); and low intakes of (v) saturated fatty acids, (vi) dietary cholesterol, and (vii) food with a high glycemic index. The score was calculated adding one point for each fulfilled component, thus ranging from zero (no adherence) to seven (complete adherence). The odds ratios (ORs) and 95% confidence intervals (CIs) were estimated through the logistic regression model., Results: Scores 5-7 were associated with reduced cancer risk (OR = 0.30; 95% CI: 0.18-0.52) compared to scores 0-2., Conclusions: Adherence to a plant-based cholesterol-lowering diet was associated with a reduced risk of pancreatic cancer.

Competing Interests: The authors declare no conflict of interest.

Amelanotic/hypomelanotic melanoma (AHM) may be difficult to diagnose because of a lack of pigmentation. To evaluate whether dermoscopy can be useful for the diagnosis of early AHM, 133 digital dermoscopic images of lesions histopathologically diagnosed as amelanotic/hypomelanotic superficial spreading melanoma with ≤1 mm thickness (AHSSMs) (n = 27), amelanotic/hypomelanotic non-melanocytic lesions (AHNMLs) (e.g., seborrhoeic keratosis and basal cell carcinoma) (n = 79), and amelanotic/hypomelanotic benign melanocytic lesions (AHBMLs) (e.g., compound and dermal nevi) (n = 27), were dermoscopically assessed by three blinded dermatologists. Using multivariate analysis, we found a significantly increased risk of diagnosing AHSSM versus AHNML and AHBML when the lesion was characterized by the presence of more than one shade of pink (odds ratio [OR] 37.11), irregular dots/globules (OR 23.73), asymmetric pigmentation (OR 8.85), and structureless pattern (OR 7.33). In conclusion, dermoscopy may improve early AHM detection, discriminating AHSSM from amelanotic/hypomelanotic non melanoma lesions., (© 2024 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Loss-of-function mutations in NFKBIE, which encodes for the NF-κB inhibitor IκBε, are frequent in chronic lymphocytic leukemia (CLL) and certain other B-cell malignancies and have been associated with accelerated disease progression and inferior responses to chemotherapy. Using in vitro and in vivo murine models and primary patient samples, we now show that NFKBIE-mutated CLL cells are selected by microenvironmental signals that activate the NF-κB pathway and induce alterations within the tumor microenvironment that can allow for immune escape, including expansion of CD8+ T-cells with an exhausted phenotype and increased PD-L1 expression on the malignant B-cells. Consistent with the latter observations, we find increased expression of exhaustion markers on T-cells from patients with NFKBIE-mutated CLL. In addition, we show that NFKBIE-mutated murine CLL cells display selective resistance to ibrutinib and report inferior outcomes to ibrutinib treatment in NFKBIE-mutated CLL patients. These findings suggest that NFKBIE mutations can contribute to CLL progression through multiple mechanisms, including a bidirectional crosstalk with the microenvironment and reduced sensitivity to BTK inhibitor treatment., (© 2024. The Author(s).)

Purpose: Numerous studies underscore the relevance of tumor-infiltrating-lymphocytes (TILs) as important prognostic factors for melanoma. This meta-analysis aims to provide a comprehensive literature overview elucidating their role in predicting patient outcomes, specifically investigating the association between TIL density and prognosis., Methods: From an initial pool of 6094 records, 16 met the eligibility criteria, encompassing a collective cohort of 16021 patients. Data on TIL counts, clinical characteristics, and survival metrics (5-year overall survival [5yOS], 10-year overall survival [10yOS], and 5-year melanoma-specific survival [5yMSS]) were extracted from each study and expressed as proportions. Results were graphically presented using forest plots, reporting the estimates from individual studies, summary estimates, and corresponding 95 % confidence intervals (CI)., Results: Analysis revealed a statistically significant difference in 5yOS concerning subgroup differences However, 10yOS and 5yMSS did not exhibit statistical significance. Nonetheless, a consistent trend emerged indicating a higher survival rate corresponding to increased immune cell density, ranging from absent TILs to brisk levels., Conclusions: TILs present potential as a readily applicable prognostic factor. Yet, further investigations into their density and phenotypic subpopulation characteristics could enhance our understanding of their predictive value in tailoring optimal patient-specific therapies., Competing Interests: M.G. reports receipts of honoraria or consultation fees from Novartis, Eli Lilly, PierreFabre, Roche, MSD, Daichii Sankyo, Organon and travel fees from Daichii Sankyo, all outside the submitted work. F.P. reports the receipt of grants/research support from AstraZeneca, Eisai, and Roche, and receipts of honoraria or consultation fees from Amgen, AstraZeneca, Daichii Sankyo, Celgene, Eisai, Eli Lilly, Gilead, GSK, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche, Seagen, Takeda, Menarini, and Viatris, all outside the submitted work., (© 2024 Published by Elsevier Ltd.)

The dermoscopic diagnosis of amelanotic/hypomelanotic lentigo maligna/lentigo maligna melanoma (AHLM/LMM) may be very difficult in its early stages because of lack of pigment. Reflectance confocal microscopy (RCM) is an imaging technique that is especially helpful for the diagnosis of lentigo maligna. To determine the diagnostic performances of dermoscopy and RCM in the diagnosis of AHLM/LMMs we evaluated dermoscopic and RCM images of consecutive cases of histopathologically confirmed AHLM/LMMs, amelanotic/hypomelanotic basal cell carcinoma and squamous cell carcinoma (AHBCCs/AHSCCs), amelanotic/hypomelanotic benign lesions (AHBLs), and actinic keratoses (AKs) from five participating centers. Sensitivity, specificity, accuracy, predictive values, and level of diagnosis confidence were calculated for both diagnostic procedures. Both dermoscopy and RCM showed diagnostic performance >97% in the diagnosis of AHLM/LMMs versus AHBCC/AHSCCs and their combination slightly improved diagnostic performance, with accuracy increasing from 98.0% to 99.1%. Similarly, RCM in combination with dermoscopy showed a tiny increase in the diagnostic performance in the diagnosis of AHLM/LMMs versus AHBLs (accuracy increased from 87.2% to 88.8%) and versus AKs (accuracy increased from 91.4% to 93.4%). Although the increase in diagnostic performance due to RCM was modest, the combination of dermoscopy and RCM greatly increased the level of confidence; high confidence in the diagnosis of AHLM/LMMs versus AHBLs increased from 36.2% with dermoscopy alone to 76.6% with dermoscopy plus RMC. Based on our results, dermoscopy and RCM should be complementary to improve not only diagnostic accuracy but also the level of diagnostic certainty in the diagnosis of AHLM/LMMs., (© 2024 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites. Genomic, exposure, and clinical data will be publicly available through the International Cancer Genome Consortium Accelerating Research in Genomic Oncology platform. The Mutographs sample and metadata biorepository constitutes a legacy resource for new projects and collaborations aiming to increase our current research efforts in cancer genomic epidemiology globally., Competing Interests: Declaration of interests M.R.S. is founder of, consultant to, and stockholder in Quotient Therapeutics. L.B.A. is a compensated consultant and has equity interest in io9, LLC, and Genome Insight. His spouse is an employee of Biotheranostics, Inc. L.B.A. is also an inventor of a US patent 10,776,718 for source identification by non-negative matrix factorization. L.B.A. declares US provisional applications with serial numbers 63/289,601; 63/269,033; and 63/483,237. L.B.A. also declares US provisional applications with serial numbers 63/366,392; 63/367,846; 63/412,835; and 63/492,348., (Copyright © 2024. Published by Elsevier Inc.)

Instrumental activities of daily living (IADL) are significant health indicators closely related to executive functions and able to detect mild cognitive impairment. A decline in IADL usually precedes ADL limitation, including taking medications, and may therefore predict a cognitive decline. We aimed to investigate the association of patients' IADL score with other clinical factors, with a particular focus on the presence of a caregiver, and the impact on adherence to androgen receptor pathway inhibitors (ARPIs) and survival outcomes within the Meet-URO 5-ADHERE study. It was a large prospective multicentre observational cohort study monitoring adherence to ARPIs in 234 metastatic castrate-resistant PC (mCRPC) patients aged ≥ 70. We observed an association between impaired IADL and lower geriatric G8 scores (p < 0.01), and lower adherence to ARPIs whether assessed by pill counting (p = 0.01) or self-reported by the patient himself (p = 0.03). The combination of an IADL < 6 and the absence of a caregiver resulted in a significantly high risk of non-adherence to the ARPIs at the multivariable analysis (HR 9.23, 95% confidence interval 2.28-37.43, p = 0.01). IADL alongside the geriatric G8 scales represent essential tools to identify frail and less auto-sufficient patients who are extremely vulnerable particularly if not supported by a caregiver and have the highest risk of nonadherence to ARPIs., (© 2024. The Author(s).)

Off-stoichiometric Cu-Cr-O delafossite thin films with different thicknesses were grown by metal organic chemical vapor deposition on substrates with different coefficients of thermal expansion. Seebeck thermoelectric coefficient and resistivity measurements were performed on the range of 300-850 K. A qualitative change in the temperature-dependence of the resistivity is observed at the temperature corresponding to the deposition process, where the transition from tensile to compressive strain takes place. Arrhenius plots reveal different slopes in these two thermal ranges. The fact that the shift is more pronounced for the thinner films might indicate the induced strain plays a role in changing electrical behaviour. Furthermore, changes below 0.1% in electrical mobility were measured when the strain is induced by mechanical bending., (Creative Commons Attribution license.)

Background: A cholesterol-lowering diet score was previously developed for epidemiological studies; its association with serum lipid profile was not confirmed yet., Methods: The score was developed as an adaptation of the dietary portfolio for cholesterol reduction, assigning one point for adherence to seven dietary indicators and ranging from 0 (null adherence) to 7 (highest adherence). The score was calculated for breast cancer patients enrolled in the DEDiCa study using a 7-day food record; serum lipid profile, including total and low-density lipoprotein cholesterol (LDL-C), was evaluated in serum at baseline., Results: Patients with the highest adherence to the cholesterol-lowering diet (i.e., score ≥ 4) reported lower LDL-C level than women with score 0-1 (median: 107 mg/dL and 122 mg/dL, respectively; p < 0.01). The proportion of women with LDL-C above the recommended limit of 116 mg/dL was 60.0% with score 0-1 and 42.6% with score ≥4. Although the score directly correlates with consumption of foods from vegetal sources, it was mildly associated with the healthful plant-based diet index (r-Spearman = 0.51) and the Mediterranean Diet Adherence Screener (r-Spearman = 0.30) Conclusions: These results provide experimental evidence that the cholesterol-lowering diet score is capable of detecting a specific plant-based dietary pattern that affects circulating cholesterol levels.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16 INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Poor oral health has been identified as a prognostic factor potentially affecting the survival of patients with head and neck squamous cell carcinoma. However, evidence to date supporting this association has emanated from studies based on single cohorts with small-to-modest sample sizes., Methods: Pooled analysis of 2449 head and neck squamous cell carcinoma participants from 4 studies of the International Head and Neck Cancer Epidemiology Consortium included data on periodontal disease, tooth brushing frequency, mouthwash use, numbers of natural teeth, and dental visits over the 10 years prior to diagnosis. Multivariable generalized linear regression models were used and adjusted for age, sex, race, geographic region, tumor site, tumor-node-metastasis stage, treatment modality, education, and smoking to estimate risk ratios (RR) of associations between measures of oral health and overall survival., Results: Remaining natural teeth (10-19 teeth: RR = 0.81, 95% confidence interval [CI] = 0.69 to 0.95; ≥20 teeth: RR = 0.88, 95% CI = 0.78 to 0.99) and frequent dental visits (>5 visits: RR = 0.77, 95% CI = 0.66 to 0.91) were associated with better overall survival. The inverse association with natural teeth was most pronounced among patients with hypopharyngeal and/or laryngeal, and not otherwise specified head and neck squamous cell carcinoma. The association with dental visits was most pronounced among patients with oropharyngeal head and neck squamous cell carcinoma. Patient-reported gingival bleeding, tooth brushing, and report of ever use of mouthwash were not associated with overall survival., Conclusions: Good oral health as defined by maintenance of the natural dentition and frequent dental visits appears to be associated with improved overall survival among head and neck squamous cell carcinoma patients., (© The Author(s) 2023. Published by Oxford University Press.)

Although chronic lymphocytic leukemia (CLL) predominantly affects the elderly, limited data exists about the outcomes of over 80-year-old patients, usually underrepresented in clinical trials. We conducted a multicenter study enrolling 79 consecutive CLL patients ≥80 years at the time of frontline therapy, all treated with ibrutinib. Nearly 48% of cases exhibited unmutated IGHV genes, 32% 17p deletion, and 39.2% TP53 mutations; 63.3% displayed a cumulative illness rating scale (CIRS) > 6. The overall response rate on ibrutinib, computed in 74/79 patients (5 patients excluded for early withdrawal), was 89.9%. After a median follow-up of 28.9 months, the median progression-free survival (PFS) and overall survival (OS) were 42.5 and 51.8 months, respectively. CIRS>6 and temporary discontinuation of ibrutinib lasting for 7-30 days were the only parameters associated with a significantly shorter PFS and were both relevant in predicting a shorter PFS compared to patients with CIRS≤6 and therapy discontinuation ≤7 days. The most common grade≥3 adverse events were infections (25.5%), neutropenia (10.1%), and anemia (2.5%). Eighteen patients (22.8%) experienced a cardiovascular event, including grade-2 atrial fibrillation (n = 9; 11%), grade-2 hypertension (n = 5; 6%), heart failure (n = 3; 3%), and acute coronary syndrome (n = 1; 1%). Mild bleeding events were observed in 27 patients (34.2%). Ibrutinib was permanently discontinued in 26 patients due to progressive disease (n = 11, including 5 Richter's syndromes), secondary malignancies (n = 6), infections (n = 3), cardiac failure (n = 3), severe bleeding (n = 2), and sudden death (n = 1). In conclusion, our analyses confirmed the overall effectiveness and favorable safety profile of the ibrutinib-single agent therapeutic approach in CLL patients ≥80 years., (© 2024 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)

Objectives: The aim of this study was to determine the impact of the involvement of the superior pharyngeal constrictor muscle (SPCM) evaluated by magnetic resonance imaging (MRI) on outcome in oropharyngeal squamous cell carcinomas (OPSCCs)., Methods: A retrospective study including consecutive patients with OPSCC treated with curative intent., Results: A total of 82 consecutive patients with OPSCC met inclusion criteria. At multivariate analysis, patients with SPCM infiltration were at significantly higher risk of death (HR: 3.37, CI: 1.21-9.38) and progression (HR: 3.39, CI: 1.38-8.32). In a multivariate model conditioned on HPV status, a significantly higher risk of death and progression was observed by combining both SPCM and HPV status with patients harboring an HPV-negative OPSCC with SPCM infiltration showing the poorest outcome., Conclusion: MRI evidence of SPCM involvement significantly and independently increases the risk of death and progression in subjects with OPSCC. Considering both MRI-assessed SPCM infiltration and HPV status significantly improved risk stratification in these malignancies., (© 2023 The Authors. Head & Neck published by Wiley Periodicals LLC.)

Introduction: The presence of cervical lymph node metastases is an unfavorable prognostic factor in head and neck squamous cell carcinoma (HNSCC) and a potential cause of treatment failure. Occult lymph node metastasis occurs in approximately 15-20% of HNSCC patients with a clinically negative neck (cN0), greatly impacting on their prognosis. The present study aimed to investigate the role of pre-treatment peripheral blood markers in predicting clinically occult cervical lymph node metastasis., Methods: This multicenter, retrospective study was performed in a cohort of 472 patients diagnosed with cN0 HNSCC who underwent up-front surgery. Baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammatory marker (SIM), and systemic immune-inflammation index (SII) were calculated from available blood parameters., Results: Oro-hypopharyngeal and oral cancers, locally advanced stage, moderately (G2), and poorly (G3) differentiated grade were associated with an increased risk of pathological lymph node involvement. NLR, LMR, PLR, SIM, and SII were significantly associated at multivariable analysis. NLR &gt;2.12 was the most reliable at predicting occult lymph node metastasis (OR = 5.22; 95% CI: 2.14-12.75). We describe a predictive score integrating cancer site, local stage, and NLR which is effective at predicting positive lymph node pathological status., Conclusions: The present study provides evidence that pre-treatment peripheral blood markers, in particular NLR, represent reliable predictors of clinically occult cervical lymph node metastasis in cN0 HNSCC. Therefore, the present study provides a novel useful predictive score for directing the elective management of the neck in patients with cN0 HNSCC., (© 2023 S. Karger AG, Basel.)

Background: Despite the feasibility and promising activity data on intensity-modulated RT and simultaneous integrated boost (IMRT-SIB) dose escalation in preoperative chemoradiation (CRT) for locally advanced rectal cancer (LARC), few data are currently available on long-term outcomes., Patients and Methods: A cohort of 288 LARC patients with cT3-T4, cN0-2, cM0 treated with IMRT-SIB and capecitabine from March 2013 to December 2019, followed by a total mesorectal excision (TME) or an organ-preserving strategy, was collected from a prospective database of 10 Italian institutions. A dose of 45 Gy in 25 fractions was prescribed to the tumor and elective nodes, while the SIB dose was prescribed according to the clinical practice of each institution on the gross tumor volume (GTV). Concurrent capecitabine was administered at a dose of 825 mg/m 2 twice daily, 7 days a week. The primary objective of the study was to evaluate long-term outcomes in terms of local control (LC), progression-free survival (PFS) and overall survival (OS). The secondary objective was to confirm the previously reported feasibility, safety and efficacy (pCR, TRG1-2 and downstaging rates) of the treatment in a larger patient population., Results: All patients received a dose of 45 Gy to the tumor and elective nodes, while the SIB dose ranged from 52.5 Gy to 57.5 Gy (median 55 Gy). Acute gastrointestinal and hematologic toxicity rates of grade 3-4 were 5.7% and 1.8%, respectively. At preoperative restaging, 36 patients (12.5%) with complete or major clinical responses (cCR or mCR) were offered an organ-preserving approach with local excision (29 patients) or a watch and wait strategy (7 patients). The complete pathologic response rate (pCR) in radically operated patients was 25.8%. In addition, 4 TME patients had pT0N1 and 19 LE patients had pT0Nx, corresponding to an overall pT0 rate of 31.3%. Of the 36 patients selected for organ preservation, 7 (19.5%) required the completion of TME due to unfavorable pathologic features after LE or tumor regrowth during W-W resulting in long-term rectal preservation in 29 of 288 (10.1%) of the total patient population. Major postoperative complications occurred in 14.2% of all operated patients. At a median follow-up of 50 months, the 5-year PFS and OS rates were 72.3% (95% CI: 66.3-77.4) and 85.9% (95% CI: 80.2-90.1), respectively. The 5-year local recurrence (LR) rate was 9.2% (95% CI: 6.0-13.2), while the distant metastasis (DM) rate was 21.3% (95% CI: 16.5-26.5). The DM rate was 24.5% in the high-risk subset compared to 16.2% in the low-intermediate risk group ( p = 0.062) with similar LR rates (10% and 8%, respectively). On multivariable analysis, cT4 and TRG3-5 were significantly associated with worse PFS, OS and metastasis-free survival., Conclusions: Preoperative IMRT-SIB with the moderate dose intensification of 52.5-57.5 Gy (median 55 Gy) and the full dose of concurrent capecitabine confirmed to be feasible and effective in our real-life clinical practice. Organ preservation was shown to be feasible in carefully selected, responsive patients. The favorable long-term survival rates highlight the efficacy of this intensified treatment program. The incorporation of IMRT-SIB with a more effective systemic therapy component in high-risk patients could represent a new area of investigational interest.

Background: Despite a growing number of publications highlighting the potential impact on the therapy outcome, rare genetic variants (minor allele frequency < 1%) in genes associated to drug adsorption, distribution, metabolism, and elimination are poorly studied. Previously, rare germline DPYD missense variants were shown to identify a subset of fluoropyrimidine-treated patients at high risk for severe toxicity. Here, we investigate the impact of rare genetic variants in a panel of 54 other fluoropyrimidine-related genes on the risk of severe toxicity., Methods: The coding sequence and untranslated regions of 54 genes related to fluoropyrimidine pharmacokinetics/pharmacodynamics were analyzed by next-generation sequencing in 120 patients developing grade 3-5 toxicity (NCI-CTC vs3.0) and 104 matched controls. Sequence Kernel Association Test (SKAT) analysis was used to select genes with a burden of genetic variants significantly associated with risk of severe toxicity. The statistical association of common and rare genetic variants in selected genes was further investigated. The functional impact of genetic variants was assessed using two different in silico prediction tools (Predict2SNP; ADME Prediction Framework)., Results: SKAT analysis highlighted DPYS and PPARD as genes with a genetic mutational burden significantly associated with risk of severe fluoropyrimidine-related toxicity (Bonferroni adjusted P = 0.024 and P = 0.039, respectively). Looking more closely at allele frequency, the burden of rare DPYS variants was significantly higher in patients with toxicity compared with controls (P = 0.047, Mann-Whitney test). Carrying at least one rare DPYS variant was associated with an approximately fourfold higher risk of severe cumulative (OR = 4.08, P = 0.030) and acute (OR = 4.21, P = 0.082) toxicity. The burden of PPARD rare genetic variants was not significantly related to toxicity. Some common variants with predictive value in DPYS and PPARD were also identified: DPYS rs143004875-T and PPARD rs2016520-T variants predicted an increased risk of severe cumulative (P = 0.002 and P = 0.001, respectively) and acute (P = 0.005 and P = 0.0001, respectively) toxicity., Conclusion: This work demonstrated that the rare mutational burden of DPYS, a gene strictly cooperating with DPYD in the catabolic pathway of fluoropyrimidines, is a promising pharmacogenetic marker for precision dosing of fluoropyrimidines. Additionally, some common genetic polymorphisms in DPYS and PPARD were identified as promising predictive markers that warrant further investigation., (© 2023. The Author(s).)

Background: In addition to pharmacological prevention, chemotherapy-induced nausea and vomiting (CINV) can be mitigated through patient education; written supporting materials can be beneficial., Methods: This is a randomized, controlled trial which randomly assigned patients undergoing first chemotherapy cycle to receive oral information regarding CINV prevention and management (control arm) or oral information plus an informative booklet (experimental arm). Overall, 384 cancer patients fulfilling the following inclusion criteria were enrolled: age ≥18 years; life expectancy ≥6 months; no cognitive impairment; written informed consent. After the first cycle, CINV occurrence and its impact on daily activities were assessed using the Functional Living Index Emesis (FLIE)., Results: Severe nausea was self-reported by 3.0% and 10.8% of patients in the experimental and control group, respectively (difference: 7.8%; 95% confidence interval: 2.3% to 13.1%). Moderate/high impact of nausea on daily activities was lower in patients also receiving the booklet than in the control group (4.2% and 10.1%, respectively; difference: 5.9%; 95% confidence interval: 0.3% to 11.5%). Vomiting was not statistically different between study arms., Conclusions: This integrated nursing approach was effective in aiding cancer patients in CINV self-management. Although the beneficial effect was moderate, this intervention demands minimal resources in terms of costs and time.

Background and Aims: Diversity is a key element of diet quality. The Food Variety Score (FVS) is used to assess diversity, especially in low- and middle-income countries. It sums up the number of foods consumed ignoring their nutrient content. A more suitable index should combine the number of foods consumed and their nutritional composition. We adapted the Nutritional Functional Diversity indicator (NFD), proposed by ecologists, to measure diversity in the human diet. We compared NFD and FVS evaluating subjects' distributions across quartiles of the two diversity indices. To evaluate which one reflected a higher diet quality, we estimated associations between these two diversity indices and diet quality measures, i.e., the Mediterranean Diet Score (MDS) and the Healthy Eating Index-2015 (HEI-2015). Associations were expressed by odds ratios (OR) and corresponding 95% confidence intervals (CI)., Materials and Methods: We used the data of controls only derived from an integrated series of hospital-based case-control cancer studies conducted in different Italian areas. The NFD identifies groups of foods based on a set of nutrients according to a cluster analysis. Some steps are required: creating a food-nutrient matrix; clustering of the Euclidean food-food distance matrix to identify groups of foods with nutritional (dis)similarities; and calculating the NFD as the ratio between the sum of branch lengths of the dendrogram belonging to the number of foods consumed by individuals (i.e., subject-specific diversity) and the sum of all branch lengths of the dendrogram (i.e., maximal diversity)., Results: More than one quarter of individuals (28.4%) were differently classified within quartiles of the two diversity indices. For both indices, increasing the diversity level increased the risk for adhering to MDS (OR for NFD = 11.26; 95% CI: 7.88-16.09, and OR for FVS = 6.80; 95% CI: 4.84-9.54) and to HEI-2015 (OR for NDF = 2.86; 95% CI: 2.39-3.42, and OR for FVS = 2.72; 95% CI: 2.27-3.26). Associations were stronger for NFD., Conclusion: Our findings showed a greater ability of NFD to assess diet quality quantifying the degree of diversity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Di Maso, Bravi, Polesel, Dal Maso, Patel, La Vecchia and Ferraroni.)

Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which is the risk of dose dependence. The potential cardiotoxicity, which increases with higher doses, poses a significant challenge to its safe and effective application. To try to overcome these undesired effects, encapsulation of doxorubicin in liposomes has been proposed. Caelyx and Myocet are different formulations of pegylated (PLD) and non-pegylated liposomal doxorubicin (NPLD), respectively. Both PLD and NPLD have shown similar activity compared with free drugs but with reduced cardiotoxicity. While the hand-foot syndrome exhibits a high occurrence among patients treated with PLD, its frequency is notably reduced in those receiving NPLD. In this prospective, multicenter, one-stage, single-arm phase II trial, we assessed the combination of NPLD and ifosfamide as first-line treatment for advanced/metastatic soft tissue sarcoma (STS). Patients received six cycles of NPLD (50 mg/m 2 ) on day 1 along with ifosfamide (3000 mg/m 2 on days 1, 2, and 3 with equidose MESNA) administered every 3 weeks. The overall response rate, yielding 40% (95% CI: 0.29-0.51), resulted in statistical significance; the disease control rate stood at 81% (95% CI: 0.73-0.90), while only 16% (95% CI: 0.08-0.24) of patients experienced a progressive disease. These findings indicate that the combination of NPLD and ifosfamide yields a statistically significant response rate in advanced/metastatic STS with limited toxicity.

Background: The aim of this study was to psychophysically evaluate the prevalence of smell and taste dysfunction 2 years after mildly symptomatic severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection compared to that observed at 1-year follow-up and while considering the background of chemosensory dysfunction in the no-coronavirus disease 2019 (COVID-19) population., Method: This is a prospective case-control study on 93 patients with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection and 93 matched controls. Self-reported olfactory and gustatory dysfunction was assessed by 22-item Sino-Nasal-Outcome Test (SNOT-22), item "Sense of smell or taste." Psychophysical orthonasal and retronasal olfactory function and gustatory performance were estimated using the extended Sniffin' Sticks test battery, 20 powdered tasteless aromas, and taste strips test, respectively. Nasal trigeminal sensitivity was assessed by sniffing a 70% solution of acetic acid., Results: The two psychophysical assessments of chemosensory function took place after a median of 409 days (range, 366-461 days) and 765 days (range, 739-800 days) from the first SARS-CoV-2-positive swab, respectively. At 2-year follow-up, cases exhibited a decrease in the prevalence of olfactory (27.9% vs. 42.0%; absolute difference, -14.0%; 95% confidence interval [CI], -21.8% to -2.6%; p = 0.016) and gustatory dysfunction (14.0% vs. 25.8%; absolute difference, -11.8%; 95% CI, -24.2% to 0.6%; p = 0.098). Subjects with prior COVID-19 were more likely than controls to have an olfactory dysfunction (27.9% vs. 10.8 %; absolute difference, 17.2%; 95% CI, 5.2% to 28.8%) but not gustatory dysfunction (14.0% vs. 9.7%; absolute difference, 4.3%; 95% CI, -5.8% to 14.4% p = 0.496) still 2 years after the infection. Overall, 3.2% of cases were still anosmic 2 years after the infection., Conclusions: Although a proportion of subjects recovered from long-lasting smell/taste dysfunction more than 1 year after COVID-19, cases still exhibited a significant excess of olfactory dysfunction 2 years after SARS-CoV-2 infection when compared to matched controls., (© 2023 ARS-AAOA, LLC.)

Background: Nail changes are among the most common dermatological adverse events in paclitaxel-receiving patients. Although effective, low-temperature prophylactic cryotherapy is discomforting and a potential cause of side effects, resulting in low patients' adherence., Patients and Methods: A phase II single-arm study evaluating mild cryotherapy for the reduction of 12-week, grade 2 nail toxicity was conducted on 67 taxane-naïve breast cancer patients (age 18-74 years) undergoing weekly adjuvant chemotherapy with paclitaxel. Instant-ice packs were fixed over the fingers and toes for a total of 70 minutes during paclitaxel infusion at a temperature between -5 °C and +5 °C. Nail toxicity was evaluated weekly (CTCAE vs 4.03), including grade 2 (ie, onycholysis, subungual hematoma, onychomadesis) and grade 1 nail toxicities., Results: Twelve patients experienced grade 2 nail toxicities (17.9%, 95% confidence interval [CI] 9.6%-29.2%; median time to onset: 56 days): onycholysis was the most frequent grade 2 toxicity (13.4%), followed by subungual hematoma (9.0%) and onychomadesis (1.5%). Grade 1 toxicity occurred in 33 patients (63.5%, 95% CI 49.0%-76.4%) with nail discoloration representing by far the most frequent toxicity (59.6%). Seventeen patients (25.4%) reported no nail toxicity. 62.7% of patients reported no pain and 22.4% suffered moderate pain. No patient experienced severe pain or others adverse effects., Conclusions: Instant-ice pack is a feasible prophylactic intervention for nail toxicity, well tolerated by patients and with limited impact on routine workload. It could be considered for patients refusing (or interrupting) cryotherapy, and it can be implemented when frozen gloves management is not feasible., Competing Interests: Disclosure None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the prognostic value of pre-treatment prognostic-nutritional index (PNI) in patients with HPV-negative head and neck squamous cell carcinoma (HNSCC)., Methods: A multi-institutional retrospective series of HPV-negative, Stages II-IVB, HNSCCs treated with upfront surgery was evaluated. Correlation of pre-operative blood markers and PNI with 5-year overall (OS) and relapse-free (RFS) survival was tested using linear and restricted cubic spline models, as appropriate. The independent prognostic effect of patient-related features was assessed with multivariable models., Results: The analysis was conducted on 542 patients. PNI ≥ 49.6 (HR = 0.52; 95% CI, 0.37-0.74) and Neutrophil-to-Lymphocyte Ratio (NLR) > 4.2 (HR = 1.58; 95% CI, 1.06-2.35) confirmed to be independent prognosticators of OS, whereas only PNI ≥ 49.6 (HR = 0.44; 95% CI, 0.29-0.66) was independently associated with RFS. Among pre-operative blood parameters, only higher values of albuninaemia and lymphocyte count (> 1.08 x 10 3 /microL), and undetectable basophile count (= 0 10 3 /microL) were independently associated with better OS and RFS., Conclusions: PNI represents a reliable prognostic tool providing an independent measure of pre-operative immuno-metabolic performance. Its validity is supported by the independent prognostic role of albuminaemia and lymphocyte count, from which it is derived., (Copyright © 2023 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer., (© 2023 UICC.)

Background: Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors., Methods: We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses' Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial., Results: Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59)., Conclusions: Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations., (© The Author(s) 2023. Published by Oxford University Press.)

Background: The prevalence and incidence of oropharyngeal squamous cell carcinomas (OPSCCs) driven by human papillomavirus (HPV) infection are increasing worldwide, being higher in high-income countries. However, data from Italy are scanty. p16 INK4a overexpression is the standard in determining HPV-driven carcinogenesis, but disease prevalence impacts on its positive predictive value., Methods: This is a multicenter retrospective study enrolling 390 consecutive patients aged ≥18 years, diagnosed with pathologically confirmed OPSCC in Northeastern Italy between 2000 and 2022. High-risk HPV-DNA and p16 INK4a status were retrieved from medical records or evaluated in formalin-fixed paraffin-embedded specimens. A tumor was defined as HPV-driven when double positive for high-risk HPV-DNA and p16 INK4a overexpression., Results: Overall, 125 cases (32%) were HPV-driven, with a significant upward temporal trend from 12% in 2000-2006 to 50% in 2019-2022. The prevalence of HPV-driven cancer of the tonsil and base of the tongue increased up to 59%, whereas it remained below 10% in other subsites. Consequently, the p16 INK4a positive predictive value was 89% for the former and 29% for the latter., Conclusions: The prevalence of HPV-driven OPSCC continued to increase, even in the most recent period. When using p16 INK4a overexpression as a surrogate marker of transforming HPV infection, each institution should consider the subsite-specific prevalence rates of HPV-driven OPSCC as these significantly impact on its positive predictive value.

Objective: We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries., Subjects and Methods: The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared., Results: The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites., Conclusion: These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer., (© 2022 Wiley Periodicals LLC.)

Objectives: To estimate the prevalence of two most common and mutually exclusive -124 C > T and -146 C > T TERT promoter mutations in HNSCC and analyse their prognostic role., Materials and Methods: The databases Medline (via Ovid), Embase (via Ovid), Cochrane Library, Scopus, and Web of Science (Core Collection) were searched from inception to December 2022 to identify studies analysing TERT promoter mutations in HNSCC. Pooled prevalence of TERT promoter mutations and hazard ratio (sHR) of death/progression, with corresponding confidence intervals (CI), were estimated., Results: The initial search returned 6416 articles, of which 17 studies, including 1830 patients, met the criteria for prevalence meta-analysis. Among them, 8 studies fitted the inclusion criterion to analyse the prognostic impact of TERT promoter mutations. Overall, 21% (95% CI: 12%-31%) of HNSCCs harboured TERT promoter mutation. TERT promoter mutations were more commonly found in oral cavity cancer (prevalence = 47%, 95% CI: 33%-61%), followed by laryngeal/hypopharyngeal cancer (prevalence = 12%, 95% CI: 4%-25%), while they were quite rare in oropharyngeal cancer (prevalence = 1%, 95% CI: 0%-4%). TERT promoter mutation -124 C > T was associated with a higher risk of death (sHR = 2.01, 95% CI: 1.25-3.23) and progression (sHR = 2.79, 95% CI: 1.77-4.40), while -146 C > T TERT promoter mutation did not show any significant correlation neither to overall nor progression-free survival., Conclusion: TERT promoter mutations were mainly topographically restricted to oral cavity cancer. -124 C > T was the most common TERT promoter mutation and was significantly associated to worse outcome in HNSCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Aims: Patients on treatment with oral fixed dose imatinib are frequently under- or overexposed to the drug. We investigated the association between the gene activity score (GAS) of imatinib-metabolizing cytochromes (CYP3A4, CYP3A5, CYP2D6, CYP2C9, CYP2C19, CYP2C8) and imatinib and nor-imatinib exposure. We also investigated the impact of concurrent drug-drug-interactions (DDIs) on the association between GAS and imatinib exposure., Methods: Serial plasma samples were collected from 33 GIST patients treated with imatinib 400 mg daily within a prospective clinical trial. Imatinib and nor-imatinib C trough were quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). Genetic polymorphisms with a functional impact on imatinib-metabolizing cytochromes were identified and a GAS was calculated for each gene. A DDI-adjusted GAS was also generated., Results: Imatinib and nor-imatinib C trough were measured in 161 plasma samples. CYP2D6 GAS and metabolizer status based on genotype were associated with imatinib and (imatinib + nor-imatinib) C trough . CYP2D6 poor and intermediate metabolizers were predicted to have a lower nor-imatinib/imatinib metabolic ratio than normal metabolizers (0.197 and 0.193 vs. 0.247, P = .0205), whereas CYP2C8*3 carriers had a higher ratio than CYP2C8*1/*1 patients (0.263 vs. 0.201, P = .0220). CYP2C9 metabolizer status was inversely related to the metabolic ratio with an effect probably driven by the linkage disequilibrium between CYP2C9*2 and CYP2C8*3. The CYP2D6 DDI-adjusted GAS was still predictive of imatinib exposure., Conclusions: These findings highlight that CYP2D6 plays a major role in imatinib pharmacokinetics, but other players (i.e., CYP2C8) may influence imatinib exposure. These findings could drive the selection of patients more susceptible to imatinib under- or overexposure who could be candidates for personalized treatment and intensified monitoring strategies., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Markers of pathological complete response (pCR) to preoperative radiation-based therapy in locally advanced rectal cancer (LARC) are strongly needed. This meta-analysis aimed at elucidating the predictive/prognostic role of tumor markers in LARC. We systematically reviewed the impact of RAS , TP53, BRAF , PIK3CA , and SMAD4 mutations and MSI status on response (pCR, downstaging) and prognosis (risk of recurrence, survival) in LARC according to PRISMA guidelines and the PICO model. PubMed, Cochrane Library, and Web of Science Core Collection were systematically searched to identify relevant studies published before October 2022. KRAS mutations were significantly associated with the risk of not achieving pCR after preoperative treatment (summary OR = 1.80, 95% CI: 1.23-2.64). This association was even more significant in patients not receiving cetuximab (summary OR = 2.17, 95% CI: 1.41-3.33) than in patients receiving cetuximab (summary OR = 0.89, 95% CI: 0.39-20.05). MSI status was not associated with pCR (summary OR = 0.80, 95% CI: 0.41-1.57). No effect of KRAS mutation or MSI status on downstaging was detected. Meta-analysis of survival outcomes was not possible due to the large heterogeneity among studies in endpoint assessment. The minimum number of eligible studies to assess the predictive/prognostic role of TP53 , BRAF , PIK3CA , and SMAD4 mutations was not reached. KRAS mutation, but not MSI status, proved to be a detrimental marker for response to preoperative radiation-based therapy in LARC. Translating this finding into the clinic could improve the management of LARC patients. More data are needed to clarify the clinical impact of TP53 , BRAF , PIK3CA , and SMAD4 mutations.

Adequate imatinib plasma levels are necessary to guarantee an efficacious and safe treatment in gastrointestinal stromal tumor (GIST) and chronic myeloid leukemia (CML) patients. Imatinib is a substrate of the drug transporters ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) that can affect its plasma concentration. In the present study, the association between three genetic polymorphisms in ABCB1 (rs1045642, rs2032582, rs1128503) and one in ABCG2 (rs2231142) and the imatinib plasma trough concentration (C trough ) was investigated in 33 GIST patients enrolled in a prospective clinical trial. The results of the study were meta-analyzed with those of other seven studies (including a total of 649 patients) selected from the literature through a systematic review process. The ABCG2 c.421C>A genotype demonstrated, in our cohort of patients, a borderline association with imatinib plasma trough levels that became significant in the meta-analysis. Specifically, homozygous carriers of the ABCG2 c.421 A allele showed higher imatinib plasma C trough with respect to the CC/CA carriers (C trough , 1463.2 ng/mL AA, vs. 1196.6 ng/mL CC + AC, p = 0.04) in 293 patients eligible for the evaluation of this polymorphism in the meta-analysis. The results remained significant under the additive model. No significant association could be described between ABCB1 polymorphisms and imatinib C trough , neither in our cohort nor in the meta-analysis. In conclusion, our results and the available literature studies sustain an association between ABCG2 c.421C>A and imatinib plasma C trough in GIST and CML patients.

Background : the Mediterranean diet, the low dietary glycemic index (GI) and the dietary inflammation index (DII®) have been associated with lower risk of breast cancer (BC) incidence and mortality. Objective : to investigate whether one-year nutrition counselling in the context of a Mediterranean diet, with or without low-GI carbohydrates counselling, may influence the DII in women with BC. Methods : data were obtained from participants of DEDiCa trial randomized to a Mediterranean diet (MD, n = 112) or a Mediterranean diet with low-GI carbohydrates (MDLGI, n = 111). The diet-derived DII and GI were calculated from 7-day food records while Mediterranean diet adherence from PREDIMED questionnaire. Differences between study arms were evaluated through Fisher's exact test or Mann-Whitney test and associations with multivariable regression analyses. Results : Mediterranean diet adherence significantly increased by 15% in MD and 20% in MDLGI with no difference between arms ( p < 0.326). Dietary GI significantly decreased from 55.5 to 52.4 in MD and 55.1 to 47.6 in MDLGI with significant difference between arms ( p < 0.001). DII significantly decreased by 28% in MD and 49% in MDLGI with no difference between arms ( p < 0.360). Adjusting for energy intake (E-DII) did not change the results. Higher Mediterranean diet adherence and lower dietary GI independently contributed to DII lowering (β-coefficient -0.203, p < 0.001; 0.046, p = 0.003, respectively). Conclusions : DII and E-DII scores decreased significantly after one-year with 4 nutrition counselling sessions on the Mediterranean diet and low GI. Increased adherence to the Mediterranean diet and low GI independently contributed to the DII changes. These results are relevant given that lowering the inflammatory potential of the diet may have implications in cancer prognosis and overall survival.

Background: Amelanotic/hypomelanotic lentigo maligna and lentigo maligna melanoma (AHLM/LMM) may be very difficult to diagnose at an early stage., Objectives: To quantify the predictive value of dermoscopic and reflectance confocal microscopy (RCM) features for AHLM/LMM., Methods: Dermoscopic and RCM images of histopathologically diagnosed AHLM/LMM, amelanotic/hypomelanotic benign lesions (AHBL), and amelanotic/hypomelanotic basal and squamous cell carcinomas (AHBCC/AHSCC) of the head and neck from consecutive patients were retrospectively collected and blindly evaluated by three observers to assess presence or absence of dermoscopic and RCM criteria., Results: Overall, 224 lesions in 216 patients including LM/LMM (n = 55, 24.6%), AHBL (n = 107, 47.8%) and AHBCC/AHSCC (n = 62, 27.7%) were analysed. Multivariable analysis showed that milky-red areas (OR = 5.46; 95% CI: 1.51-19.75), peripheral light brown structureless areas (OR = 19.10; 4.45-81.96), linear irregular vessels (OR = 5.44; 1.45-20.40), and asymmetric pigmented follicles (OR = 14.45; 2.77-75.44) at dermoscopy, and ≥3 atypical cells in five fields (OR = 10.12; 3.00-34.12) and focal follicular localization of atypical cells at dermo-epidermal junction (DEJ) (OR = 10.48; 1.10-99.81) at RCM were significantly independent diagnostic factors for AHLM/LMM vs. AHBL. In comparison with AHBCC/AHSCC, peripheral light brown structureless area (OR = 7.11; 1.53-32.96), pseudonetwork around hair follicles (OR = 16.69; 2.73-102.07), and annular granular structures (OR = 42.36; 3.51-511.16) at dermoscopy and large dendritic (OR = 6.86; 3.15-38.28) and round pagetoid cells (OR = 26.78; 3.15-227.98) at RCM led to a significantly increased risk of diagnosing AHLM/LMM., Conclusions: Amelanotic/hypomelanotic lentigo maligna and lentigo maligna melanoma may have the same dermoscopic features of AHM on other body sites, such as milky red areas, peripheral light brown structureless areas and linear irregular vessels. These features, asymmetric pigmented follicles and at RCM ≥ 3 atypical cells in five fields and focal follicular extension of atypical cells at DEJ may help in recognizing AHLM/LMM even when LM conventional features (e.g., obliteration of hair follicles under dermoscopy and large pagetoid cells under RCM) are absent or present only in very small areas of the lesion., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Purpose: This meta-analysis summarizes the incidence of treatment-related adverse events (AE) of BRAFi and MEKi., Methods: A systematic search of Medline/PubMed was conducted to identify suitable articles published in English up to 31 December 2021. The primary outcomes were profiles for all-grade and grade 3 or higher treatment-related AEs, and the analysis of single side effects belonging to both categories., Results: The overall incidence of treatment-related all-grade Aes was 99% for Encorafenib (95% CI: 0.97-1.00) and 97% for Trametinib (95% CI: 0.92-0.99; I 2 = 66%) and Binimetinib (95% CI: 0.94-0.99; I 2 = 0%). In combined therapies, the rate was 98% for both Vemurafenib + Cobimetinib (95% CI: 0.96-0.99; I 2 = 77%) and Encorafenib + Binimetinib (95% CI: 0.96-1.00). Grade 3 or higher adverse events were reported in 69% of cases for Binimetinib (95% CI: 0.50-0.84; I 2 = 71%), 68% for Encorafenib (95% CI: 0.61-0.74), and 72% for Vemurafenib + Cobimetinib (95% CI: 0.65-0.79; I 2 = 84%). The most common grade 1-2 AEs were pyrexia (43%) and fatigue (28%) for Dabrafenib + Trametinib and diarrhea for both Vemurafenib + Cobimetinib (52%) and Encorafenib + Binimetinib (34%). The most common AEs of grade 3 or higher were pyrexia, rash, and hypertension for Dabrafenib + Trametinib (6%), rash and hypertension for Encorafenib + Binimetinib (6%), and increased AST and ALT for Vemurafenib + Cobimetinib (10%)., Conclusions: Our study provides comprehensive data on treatment-related adverse events of BRAFi and MEKi combination therapies, showing related toxicity profiles to offer a helpful tool for clinicians in the choice of therapy.

Microenvironmental factors such as non-classical human leukocyte antigen-G (HLA-G) have been associated with cancer invasiveness and metastatic progression. HLA-G expression has been associated with specific single-nucleotide polymorphisms (SNP) in HLA-G 3'untranslated region (UTR) in several diseases. The primary aim was to investigate the predictive role of HLA-G polymorphisms on treatment efficacy in metastatic colorectal cancer (mCRC) patients homogeneously treated with first-line FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) and their association with soluble HLA-G (sHLA-G) plasma concentration. HLA-G 3'UTR was sequenced in 248 patients. A set of eight polymorphisms and related haplotypes were analyzed for their association with best tumor response, overall survival (OS), and progression-free survival (PFS). sHLA-G was measured by immunoassay in 35 available plasma samples and correlated with HLA-G 3'UTR polymorphisms/haplotypes. Our results showed that carriers of rs371194629 (+2960)-Ins allele were at risk for lack of complete response (hazard ratio (HR):0.29, p BH = 0.0336), while carriers of rs1710 (+3010)-G allele (rs1063320 (+3142)-C allele in linkage-disequilibrium), and rs9380142 (+3187)-G allele had a higher chance of complete response according to additive models (HR:4.58, p BH = 0.0245; HR:3.18, p BH = 0.0336, respectively). The combination of rs371194629-Del, rs1710-G, and rs9380142-G alleles forms the UTR1 haplotype. Patients who were carriers of UTR1/UTR-1 diplotype had a greater chance of complete response to therapy (HR:10.59, p BH = 0.0294). The same three beneficial alleles showed a trend toward higher pre-treatment sHLA-G plasma levels, supporting a functional role for polymorphisms in protein secretion. In conclusion, genetic variants of HLA-G are associated with treatment efficacy in mCRC patients treated with first-line FOLFIRI. This finding shed light on the combined effect of this immune system factor and chemotherapy in cancer patients.

Background: Identification of screening tests for the detection of head and neck cancer (HNC) at an early stage is an important strategy to improving prognosis. Our objective was to identify plasma circulating miRNAs for the diagnosis of HNC (oral and laryngeal subsites), within a multicenter International Head and Neck Cancer Epidemiology consortium., Methods: A high-throughput screening phase with 754 miRNAs was performed in plasma samples of 88 cases and 88 controls, followed by a validation phase of the differentially expressed miRNAs, identified in the screening, in samples of 396 cases and 396 controls. Comparison of the fold changes (FC) was carried out using the Wilcoxon rank-sum test and the Dunn multiple comparison test., Results: We identified miR-151-3p (FC = 1.73, P = 0.007) as differentially expressed miRNAs in the screening and validation phase. The miR-151-3p was the only overexpressed miRNA in validation sample of patients with HNC with early stage at diagnosis (FC = 1.81, P = 0.008) and it was confirmed upregulated both in smoker early-stage cases (FC = 3.52, P = 0.024) and in nonsmoker early-stage cases (FC = 1.60, P = 0.025) compared with controls., Conclusions: We identified miR-151-3p as an early marker of HNC. This miRNA was the only upregulated in patients at early stages of the disease, independently of the smoking status., Impact: The prognosis for HNC is still poor. The discovery of a new diagnostic biomarker could lead to an earlier tumor discovery and therefore to an improvement in patient prognosis., (©2022 The Authors; Published by the American Association for Cancer Research.)

Hypofractionation in salvage radiotherapy (HSRT) for biochemical recurrence of prostatic cancer after prostatectomy is a debated issue and at present, it should be considered purely investigational because of the lack of evidence supporting its use. In this study, we report the outcomes of patients presenting with biochemical recurrence after radical prostatectomy who received HSRT. The additional aim of this study is to compare two moderately HSRT schedules. Patients treated to prostate bed with daily Image Guided-VMAT and a total dose of 65 Gy/26 fractions (Group A) or 66 Gy/30 fractions (Group B) were included in the study. Inclusion criteria were: pN0/pNx, pre-HSRT PSA ≥0.2 ng/ml and ≤1 ng/ml, no evidence of pelvic/extrapelvic disease at restaging, no pelvic irradiation or dose boost on macroscopic local recurrence, no neoadjuvant/concomitant Androgen Deprivation Therapy (ADT), follow-up ≥36 months, and available pre/post HSRT data. Genitourinary (GU) and gastrointestinal (GI) toxicities, early and late, were assessed using CTCAE Vers. 5.0. One hundred patients were retrospectively identified to 50 in each group. Median follow-up was 59 months. All patients completed the prescribed HSRT. 5-year biochemical failure-free survival, local control, distant relapse-free survival, and ADT- free survival were 52.1%, 85.9%, 63.7%, and 73.2%, respectively. No significant differences in these outcomes were found between the two groups. On multivariate analysis, a hypofractionation schedule was not associated with any outcome, but ISUP score ≥ 4 and pre-HSRT PSA were associated with worse biochemical failure-free survival while only ISUP score ≥ 4 was associated with worse distant relapse-free survival. No Grade 3 GU/GI acute event was reported; 6 (6%) and 2 (2%) patients experienced late Grade ≥ 2 GU and GI events, respectively. No difference was found between the two groups neither in acute nor in late GU/GI toxicities. Our findings demonstrate that HSRT is feasible, effective, and safe. Our analysis did not show any significant difference between the two hypofractionated schedules. Further studies and randomized controlled trials are required in order to confirm these results and to identify the optimal hypofractionated schedule in the salvage setting.

Purpose: Primary: To determine the rate of occult cervical metastases in primary temporal bone squamous cell carcinomas (TBSSC). Secondary: to perform a subgroup meta-analysis of the risk of occult metastases based on the clinical stage of the tumour and its risk based on corresponding levels of the neck., Methods: A systematic review and meta-analysis of papers searched through Medline, Cochrane, Embase, Scopus and Web of Science up to November 2021 to determine the pooled rate of occult lymph node/parotid metastases. Quality assessment of the included studies was assessed through the Newcastle-Ottawa scale., Results: Overall, 13 out of 3301 screened studies met the inclusion criteria, for a total of 1120 patients of which 550 had TBSCC. Out of the 267 patients who underwent a neck dissection, 33 had positive lymph nodes giving a pooled rate of occult metastases of 14% (95% CI 10-19%). Occult metastases rate varied according to Modified Pittsburg staging system, being 0% (0-16%) among 12 pT1, 7% (2-20%) among 43 pT2 cases, 21% (11-38%) among 45 pT3, and 18% (11-27%) among 102 pT4 cases. Data available showed that most of the positive nodes were in Level II., Conclusion: The rate of occult cervical metastases in TBSCC increases with pathological T category with majority of nodal disease found in level II of the neck., (© 2022. The Author(s).)

Cystic masses of the lateral neck are mostly benign. However, the incidence of metastatic squamous cell carcinoma (SCC) in cervical cystic masses initially diagnosed as benign is quite high in patients older than 40 years. The aim of this study was to compare the diagnostic accuracy of preoperative cytology and intraoperative frozen section (FS) in detecting malignancy in cystic masses of the neck. We reviewed 61 patients who underwent preoperative ultrasound-guided fine-needle aspiration cytology (FNAC) and neck biopsy of a cystic neck mass, and analysed the concordance between FNAC and intraoperative FS with respect to definitive histology. HPV status was also tested. Of 49 eligible cases, the accuracy of preoperative FNAC was 70.5% (weighted kappa 0.53), meaning moderate agreement between cytology and final diagnosis. Intraoperative FS consultations detected 16 cases of SCC metastasis while the remaining 33 cases were negative for SCC, showing perfect agreement with histology. Since FS results were useful in evaluating cystic neck masses, despite a moderate accuracy of cytology, we suggest intraoperative FS analysis for all cystic neck masses. This technique can allow us to switch to therapeutic neck dissection, multiple upper aerodigestive tract biopsies, tongue base mucosectomy, and bilateral tonsillectomy in the same surgical setting., Competing Interests: Conflict of interest We have no conflicts of interest., (Copyright © 2022 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.)