Treatment of Basal Cell Carcinoma of the Lower Eyelid With High-Dose-Rate Brachytherapy.

Objective To report the outcomes with high-dose-rate (HDR) brachytherapy (BT) treatment in patients with lower eyelid basal cell carcinoma (BCC) and to evaluate the relationship between dosimetric parameters and acute and late toxicities. Material and methods A retrospective unicentric study with patients diagnosed with lower eyelid biopsy-proven BCC treated with HDR BT between January 2012 and December 2019. The prescribed dose was 36 Gy to 40 Gy in 9 to 10 fractions, twice daily, over five days. The primary endpoint was local control, and the secondary endpoints were acute and late toxicities, registered according to CTCAE v4.0. The cosmetic result was evaluated on a qualitative scale (the CAIB scale). Local control was calculated according to the Kaplan-Meier test. Two sample T-tests and a Wilcoxon signed-rank test were used to determine the association between dosimetric parameters and side effects. Results Fifty-eight patients with a median age of 76 years were included. Among these patients, 55.2% received adjuvant HDR BT and 44.8% received radical HDR BT. At a median follow-up of 44 months, there were four local relapses, achieving a probability of local control at four years of 95% and 100% in the adjuvant and radical groups, respectively. Acute toxicity occurred in 76% of patients with only one grade 3 event (radiation dermatitis). Late toxicity was present in 56%. Eight patients underwent treatment for grade 3 cataracts during follow-up. Cosmetic results were excellent or very good in 93% of patients. Acute conjunctival hyperemia is strongly associated with the dose received by the ocular globe (volumes of 0.1cc, 1cc, and 2 cc) (p<0.05). Conclusion Lower eyelid BCC treatment with interstitial HDR BT is associated with excellent local control, acceptable long-term side effects, and good cosmetic results.

Epidemiology, Management, and Survival Outcomes of Germ Cell Cancer in Southern Portugal: A Population-Based Study (2008-2012).

INTRODUCTION: Building on previous suboptimal survival results, we aimed to perform a study of the epidemiological status, management, and outcomes of germ cell tumors (GCT) in the Portuguese population. MATERIALS AND METHODS: Retrospective populational study of GCT cases diagnosed between 2008 and 2012 in southern Portugal. Joinpoint regression was used to compute average annual percentage change (AAPC) in incidence rate. ESMO/EAU guidelines served as references to evaluate compliance. Association between compliance with guidelines and hospital GCT case load was performed by generalized estimating equation. Survival was calculated by Kaplan-Meier and prognostic factors by Cox models. RESULTS: The study included 401 GCT male cases. The AAPC was 5.4% (IC 95% 3.3-7.4, P < .001) from 1999 (an earlier cohort published) to 2012. The median time to diagnosis was 63 days (Q25 = 33 days; Q75 = 114 days; IQR = 81 days). For stage II/III the median time to start chemotherapy was 34 days (Q25 = 22 days; Q75 = 56 days; IQR = 22 days). In 86% cases there was noncompliance with guidelines for the orchiectomy report, 6% for staging, 38% for tumor markers evaluation, 20% for treatment and 25% for chemotherapy dose intensity. The 5-year overall survival was 93.8% (95% CI, 91.3%-96.4%). Hospitals that managed ≤ 3 GCT cases/ year had higher odds for noncompliance with guidelines of blood markers, treatment and dose intensity. None of GCT healthcare access and management factors studied were associated with prognosis. CONCLUSIONS: The burden of GCT is rising in Portugal. Although survival has improved, efforts must be made to nationally enhance training and expertise in GCT and support region adapted models of centralization of care.

Dynamic treatment regimes (DTRs) to study treatment sequencing in oncology: a scoping review protocol.

INTRODUCTION: The rapid evolution of the therapeutic landscape in oncology poses challenges to optimal treatment sequencing. Evidence for clinical decision-making is often limited to studies focused on treatment evaluation at a single decision point, with limited capability of identifying delayed effects of prior treatment decisions on the efficacy and feasibility of future treatments. There is a growing interest in dynamic treatment regimes (DTRs) evaluation as it provides guidance on treatment individualisation based on evolving treatment and patient characteristics. In this scoping review we aim to systematically map how and to what extent DTRs have been evaluated in clinical studies to generate evidence for clinical decision-making in oncology. METHODS AND ANALYSIS: We will do a systematic literature search in MEDLINE (PubMed), Web of Science, Scopus and WHO international clinical trials registry platform to identify clinical studies (including protocols of ongoing studies), with either experimental or observational design, that aim to answer a clinical question and explore treatment sequencing issues in oncology using the concept of DTR. Data extraction will comprise information concerning cancer disease, clinical setting, treatments, tailoring variables, decision rules, decision points and outcomes, type of data, study design and statistical methods used for DTR evaluation. The review will be conducted according to Joanna Briggs Institute Reviewer's manual for scoping reviews. No patients will be involved. ETHICS AND DISSEMINATION: Ethics committee approval is not required as this scoping review will undertake secondary analysis of published literature. Results will be disseminated through a peer-reviewed scientific journal and presented in relevant conferences. This scoping review will provide a better understanding of the methods used to generate evidence on treatment sequencing in oncology and will contribute to the identification of knowledge and methodological gaps that should be addressed.

Distribution and Clinical Significance of HPV16 Variants in Head and Neck Squamous Cell Carcinomas: Data from a Portuguese Cohort and Systematic Review.

INTRODUCTION: Genomic variants of the human papillomavirus type 16 (HPV16) are thought to play differential roles in the susceptibility to head and neck squamous cell carcinomas (HNSCC) and its biological behaviour. This study aimed to establish the prevalence of HPV16 variants in an HNSCC cohort and associate them with clinical pathological characteristics and patient survival. METHODS: We retrieved samples and clinical data from 68 HNSCC patients. DNA samples were available from tumour biopsy at the time of the primary diagnosis. Targeted next-generation sequencing was used to obtain whole-genome sequences, and variants were established based on phylogenetic classification. RESULTS: 74% of samples clustered in lineage A, 5.7% in lineage B, 2.9% in lineage C, and 17.1% in lineage D. Comparative genome analysis revealed 243 single nucleotide variations. Of these, one hundred were previously reported, according to our systematic review. No significant associations with clinical pathological variables or patient survival were observed. The E6 amino acid variations E31G, L83V, and D25E and E7 N29S, associated with cervical cancer, were not observed, except for N29S in a single patient. CONCLUSION: These results provide a comprehensive genomic map of HPV16 in HSNCC, highlighting tissue-specific characteristics which will help design tailored therapies for cancer patients.

Differentiated Thyroid Cancer in a Pediatric Population: Estimating the Risk of Recurrence and Evolution Over Time.

Background Differentiated thyroid cancer (DTC) is the most common endocrine cancer during childhood, and the prognosis is usually good. The 2015 American Thyroid Association (ATA) pediatric guidelines for DTC classify patients into three categories (low, intermediate, and high) that represent the risk for persistent/recurrent disease. The "Dynamic Risk Stratification" (DRS) System showed that, in adults, reassessment of disease status during follow-up was a better predictor of disease status at the end of follow-up when compared to ATA risk stratification. This system is still not validated for the pediatric population with DTC. Our aim was to evaluate the usefulness of the DRS system in predicting DTC disease behaviour in this specific population. We also aimed to evaluate potential clinical-pathological factors associated with persistent disease at the end of follow-up. Methods A retrospective analysis of 39 pediatric patients (≤18 years) with DTC was conducted in our institution between 2007 and 2018, including 33 patients who had follow-up ≥ 12 months; these were classified into ATA risk groups and re-stratified according to their response to treatment at 12-24 months of follow-up. The associations between the ordinal variables of the baseline ATA risk group and the disease status re-evaluated 12-24 months after diagnosis (as per the DRS system) and at the end of follow-up were evaluated using a linear-by-linear association test. Gender, age at diagnosis, tumor size, multicentricity, extrathyroid extension, vascular invasion, lymph node metastasis, distant metastasis, and stimulated thyroglobulin (sTg) during the first RAI administration were evaluated as potential factors associated with persistent disease at 27 months after diagnosis using Firth's bias-reduced penalized-likelihood logistic regression. Results In this study, 39 patients were retrospectively analyzed, including 33 patients who had follow-ups ≥ 12 months with a median time of 56 (27-139) months who were classified in ATA risk groups and then re-stratified depending on their response to treatment between 12 and 24 months of follow-up. There was a statistically significant association between ATA risk groups and re-evaluation at 12 and 24 months (p=0.001) and between these two stratifications and the state of disease at final follow-up (p<0.001 for both). Factors with a statistically significant association with persistent disease at 27 months of follow-up were male sex, lymph node metastases at diagnosis, distant metastasis, extrathyroidal extension, and stimulated Tg values. Conclusions The assessment of the response to treatment between 12 and 24 months and at the end of follow-up refines the initial ATA risk stratification, confirming that dynamic risk evaluation is also helpful in the pediatric population.

Adjuvant Chemotherapy De-Escalation with Genomic Assay Protocol in Patients with Early Breast Cancer: A Single-Centre Prospective Cohort Study.

INTRODUCTION: Genomic assays are useful tools for tailoring adjuvant treatment in early breast cancer. We aimed to analyse the role of an institutional protocol of a genomic assay for chemotherapy de-escalation. MATERIAL AND METHODS: Prospective cohort study of all consecutive women diagnosed with hormone receptor-positive and human epidermal growth factor receptor 2-negative early breast cancer, tested with the 21-gene Recurrence Score (RS) assay from August 2015 to July 2018 at a Portuguese cancer centre. For being tested, patients should meet at least one of the pre-defined inclusion criteria: i) luminal A-like, pT2pN0; ii) luminal A-like, 1 - 3 positive nodes and comorbidities with higher risk of chemotherapy-induced toxicity; iii) pT1-2pN0, progesterone receptor ≤ 20% and/or Ki67 14% - 40%. Adjuvant treatment was de-escalated to isolated endocrine therapy if RS was less than 18. We measured the reduction in chemotherapy prescribing and its clinical impact, the RS association with pathologic features, and the protocol feasibility. RESULTS: We tested 154 women with a median age of 61 years old (range: 25 - 79), 69% postmenopausal. Tumours were mainly pT1 (55%), pN0 (82%), invasive ductal (73%), G2 (86%), luminal B-like (69%) and stage IA (85%). We obtained a RS less than 18 in 60% of women, with an overall adjuvant chemotherapy reduction of 65%. Seven (95% confidence interval: 5 - 10) patients needed to be screened with the 21-gene RS assay to prevent one clinically relevant adverse event during the first six months of adjuvant treatment. Considering the currently used RS cut-off, only 9% of node-negative and 11% of node-positive patients had RS over 25. We found no relevant associations between RS and pathologic features. The protocol was feasible and did not compromise the adequate timing for adjuvant treatment. CONCLUSION: These criteria allowed the de-escalation of adjuvant systemic treatment in at least six out of ten women.

Preoperative serum inflammation-based scores in medullary thyroid cancer.

INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) are prognostic factors in several tumours, though little is known in medullary thyroid cancer (MTC). OBJECTIVE: To evaluate the association between preoperative NLR, PLR and SII with MTC clinicopathological and molecular features, and their predictive value for lymph node and distant metastasis. METHODS: We retrospectively analysed 75 patients with MTC who underwent surgery at our institution. The familial form of MTC was found in 12% of patients. RESULTS: In our cohort, 56% were females, the median age at diagnosis was 57 years (44-69), the median tumour diameter was 25mm (15-50); 21.3% were multifocal and 34.7% had extrathyroidal extension. Lymph node and distant metastasis were observed in 36 (48.0%) and 8 (10.7%) patients, respectively. Higher NLR was associated with preoperative calcitonin, angioinvasion, extrathyroidal extension, moderate/severe fibrosis; higher PLR was associated with extrathyroidal extension and advanced T stages; lower SII and NLR were associated with biochemical cure after surgery. Increased PLR, NLR and SII were associated with advanced MTC stages. In the univariate analysis, only NLR was associated with lymph node metastasis (odds ratio (OR)=2.69, 95% confidence interval (CI): 1.50-5.84; p=0.004); however, in the multivariate model, NLR was no longer a predictive factor for lymph node metastasis. None of these serum inflammatory markers predicted the occurrence of distant metastasis. CONCLUSION: In conclusion, NLR, PLR and SII are associated with aggressive MTC, but do not predict lymph node or distant metastasis.

Basal Cell Adenoma and Basal Cell Adenocarcinoma: a 50-year Experience From a Single Institution.

BACKGROUND: Basal cell adenoma (BCA) and adenocarcinoma (BCAd) are two of the least frequent salivary gland tumors. We describe the largest series of these neoplasms, spanning over a period of 50 years (1970-2020), diagnosed and treated in a single Institution. METHODS: Sixty-eight cases were identified. Clinical and pathological data were collected and correlated with outcome. RESULTS: Forty-one BCA and 27 BCAd were identified. BCA cases had almost pristine prognosis, with only a relapse in a tumor inadequately excised. Ten patients with BCAd developed metastases, and 14 died from the disease. The 2-year and 5-year survival was of 76% and 42%. CONCLUSIONS: The importance of adequate excision is reinforced in BCA, with no recurrences occurring when margins were negative. Contrary to previous reports, BCAd was not associated with a good prognosis. A better understanding of the genetics of these neoplasms may identify therapeutic options when dealing with inoperable or metastatic disease.

Screening a Targeted Panel of Genes by Next-Generation Sequencing Improves Risk Stratification in Real World Patients with Acute Myeloid Leukemia.

Although mutation profiling of defined genes is recommended for classification of acute myeloid leukemia (AML) patients, screening of targeted gene panels using next-generation sequencing (NGS) is not always routinely used as standard of care. The objective of this study was to prospectively assess whether extended molecular monitoring using NGS adds clinical value for risk assessment in real-world AML patients. We analyzed a cohort of 268 newly diagnosed AML patients. We compared the prognostic stratification of our study population according to the European LeukemiaNet recommendations, before and after the incorporation of the extended mutational profile information obtained by NGS. Without access to NGS data, 63 patients (23%) failed to be stratified into risk groups. After NGS data, only 27 patients (10%) failed risk stratification. Another 33 patients were re-classified as adverse-risk patients once the NGS data was incorporated. In total, access to NGS data refined risk assessment for 62 patients (23%). We further compared clinical outcomes with prognostic stratification, and observed unexpected outcomes associated with FLT3 mutations. In conclusion, this study demonstrates the prognostic utility of screening AML patients for multiple gene mutations by NGS and underscores the need for further studies to refine the current risk classification criteria.

PIK3CA Gene Mutations in HNSCC: Systematic Review and Correlations with HPV Status and Patient Survival.

PIK3CA mutations are believed to contribute to the pathogenesis of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). This study aims to establish the frequency of PIK3CA mutations in a Portuguese HNSCC cohort and to determine their association with the HPV status and patient survival. A meta-analysis of scientific literature also revealed widely different mutation rates in cohorts from different world regions and a trend towards improved prognosis among patients with PIK3CA mutations. DNA samples were available from 95 patients diagnosed with HNSCC at the Portuguese Institute of Oncology in Lisbon between 2010 and 2019. HPV status was established based on viral DNA detected using real-time PCR. The evaluation of PIK3CA gene mutations was performed by real-time PCR for four mutations (H1047L; E542K, E545K, and E545D). Thirty-seven cases were found to harbour PIK3CA mutations (39%), with the E545D mutation (73%) more frequently detected. There were no significant associations between the mutational status and HPV status (74% WT and 68% MUT were HPV (+); p = 0.489) or overall survival (OS) (3-year OS: WT 54% and MUT 65%; p = 0.090). HPV status was the only factor significantly associated with both OS and disease-free survival (DFS), with HPV (+) patients having consistently better outcomes (3-year OS: HPV (+) 65% and HPV (-) 36%; p = 0.007; DFS HPV (+) 83% and HPV (-) 43%; p = 0.001). There was a statistically significant interaction effect between HPV status and PIK3CA mutation regarding DFS (Interaction test: p = 0.026). In HPV (+) patients, PIK3CA wild-type is associated with a significant 4.64 times increase in the hazard of recurrence or death (HR = 4.64; 95% CI 1.02-20.99; p = 0.047). Overall, PIK3CA gene mutations are present in a large number of patients and may help define patient subsets who can benefit from therapies targeting the PI3K pathway. The systematic assessment of PIK3CA gene mutations in HNSCC patients will require further methodological standardisation.

PIK3CA Mutations in Diffuse Gliomas: An Update on Molecular Stratification, Prognosis, Recurrence, and Aggressiveness.

INTRODUCTION: PIK3CA is one of the most mutated oncogenes in solid tumors. In breast cancer (ER-positive, HER2-negative), these events represent a predictive biomarker of response to alpelisib. In glioblastomas (GBM), PIK3CA mutations were described as early constitutive events. Here, we investigated PIK3CA mutational profile across glioma molecular subgroups and its relevance during glioma recurrence. Furthermore, PIK3CA mutations' effect in PI3K pathway, prognosis, and response to therapy was also explored. MATERIAL AND METHODS: Exons 10 and 21 of PIK3CA mutations were evaluated in 394 gliomas and 19 glioma recurrences from Instituto Português de Oncologia Lisboa Francisco Gentil (IPOLFG) and compared with The Cancer Genome Atlas (TCGA) data. TIMER2.0 and NetMHCpan4.1 were used to assess the immune-microenvironment contribution. RESULTS: PIK3CA mutations were identified among all glioma subgroups, although with no impact on their stratification or prognosis. In both cohorts (IPOLFG and TCGA), PIK3CA mutation frequencies in IDH-mutant and IDH-wild-type GBM were similar (IPOLFG: 9% and 3%; TCGA: 8% and 2%). These mutations were not mutually exclusive with PTEN deletion and EGFR amplification. Despite their reduced frequency, we discovered PIK3CA mutations were maintained during glioma recurrence regardless of administered therapies. The immune microenvironment might not contribute to this phenotype as PIK3CA mutations did not influence immune cell infiltration. CONCLUSIONS: Despite the absence of a predominant effect in glioma stratification, PIK3CA mutations were maintained during glioma recurrence, possibly contributing to glioma cell survival, representing promising therapeutic targets in recurrent glioma. Nevertheless, understanding the potential synergistic effects between PIK3CA mutations, PTEN deletion, and EGFR amplification is pivotal to targeted therapies' efficiency.

End of treatment FDG-PET in primary mediastinal B-cell lymphoma treated with R-chemotherapy: Prognostic indicator and implications for consolidation radiotherapy.

The ideal therapeutic regimen in primary mediastinal B-cell lymphoma (PMBCL) is controversial and may include consolidation radiotherapy (RT). An adequate strategy is essential in a population where long-term effects of RT are significant. We evaluated the prognostic value of end-of-treatment (EOT) FDG-PET in 50 patients receiving rituximab and anthracycline-containing chemotherapy and its implications for consolidative RT. Thirty patients (60%) obtained complete metabolic response (CMR), five received consolidation RT. The remaining patients had partial response (14) and progression (6). Of these, 12 received mediastinal RT, six salvage chemotherapy, and two no further treatment. Five-year progression free survival was 100% and 48% (95% CI 30%-77%) in patients with negative and positive EOT FDG-PET, respectively (P < .001). Five-year overall survival for negative and positive EOT FDG-PET was 100% and 67% (95% CI 48%-93%) respectively (P = .001). Within positive EOT FDG-PET cases, an association was found between Deauville score and survival. The negative predictive value (NPV) of EOT FDG-PET for disease relapse/progression was 100% (95% CI 0.88-1.00); the positive predictive value was 47% (95% CI 0.24-0.71). This study demonstrates the importance of metabolic assessment in PMBCL and is relevant for its high NPV. Our data favor the use of EOT FDG-PET for decisions concerning RT.

P16 and HPV Genotype Significance in HPV-Associated Cervical Cancer-A Large Cohort of Two Tertiary Referral Centers.

The expression of p16 is a good surrogate of human papillomavirus (HPV) infection in HPV-associated cancers. The significance of p16 expression, HPV genotype and genera in the outcome of patients with HPV-associated cervical cancer (CC) is unclear. Our aim is to ascertain the prognostic significance of these factors. Data from 348 patients (median age: 47.5 years old) with CC, diagnosed in two referral centers, were retrospectively collected. Advanced disease (FIGO2018 IB2-IV) was present in 68% of patients. A single HPV genotype was identified in 82.8% of patients. The most common HPVs were HPV16 (69%) and HPV18 (14%). HPV genera reflected this distribution. HPV16 tumors presented at an earlier stage. P16 was negative in 18 cases (5.2%), 83.3% of which were squamous cell carcinomas. These cases occurred in older patients who tended to have advanced disease. In the univariate analysis, HPV16 (HR: 0.58; p = 0.0198), α-9 genera (HR: 0.37; p = 0.0106) and p16 overexpression (HR: 0.54; p = 0.032) were associated with better survival. HPV16 (HR: 0.63; p = 0.0174) and α-9 genera (HR: 0.57; p = 0.0286) were associated with less relapse. In the multivariate analysis, only the International Federation of Gynecology and Obstetrics (FIGO) stage retained an independent prognostic value. HPV16, α-9 genera and p16 overexpression were associated with better survival, although not as independent prognostic factors. Patients with p16-negative HPV-associated CC were older, presented with advanced disease and had worse prognosis.

Cynotherapy in Cancer Pain Management: A Pilot Study.

OBJECTIVES: This was a pilot study to evaluate the feasibility and impact of a single dog-assisted therapy (cynotherapy) session in reducing pain and emotional distress in oncological outpatients compared with typical waiting room experience (control). DESIGN: This was a quasi-experimental before-after controlled study that took place at a chronic pain outpatient clinic of a tertiary cancer center, whose participants were adult oncological patients, able to consent and without medical contraindication. SETTING: Chronic pain outpatient clinic of a tertiary cancer center. PARTICIPANTS: Adult oncological patients able to consent and without medical contraindication. METHODS: All participants completed self-reported questionnaires including a numeric rating scale for pain and distress thermometer at admission and immediately before departure from the clinic. RESULTS: Eighty-one patients were enrolled over a 10-month study period, 41 in the cynotherapy group and 40 controls. Improvement was greater in cynotherapy than control group for pain (median difference score = -1.0 vs 0.0; P = 0.037), distress levels (median = -1.0 vs 0.0; P = 0.017), and depression (median = -1.0 vs 0.0; P = 0.030). The proportion of patients with a clinically relevant improvement in pain (reduction ≥2 points) was approximately twofold in the cynotherapy group when compared with controls, although not statistically significant (39% vs 20%, odds ratio = 2.53, 95% confidence interval = 0.86-8.02; P = 0.088). The mean satisfaction rate was 9.3/10, and no negative occurrences were reported. CONCLUSION: A single session of dog-assisted therapy can provide immediate improvement in the perception of pain and distress for patients with chronic cancer pain in an outpatient setting, with high satisfaction rates and no negative occurrences. This nonrandomized pilot study points toward the clinical relevance of implementing cynotherapy at a cancer pain clinic and developing a larger scale, more directed study.

Validation of the Portuguese version of Amsterdam Preoperative Anxiety and Information Scale (APAIS).

BACKGROUND: Preoperative anxiety is common among the oncological surgical population. Due to its psychological and physiological detrimental effects, identifying and addressing it is of uttermost importance to improve anesthetic management and patient's outcomes. The aim of this study is to validate the Portuguese version of Amsterdam Preoperative Anxiety and Information Scale (APAIS) in the oncological population. METHODS: Following forward and backward translation of the original APAIS scale, further adaptation was obtained through cognitive interviewing. The resulting instrument was tested on the day before surgery on a sample of adult cancer surgical patients from a Portuguese oncology centre. Psychometric evaluation was derived from inter-item correlation, confirmatory factor analysis, Cronbach's alpha, correlation with comparative scales, receiver operating characteristic curve and Youden index. RESULTS: 109 patients (58 males, 51 females) were included. A three-dimensional model-anxiety about anesthesia, anxiety about surgery and desire for information, showed the best fit to the data. The questionnaire revealed high internal consistency (Cronbach alpha 0.81) and good inter-item correlation. Also, Portuguese APAIS correlated well with the gold standard anxiety scale. Therefore, the psychometric properties of this scale version make it a valid and reliable instrument. The optimal cutoff to maximize both sensitivity and specificity was 12 for the APAIS global anxiety score. CONCLUSIONS: Portuguese APAIS version is an accurate tool to identify preoperative anxiety among cancer patients and might impact its management, from premedication choice to provision of information and reassurance about either anesthesia or surgery.

A Potential Link Between Prolonged Cork Exposure and Intestinal-Type Sinonasal Adenocarcinoma - Special Findings of a Retrospective Cohort Analysis.

INTRODUCTION: intestinal-type sinonasal adenocarcinoma (ITAC) is a rare epithelium tumor of the nasal cavities and paranasal sinuses. Exposure to wood and leather dusts is a strong etiological factor related to its development. Prolonged cork exposure has rarely been associated. MATERIALS AND METHODS: thirty-seven-year (1981-2018) retrospective cohort analysis of all consecutive patients with sinonasal cancer (SNC) followed at our institution. Medical records were reviewed to determine patient demographics, occupational/environmental exposure, location and extent of the tumor, stage, histopathology findings, treatment strategies, and oncologic outcomes. Survival analysis was done using Kaplan-Meier method. RESULTS: we evaluated 379 patients with SNC, including 39 (10.3%) ITAC. Patient median age was 73 years (range 49-87), 56% male and 69% with identified professional occupational exposure (54% for cork; 69.2% considering only those for which an agent has been identified). Seventy-two percent had locally advanced disease (stage III or IVA-B). The initial treatment was surgery in 77%, and 54% received adjuvant radiotherapy. The median time to progression, progression-free survival, and overall-survival was 2.36 years (95% CI 1.54-8.70), 1.96 years (95% CI 1.43-3.74), and 3.51 years (95% CI 2.33-10.02), respectively. CONCLUSION: ITAC is an uncommon malignancy that grows silently, which contributes to delayed diagnosis, advanced stage and low survival rates. In our cohort, we observed a high prevalence of cork occupational exposure. This finding may lead to the implementation of protection measures and suggest a potential link to be further studied.

Surgery versus radiotherapy: Long term outcomes of T1 glottic cancer.

AIM: The aim of this study was to compare the outcomes, patterns of failure and laryngeal preservation rates in patients with T1N0 glottic cancer treated with surgery or radiotherapy. MATERIALS/METHODS: Retrospective study of T1N0 glottic cancer patients treated in our institution between January 2007 and December 2017. Histologically proven squamous cell carcinoma patients, treated with upfront cordectomy/partial laryngectomy (S group) or radiotherapy (RT group) were included. Elective treatment of the neck was not permitted. Local failure (LF), disease-free survival (DFS), ultimate disease-free survival (UDFS), laryngectomy-free survival (LFS), disease-specific mortality (DSM) and overall survival (OS) were evaluated. RESULTS: Two hundred and one patients were eligible (172 S group, 29 RT group), with a median follow-up of 38.8 months. Overall, 33 (16%) patients had a recurrence, 30 (17%) in the S group and 3 (10%) in the RT group. Local failure was the predominant site of failure (28 S, 2 RT). Overall, of all those that were salvaged, 17 (8%) underwent total laryngectomy (15 S, 2 RT). There was no significant difference in the 5-year cumulative incidence of LF (20.8% S, 8.1% RT, p = 0.138), 5-y LFS (85.0% vs. 91.7%, p = 0.809), 5-y DFS (67.5% vs. 82.1%, p = 0.343), 5-y UDFS (82.5% vs. 90.3%, p = 0.647) and 5-y OS (84.5% vs. 90.3%, p = 0.892). Multivariate analysis showed no correlation between initial treatment and the analyzed outcomes. CONCLUSION: Primary surgery or radiotherapy were similar first line options, since they do not differ in all outcomes. Patients' and physician's preferences must be considered when choosing first treatment.

Cervical cancer recurrence - can we predict the type of recurrence?

PURPOSE: We aimed to identify if there is an association between the severity of cervical cancer at diagnosis and the pattern of recurrence. METHODS: We conducted a retrospective study of recurrent cervical cancers diagnosed between 2016 and 2018. We characterized the cases according to histology, size, FIGO stage (according to 2009 and 2018 FIGO classifications) and nodal involvement at diagnosis, symptoms at the time of recurrence, interval between the end of treatment and recurrence, imaging methods used, and location of the recurrence. Statistical analysis was performed between histology, size, FIGO stage and nodal involvement at diagnosis and time to recurrence and type of recurrence (locoregional versus lymph node, distant or multiple site involvement). RESULTS: We included 48 patients with recurrent cervical cancer. At diagnosis, mean tumor size was 5 cm and 83% of the patients had squamous cell carcinoma. The FIGO stage changed in 43.8% of patients between the 2009 and the 2018 classifications. A mean of 26 months elapsed between the end of treatment and recurrence. Recurrence was symptomatic in 64.6% of patients. Imaging identified recurrence in 97.9% of patients. The most frequent recurrence sites were locoregional and lymph node metastases. We found a statistically significant association between 2009 FIGO stage and time to recurrence (P = 0.030) and lymph node involvement at diagnosis and type of recurrence (P = 0.022). As expected patients with more advanced disease recurred sooner, though this was only observed for the 2009 FIGO classification. Absence of lymph nodes at initial diagnosis was associated with locoregional recurrence, while presence of lymph node involvement was associated with lymph node, distant or multiple site involvement of recurrence. No other significant associations were found. CONCLUSION: In our cohort of recurrent cervical cancer, we found an association between patients without lymph node metastases at initial diagnosis and locoregional recurrence. Further studies are needed in order to evaluate whether this association has predictive value.

Improved long-term results of intensity-modulated radiotherapy for a non-endemic European nasopharyngeal carcinoma cohort: single-center retrospective study.

PURPOSE: Report our matured outcomes of European nasopharyngeal carcinoma (NPC) treatment from a non-endemic region in the IMRT era. METHODS: We reviewed 109 consecutive patients with biopsy proven NPC treated between 2009 and 2013. All received IMRT as per RTOG 0615. Toxicity was scored accordingly to CTCAE 4.03. Platinum-based chemotherapy was delivered following the Intergroup 0099. RESULTS: Median age of 53 years; 97% Caucasian; 74% male; 72% WHO grade III; 43% T1; 14% T2; 18% T3, 25% T4; 17% N0; 17% N1; 39% N2; 27% N3. Compliance to adjuvant chemotherapy was 88%. With a median follow up of 56 months, the 4-year local control was 90.2% (88.6% for T1; 100% for T2; 85% for T3; and 91.7% for T4), the 4-year distant metastases-free survival was 86% and an overall survival rate was 77%. Local control and survival were better in G3 (p < 0.001 and p = 0.032, respectively). Xerostomia was the most frequent late toxicity in 55% (n = 60). Hypothyroidism requiring hormonal reposition occurred in 15.5% (n = 17). From the 36 deaths, 20 were due to distant metastases, 3 grade 5 toxicity, 2 from local progression, 5 non-cancer deaths and unknown cause in the remaining 6. On multivariable analysis, age (p = 0.017), local recurrence and distant metastases were associated with death (p < 0.001, both). CONCLUSION: Our matured data from the IMRT era showed a major improvement from our 3D cohort series reaching excellent local and regional control, even in T4. Local recurrences, despite few, and distant metastases were correlated with the risk of death.

High-Throughput Sequencing Identifies 3 Novel Susceptibility Genes for Hereditary Melanoma.

Cutaneous melanoma is one of the most aggressive human cancers due to its high invasiveness. Germline mutations in high-risk melanoma susceptibility genes have been associated with development hereditary melanoma; however, most genetic culprits remain elusive. To unravel novel susceptibility genes for hereditary melanoma, we performed whole exome sequencing (WES) on eight patients with multiple primary melanomas, high number of nevi, and negative for high and intermediate-risk germline mutations. Thirteen new potentially pathogenic variants were identified after bioinformatics analysis and validation. CDH23, ARHGEF40, and BRD9 were identified as the most promising susceptibility genes in hereditary melanoma. In silico analysis of CDH23 and ARHGEF40 variants provided clues for altered protein structure and function associated with the identified mutations. Then, we also evaluated the clinical value of CDH23, ARHGEF40, and BRD9 expression in sporadic melanoma by using the TCGA dataset (n = 461). No differences were observed in BRD9 expression between melanoma and normal skin samples, nor with melanoma stage, whereas ARHGEF40 was found overexpressed, and CDH23 was downregulated and its loss was associated with worse survival. Altogether, these results reveal three novel genes with clinical relevance in hereditary and sporadic melanoma.