Physical performance and plasma metabolic profile as potential prognostic factors in metastatic lung cancer patients.

BACKGROUND: Low physical performance is associated with higher mortality rate in multiple pathological conditions. Here, we aimed to determine whether body composition and physical performance could be prognostic factors in non-small cell lung cancer (NSCLC) patients. Moreover, we performed an exploratory approach to determine whether plasma samples from NSCLC patients could directly affect metabolic and structural phenotypes in primary muscle cells. METHODS: This prospective cohort study included 55 metastatic NSCLC patients and seven age-matched control subjects. Assessments included physical performance, body composition, quality of life and overall survival rate. Plasma samples from a sub cohort of 18 patients were collected for exploratory studies in cell culture and metabolomic analysis. RESULTS: We observed a higher survival rate in NSCLC patients with high performance in the timed up-and-go (+320%; p = .007), sit-to-stand (+256%; p = .01) and six-minute walking (+323%; p = .002) tests when compared to NSCLC patients with low physical performance. There was no significant association for similar analysis with body composition measurements (p > .05). Primary human myotubes incubated with plasma from NSCLC patients with low physical performance had impaired oxygen consumption rate (-54.2%; p < .0001) and cell proliferation (-44.9%; p = .007). An unbiased metabolomic analysis revealed a list of specific metabolites differentially expressed in the plasma of NSCLC patients with low physical performance. CONCLUSION: These novel findings indicate that physical performance is a prognostic factor for overall survival in NSCLC patients and provide novel insights into circulating factors that could impair skeletal muscle metabolism.

Cephaeline is an inductor of histone H3 acetylation and inhibitor of mucoepidermoid carcinoma cancer stem cells.

AIM: To evaluate the potential use of Cephaeline as a therapeutic strategy to manage mucoepidermoid carcinomas (MEC) of the salivary glands. MATERIAL AND METHODS: UM-HMC-1, UM-HMC-2, and UM-HMC-3A MEC cell lines were used to establish the effects of Cephaeline over tumor viability determined by MTT assay. In vitro wound healing scratch assays were performed to address cellular migration while immunofluorescence staining for histone H3 lysine 9 (H3k9ac) was used to identify the acetylation status of tumor cells upon Cephaeline administration. The presence of cancer stem cells was evaluated by the identification of ALDH enzymatic activity by flow cytometry and through functional assays using in vitro tumorsphere formation. RESULTS: A single administration of Cephaeline resulted in reduced viability of MEC cells along with the halt on tumor growth and cellular migration potential. Administration of Cephaeline resulted in chromatin histone acetylation as judged by the increased levels of H3K9ac and disruption of tumorspheres formation. Interestingly, ALDH levels were increased in UM-HMC-1 and UM-HMC-3A cell lines, while UM-HMC-2 showed a reduced enzymatic activity. CONCLUSION: Cephaeline has shown anti-cancer properties in all MEC cell lines tested by regulating tumor cells' viability, migration, proliferation, and disrupting the ability of cancer cells to generate tumorspheres.

The hidden curve behind COVID-19 outbreak: the impact of delay in treatment initiation in cancer patients and how to mitigate the additional risk of dying-the head and neck cancer model.

PURPOSE: The rapid spread of the SARS-CoV-2 pandemic around the world caused most healthcare services to turn substantial attention to treatment of these patients and also to alter the structure of healthcare systems to address an infectious disease. As a result, many cancer patients had their treatment deferred during the pandemic, increasing the time-to-treatment initiation, the number of untreated patients (which will alter the dynamics of healthcare delivery in the post-pandemic era) and increasing their risk of death. Hence, we analyzed the impact on global cancer mortality considering the decline in oncology care during the COVID-19 outbreak using head and neck cancer, a known time-dependent disease, as a model. METHODS: An online practical tool capable of predicting the risk of cancer patients dying due to the COVID-19 outbreak and also useful for mitigation strategies after the peak of the pandemic has been developed, based on a mathematical model. The scenarios were estimated by information of 15 oncological services worldwide, given a perspective from the five continents and also some simulations were conducted at world demographic data. RESULTS: The model demonstrates that the more that cancer care was maintained during the outbreak and also the more it is increased during the mitigation period, the shorter will be the recovery, lessening the additional risk of dying due to time-to-treatment initiation. CONCLUSIONS: This impact of COVID-19 pandemic on cancer patients is inevitable, but it is possible to minimize it with an effort measured by the proposed model.

Induction Chemotherapy for Advanced Oral Cavity Cancer.

PURPOSE OF REVIEW: Head and neck cancer is a heterogeneous disease, comprising multiple subsites with diverse etiologic factors, pathology and molecular features, response to treatment, and prognosis. Systemic treatment is usually incorporated in the management of locally advanced head and neck squamous cell carcinoma, and the use of induction chemotherapy has theoretical benefits on reducing the risk of distant metastasis, provide an in vivo testing of response and tumor biology and the potential to allow a more personalized and less toxic local treatment after downstaging. The aim of this review is to access the role of induction chemotherapy in patients with locally advanced oral cavity cancer. RECENT FINDINGS: Clinical trials analyzing this treatment strategy in patients with resectable disease, followed by surgery, and in unresectable disease, followed by (chemo)radiotherapy or surgery are discussed, pointing out strengths and limitations of this data and highlighting the standard treatment in each clinical scenario. Future perspectives, including the incorporation of checkpoint inhibitors and biomarkers for patient selection are discussed. Surgery followed by (chemo)radiation is the standard of care for resectable oral cavity cancer patients, and chemoradiation is the standard for those considered as unresectable. Future trials with the incorporation of immunotherapy and better patient selection based on clinical and molecular biomarkers can bring new hopes for better therapeutic results in these patients.

Young head and neck cancer patients are at increased risk of developing oral mucositis and trismus.

OBJECTIVES: To evaluate cancer treatment-related toxicities in young head and neck cancer (HNC) patients. MATERIAL AND METHODS: A total of 44 patients were included in the present retrospective cohort study, which was designed to access oral toxicities of cancer treatment in young (< 45 years of age, Group I, n = 22) and old (> 58 years of age, Group II, n = 22) HNC patients with similar tumor stage and treatment protocols. Oral mucositis (OM), xerostomia, dysphagia, dysgeusia, trismus, and radiodermatitis were assessed during days 7th, 21st, and 35th of head and neck radiotherapy (HNRT) according to previously validated scales (World Health Organization criteria and the National Cancer Institute and Common Terminology Criteria for Adverse Events version 4.0). RESULTS: Patients from both groups showed high incidence and severity of oral toxicities by the end of the HNRT with OM (81.9% (Group I); 63.6% (Group II)) and xerostomia (72.6% (Group I); 77.2% (Group II)) being the most prevalent toxicities. No differences regarding xerostomia, dysphagia, dysgeusia, and radiodermatitis incidences or severity could be observed between groups. However, higher incidences and severity of OM at 21st and 35th fractions (odds ratio = 2.22 and 5.71, respectively) and trismus at 21st and 35th fractions (odds ratio = 6.17 and 14.5, respectively) were observed throughout the treatment in young patients when compared to older patients (p < 0.01 and p < 0.05, respectively). CONCLUSION: Young HNC patients are more affected by cancer treatment-related OM and trismus despite the similarities in clinical staging and treatment protocols with elderly patients.

Molecular basis of oral squamous cell carcinoma in young patients: Is it any different from older patients?

Oral squamous cell carcinoma (OSCC) is the commonest subtype of oral cancer, mainly affecting older patients. It used to be a rare disease among individuals younger than 40 years, but recently increased incidences in this age group are being reported worldwide. The pathogenesis of OSCC affecting young patients remains controversial, and the well-known etiological factors for oral cancer, tobacco, and alcohol use are believed to play a minor role in the carcinogenesis of the neoplasm, suggesting that the etiology and the molecular basis of OSCC may differ between younger and older patients. Although several molecular markers and chromosomal abnormalities have been demonstrated to differ between both groups, most of the studies have failed to find significant differences. Moreover, divergent results have also been obtained regarding the presence of high-risk human papillomavirus infection in OSCC of young patients. Given these contradictory results and the limited methodological approaches of the majority of the studies, the exact difference between both age groups remains to be fully established. In this review, we evaluate the available data to establish the current evidence that might support the hypothesis that the molecular basis of OSCC in young patients (especially those under 40 years) differ from the older patients.

BRAF-V600E expression correlates with ameloblastoma aggressiveness.

AIMS: The aim of this study was to investigate whether the expression of BRAF-V600E determines an aggressive clinical and molecular presentation of ameloblastoma. METHODS AND RESULTS: Ninety-three cases of solid ameloblastomas were arranged in a 1.0-mm tissue microarray (TMA) block. Immunohistochemistry against a large panel of cytokeratins (CK), epidermal growth factor receptor (EGFR), parathyroid hormone-related peptide (PTHrP), syndecan-1, Ki67, p53 and BRAF-V600E were performed. Clinicopathological parameters, including sex, age, tumour size, tumour duration, tumour location, treatment, recurrences, radiographic pattern, vestibular/lingual and basal cortical plates disruption and follow-up data, were obtained from patients' medical records. Immunoexpression of BRAF-V600E was investigated in 73 cases that remained available in TMA sections. Our results indicated that 46.6% (34 cases) demonstrated cytoplasm positivity (six weak and 28 strong positivity). BRAF-V600E expression was associated significantly with the expression of CK8 (P = 0.00077), CK16 (P = 0.05), PTHrP (P = 0.0082) and p53 (P = 0.0087). Additionally, a significant association was seen with the presence of recurrences (P = 0.0008), multilocular radiographic appearance (P = 0.044) and disruption of basal bone cortical (P = 0.05). Univariate analysis showed that BRAF-positive cases (P = 0.001), EGFR-negative/weak positive cases (P = 0.03) and multilocular tumours (P = 0.04) had a significantly lower disease-free survival rate, but these parameters were not considered independent prognostic factors in the multivariate analysis (P > 0.05). CONCLUSIONS: Our findings suggest an association of BRAF-V600E with parameters of a more aggressive behaviour of ameloblastoma, supporting the future use of BRAF inhibitors for targeted therapy of this neoplasm.

Postradiation Matrix Metalloproteinase-20 Expression and Its Impact on Dental Micromorphology and Radiation-Related Caries.

Recent evidence suggests that head-and-neck radiotherapy (HNRT) increases active forms of matrix metalloproteinase-20 (MMP-20) in human tooth crowns, degrading the dentin-enamel junction (DEJ) and leading to enamel delamination, which is a pivotal step in the formation of radiation-related caries (RRC). Additional participation of enzymatic degradation of organic matrix components in caries progression was attributed to MMP-20 in dentin. Therefore, the current study tested the hypothesis that MMP-20 is overexpressed in the DEJ, dentin-pulp complex components, and carious dentin of post-HNRT patients, leading to detectable micromorphological changes to the enamel and dentin. Thirty-six teeth were studied, including 19 post-HNRT specimens and 17 nonirradiated controls. Optical light microscopy was used to investigate the micromorphological components of the DEJ, dentin-pulp complex components, and carious dentin. The samples were divided into 2 subgroups: nondemineralized ground sections (n = 20) and demineralized histological sections (n = 16). In addition, immunohistochemical analysis using the immunoperoxidase technique was conducted to semiquantitatively assess MMP-20 expression in the DEJ, dentin-pulp complex components, and carious dentin. No apparent damage to the DEJ microstructure or other dentin-pulp complex components was observed and no statistically significant differences were detected in MMP-20 expression (p > 0.05) between the irradiated and control groups. This study rejected the hypothesis that MMP-20 is overexpressed in the DEJ, dentin-pulp complex components, and carious dentin of post-HNRT patients, leading to detectable micromorphological changes. Hence, direct effects of radiation may not be regarded as an independent factor to explain aggressive clinical patterns of RRC.

Effectiveness of COVID-19 vaccines against severe COVID-19 among patients with cancer in Catalonia, Spain.

Patients with cancer were excluded from pivotal randomized clinical trials of COVID-19 vaccine products, and available observational evidence on vaccine effectiveness (VE) focused mostly on mild, and not severe COVID-19, which is the ultimate goal of vaccination for high-risk groups. Here, using primary care electronic health records from Catalonia, Spain (SIDIAP), we built two large cohorts of vaccinated and matched control cancer patients with a primary vaccination scheme (n = 184,744) and a booster (n = 108,534). Most patients received a mRNA-based product in primary (76.2%) and booster vaccination (99.9%). Patients had 51.8% (95% CI 40.3%-61.1%) and 58.4% (95% CI 29.3%-75.5%) protection against COVID-19 hospitalization and COVID-19 death respectively after full vaccination (two-doses) and 77.9% (95% CI 69.2%-84.2%) and 80.2% (95% CI 63.0%-89.4%) after booster. Compared to primary vaccination, the booster dose provided higher peak protection during follow-up. Calibration of VE estimates with negative outcomes, and sensitivity analyses with slight different population and COVID-19 outcomes definitions provided similar results. Our results confirm the role of primary and booster COVID-19 vaccination in preventing COVID-19 severe events in patients with cancer and highlight the need for the additional dose in this population.

Sotorasib (960 mg or 240 mg) once daily in patients with previously treated KRAS G12C-mutated advanced NSCLC.

BACKGROUND: Sotorasib 960 mg once daily is approved to treat KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC). Sotorasib exhibits non-dose proportional pharmacokinetics and clinical responses at lower doses; therefore, we evaluated the efficacy and safety of sotorasib 960 mg and 240 mg. METHODS: In this phase 2, randomized, open-label study, adults with KRAS G12C-mutated advanced NSCLC received sotorasib 960 mg or 240 mg once daily. Primary endpoints were objective response rate (ORR) and safety. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and pharmacokinetics. The study was not powered for formal statistical hypothesis testing. RESULTS: In the 960 mg group (n = 104), ORR was 32.7 % and DCR was 86.5 %. In the 240 mg group (n = 105), ORR was 24.8 % and DCR was 81.9 %. Median PFS was 5.4 months (960 mg) and 5.6 months (240 mg). At a median follow-up of 17.5 months, median OS was 13.0 months (960 mg) and 11.7 months (240 mg). AUC0-24 h and Cmax were 1.3-fold numerically higher with the 960 mg dose. Treatment-emergent adverse events (TEAEs, ≥10 %) for 960 mg and 240 mg doses, respectively, were diarrhea (39.4 %; 31.7 %), nausea (23.1 %; 19.2 %), increased alanine aminotransaminase (14.4 %; 17.3 %), and increased aspartate aminotransferase (13.5 %; 13.5 %). CONCLUSIONS: Patients treated with sotorasib 960 mg once daily had numerically higher ORR and DCR, and longer DOR and OS, than patients treated with 240 mg in this descriptive analysis. TEAEs were manageable with label-directed dose modifications. CLINICAL TRIAL REGISTRATION: NCT03600883.

Latin American Consensus on the Treatment of Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is well known as a serious health problem worldwide, especially in low-income countries or those with limited resources, such as most countries in Latin America. International guidelines cannot always be applied to a population from a large region with specific conditions. This study established a Latin American guideline for care of patients with head and neck cancer and presented evidence of HNSCC management considering availability and oncologic benefit. A panel composed of 41 head and neck cancer experts systematically worked according to a modified Delphi process on (1) document compilation of evidence-based answers to different questions contextualized by resource availability and oncologic benefit regarding Latin America (region of limited resources and/or without access to all necessary health care system infrastructure), (2) revision of the answers and the classification of levels of evidence and degrees of recommendations of all recommendations, (3) validation of the consensus through two rounds of online surveys, and (4) manuscript composition. The consensus consists of 12 sections: Head and neck cancer staging, Histopathologic evaluation of head and neck cancer, Head and neck surgery-oral cavity, Clinical oncology-oral cavity, Head and neck surgery-oropharynx, Clinical oncology-oropharynx, Head and neck surgery-larynx, Head and neck surgery-larynx/hypopharynx, Clinical oncology-larynx/hypopharynx, Clinical oncology-recurrent and metastatic head and neck cancer, Head and neck surgery-reconstruction and rehabilitation, and Radiation therapy. The present consensus established 48 recommendations on HNSCC patient care considering the availability of resources and focusing on oncologic benefit. These recommendations could also be used to formulate strategies in other regions like Latin America countries.

Survival inequalities in head and neck cancers: A hospital-based cohort study.

BACKGROUND: We investigated whether the socioeconomic status (SES) influenced survival rates in oropharynx cancers (OPC), oral cavity cancers (OCC), and larynx cancers (LC) in Brazilian patients. METHODS: This hospital-based cohort study assessed the age-standardized 5-year relative survival (RS) using the Pohar Perme estimator. RESULTS: Overall, we identified 37 191 cases, and 5-year RS were 24.4%, 34.1%, and 44.9% in OPC, OCC, and LC, respectively. In multiple Cox regression, the highest risk of death occurred in the most vulnerable social strata for all subsites-that is, illiterates or patients relying on publicly funded healthcare services. Disparities increased over time by 34.9% in OPC due to the rising of survival rates in the highest SES, whereas they reduced by 10.2% and 29.6% in OCC and LC. CONCLUSIONS: The potential inequities were more significant for OPC than for OCC and LC. It is urgent to tackle social disparities to improve prognoses in highly unequal countries.

Time to Recurrence as a Prognostic Factor in Parathyroid Carcinoma.

Background: Parathyroid carcinoma (PC) is a rare and challenging disease without clearly understood prognostic factors. Adequate management can improve outcomes. Characteristics of patients treated for PC over time and factors affecting prognosis were analyzed. Methods: Retrospective cohort study including surgically treated patients for PC between 2000 and 2021. If malignancy was suspected, free-margin resection was performed. Demographic, clinical, laboratory, surgical, pathological, and follow-up characteristics were assessed. Results: Seventeen patients were included. Mean tumor size was 32.5 mm, with 64.7% staged as pT1/pT2. None had lymph node involvement at admission, and 2 had distant metastases. Parathyroidectomy with ipsilateral thyroidectomy was performed in 82.2%. Mean postoperative calcium levels were different between patients who developed recurrence vs those who did not (P = .03). Six patients (40%) had no recurrence during follow-up, 2 (13.3%) only regional, 3 (20%) only distant, and 4 (26.6%) both regional and distant. At 5 and 10 years, 79% and 56% of patients were alive, respectively. Median disease-free survival was 70 months. Neither Tumor, Nodule, Metastasis system nor largest tumor dimension (P = .29 and P = .74, respectively) were predictive of death. En bloc resection was not superior to other surgical modalities (P = .97). Time between initial treatment and development of recurrence negatively impacted overall survival rate at 36 months (P = .01). Conclusion: Patients with PC can survive for decades and have indolent disease course. Free margins seem to be the most important factor in initial surgery. Recurrence was common (60%), but patients with disease recurrence within 36 months of initial surgery had a lower survival rate.

Oral squamous cell carcinoma cancer stem cells have different drug sensitive to pharmacological NFκB and histone deacetylation inhibition.

Despite many progresses in the development of new systemic therapies for oral squamous cell carcinoma (OSCC), the five-year survival rate of OSCC is low. The traditional chemotherapies approach (cisplatin - CDDP) shows some limitations like drug toxicity, limited efficacy, and drug resistance. Promising studies suggested OSCC cancer stem cells (CSC) presented resistance to CDDP. We have previously studied many targets, and we extensively showed the efficacy of the NFκB signaling and the role of histones acetylation, on different malignant tumors, including adenoid cystic carcinoma and mucoepidermoid carcinoma, but until then the effects of the NFkB inhibitor and histone deacetylase (HDAC) inhibitor on the biology of OSCC were not evaluated. Here we assessed the pharmacological inhibitor of NFκB emetine and HDAC inhibitor SAHA on the behavior of CSC derived from OSCC. Our data suggested that CDDP administration resulted in reduced viability of bulk OSCC cells and increased CSC. A single and isolated shot of emetine and SAHA were able to disrupt CSC by inhibiting the NFκB pathway and increasing the histone acetylation levels, respectively. Further, the combined administration of emetine and SAHA presented the same CSC disruption as seen in emetine alone.

Tumor glycolytic profiling through 18F-FDG PET/CT predicts immune checkpoint inhibitor efficacy in advanced NSCLC.

Background: A significant proportion of patients with non-small-cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICIs). Since metabolic reprogramming with increased glycolysis is a hallmark of cancer and is involved in immune evasion, we used 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) to evaluate the baseline glycolytic parameters of patients with advanced NSCLC submitted to ICIs, and assessed their predictive value. Methods: 18F-FDG PET/CT results in the 3 months before ICIs treatment were included. Maximum standardized uptake values, whole metabolic tumor volume (wMTV), and whole-body total lesion glycolysis (wTLG) were evaluated. Cutoff values for high or low glycolytic categories were determined using receiver-operating characteristic curves. Progression-free survival (PFS) and overall survival (OS) were evaluated. Patients with a complete response and a matching group with resistance to ICIs underwent immunohistochemistry analysis. An unsupervised k-means clustering model integrating programmed cell death ligand 1 (PD-L1) expression, glycolytic parameters, and ICIs therapy was performed. Results: In all, 98 patients were included. Lower baseline 18F-FDG PET/CT parameters were associated with responses to ICIs. Patients with low wMTV or wTLG had improved PFS and OS. High wTLG, strong tumor expression of glucose transporter-1, and lack of responses were significantly associated. Patients with low glycolytic parameters benefited from ICIs, regardless of chemotherapy. Conversely, those with high parameters benefited from the addition of chemotherapy. Patients with higher wTLG and lower PD-L1 were associated with progression and worse survival to ICIs monotherapy. Conclusions: Glycolytic metabolic profiles established through baseline 18F-FDG PET/CT are useful biomarkers for evaluating ICI therapy in advanced NSCLC.

Brief Report: Exploratory Analysis of Maintenance Therapy in Patients With Extensive-Stage SCLC Treated First Line With Atezolizumab Plus Carboplatin and Etoposide.

INTRODUCTION: In the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy. METHODS: Patients with untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo, followed by maintenance atezolizumab or placebo. The primary end points were OS and investigator-assessed PFS. A multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect and account for lead-time bias; a generalized linear model was used to identify prognostic or predictive characteristics for reaching the maintenance phase. RESULTS: A similar proportion of patients in each arm received at least the first dose of maintenance therapy (atezolizumab: 77%, n = 154 of 201; placebo: 81%, n = 164 of 202) and were included in the maintenance analysis population. An Eastern Cooperative Oncology Group performance status of 0 and absence of liver metastases at baseline were identified as prognostic factors for reaching the maintenance phase. The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics. Median OS and PFS from the start of maintenance therapy in the atezolizumab versus placebo arm were 12.5 versus 8.4 months (hazard ratio = 0.59, 95% confidence interval: 0.43-0.80) and 2.6 versus 1.8 months (hazard ratio = 0.63 [95% confidence interval: 0.49-0.80]), respectively. Treatment-related adverse events from the start of maintenance therapy occurred in 41% (n = 64 of 155) and 25% (n = 41 of 163) of safety-evaluable patients in the atezolizumab and placebo arms, respectively, and were grade 3 or 4 in 28% (n = 43 of 155) and 23% (n = 37 of 163) of the respective populations; no patient in the atezolizumab arm and one patient in the placebo arm had a grade 5 treatment-related adverse event. CONCLUSIONS: These data in the context of other immunotherapy trials in ES-SCLC suggest that induction with atezolizumab plus CP/ET and maintenance treatment with atezolizumab are important components that contributed to the OS benefit observed in IMpower133. Safety results from randomization and from the start of maintenance therapy were similar between the treatment arms despite the continuation of atezolizumab in the maintenance phase.

Letter to the editor: radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers.

A commentary on the original research article: 'Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers'. Of note, the predictor selection process, the cross-validation method, along with the lack of final testing of the developed model with a separated data set may mask overfitting, overestimating performance metrics.

Blood First Assay Screening Trial (BFAST) in Treatment-Naive Advanced or Metastatic NSCLC: Initial Results of the Phase 2 ALK-Positive Cohort.

INTRODUCTION: The Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort. METHODS: Patients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response. RESULTS: In total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6-18.7). Confirmed ORR was 87.4% (95% confidence interval [CI]: 78.5-93.5) by investigator and 92.0% (95% CI: 84.1-96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6-88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9-98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1-87.7). Safety data were consistent with the known tolerability profile of alectinib. CONCLUSIONS: These results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.

Influence of time between surgery and postoperative radiation therapy and total treatment time in locoregional control of patients with head and neck cancer: a single center experience.

OBJECTIVE: This study aimed to evaluate the effect of the delay to initiate postoperative radiation therapy (RT) on locoregional control to head and neck squamous cell carcinoma patients. METHODS: Retrospective cohort study that included patients submitted to surgery followed by adjuvant RT (with/without chemotherapy). The time interval between surgery and RT was dichotomized by the receiver operating characteristics curve method at 92 days. Other possible sources of heterogeneity with potential impact on locoregional control were explored by regressive analysis. RESULTS: A total of 168 patients were evaluated. The median time for locoregional recurrence (LRR) was 29.7 months. The relapse-free survival rates were 66.4% and 75.4% for patients who initiated RT more than and within 92 postoperative days (p=0.377), respectively. Doses lower than 60Gy were associated with worse rates of locoregional control (HR=6.523; 95%CI:2.266-18.777, p=0.001). Patients whose total treatment time (TTT) was longer than 150 days had LRR rate of 41.8%; no patient with TTT inferior to 150 days had relapses (p=0.001). CONCLUSIONS: The interval between surgery and RT did not show influence on locoregional control rates. However, doses <60Gy and the total treatment time >150 days were associated with lower locoregional control rates.