Arab male physicians' perceptions about their own smoking behaviors: a qualitative study.

BACKGROUND: Smoking remains the leading preventable cause of disease, disability, and death worldwide. Although physicians have high levels of health literacy with awareness of the consequences of smoking and their essential role in smoking cessation of patients, some physicians continue to smoke. Rates of smoking among Arab male physicians are high. This study aimed to gain insights into Arab male physician's perceptions of their own smoking behaviors and their professional role in health promotion. METHODS: Using purposive sampling, we recruited 25 Arab male physicians working in hospital and community clinic settings who currently smoke. Semi-structured, hour-long, interviews were held during January-June 2022. We then performed a thematic analysis of the interview data. RESULTS: The analysis revealed three categories, two sub-categories, and 15 emerging themes. The category 'Antecedents: prior to becoming a physician' revealed the themes: smoking experience during adolescence; social and ethnic culture; stress during medical studies; and on & off periods of quitting smoking. The category 'Physicians' perception of smoking' was sorted into two sub-categories: (1) Personal aspects, including the themes 'relaxation from stress', 'self-compensation', 'addiction', and 'enjoyable experience', and (2) Professional aspects, including the themes 'lack of knowledge about cessation', 'inadequate workplace support', 'motivation to consult patients', and 'awareness of their role as primary care physicians'. The category'Impacts' revealed the themes 'personal health and well-being', 'professional competence', and 'professional image in public'. CONCLUSIONS: This study provides an in-depth understanding of the personal, socio-cultural, and professional aspects of the phenomenon of Arab male smoking physicians from their perspective. Based on this information, we recommend developing programs that support and empower all physicians to cope better with their personal and professional stress as well as instituting programs that will provide all physicians with specific knowledge and skills related to smoking cessation. These programs should improve the ability of physicians to serve as positive role models for their patients for preventing and ceasing smoking, thus enhancing the image of the medical profession and, most importantly, improving the health of the public.

Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer.

PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424). CONCLUSION: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.

Biological insights from plasma proteomics of non-small cell lung cancer patients treated with immunotherapy.

Introduction: Immune checkpoint inhibitors have made a paradigm shift in the treatment of non-small cell lung cancer (NSCLC). However, clinical response varies widely and robust predictive biomarkers for patient stratification are lacking. Here, we characterize early on-treatment proteomic changes in blood plasma to gain a better understanding of treatment response and resistance. Methods: Pre-treatment (T0) and on-treatment (T1) plasma samples were collected from 225 NSCLC patients receiving PD-1/PD-L1 inhibitor-based regimens. Plasma was profiled using aptamer-based technology to quantify approximately 7000 plasma proteins per sample. Proteins displaying significant fold changes (T1:T0) were analyzed further to identify associations with clinical outcomes using clinical benefit and overall survival as endpoints. Bioinformatic analyses of upregulated proteins were performed to determine potential cell origins and enriched biological processes. Results: The levels of 142 proteins were significantly increased in the plasma of NSCLC patients following ICI-based treatments. Soluble PD-1 exhibited the highest increase, with a positive correlation to tumor PD-L1 status, and, in the ICI monotherapy dataset, an association with improved overall survival. Bioinformatic analysis of the ICI monotherapy dataset revealed a set of 30 upregulated proteins that formed a single, highly interconnected network, including CD8A connected to ten other proteins, suggestive of T cell activation during ICI treatment. Notably, the T cell-related network was detected regardless of clinical benefit. Lastly, circulating proteins of alveolar origin were identified as potential biomarkers of limited clinical benefit, possibly due to a link with cellular stress and lung damage. Conclusions: Our study provides insights into the biological processes activated during ICI-based therapy, highlighting the potential of plasma proteomics to identify mechanisms of therapy resistance and biomarkers for outcome.

Ovarian cancer ascites confers platinum chemoresistance to ovarian cancer cells.

Ovarian cancer (OC), the second most common form of gynecologic malignancy, has a poor prognosis and is often discovered in the late stages. Platinum-based chemotherapy is the first line of therapy. Nevertheless, treatment OC has proven challenging due to toxicity and the development of acquired resistance to therapy. Tumor microenvironment (TME) has been associated with platinum chemoresistance. Malignant ascites has been used as OC tumor microenvironment and its ability to induce platinum chemoresistance has been investigated. Our results suggest that exposure to OC ascites induces platinum chemoresistance in 11 of 13 cases (85 %) on OC cells. In contrast, 75 % of cirrhotic ascites (3 of 4) failed to confer platinum chemoresistance to OC cells. Cytokine array analysis revealed that IL -6 and to a lesser extent HGF were enriched in OC ascites, whereas IL -22 was enriched in cirrhotic ascites. Pharmaceutical inhibitors targeting the IL -6/ JAK pathway were mildly effective in overcoming platinum chemoresistance induced by malignant ascites. In contrast, crizotinib, an HGF/c- MET inhibitor, and 2-hydroxyestradiol (2HE2) were effective in restoring platinum chemosensitivity to OC. Our results demonstrate the importance of OC ascites in supporting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity of OC cells.

Prospective Observational Study of COVID-19 Vaccination in Patients with Thoracic Malignancies: Adverse Events, Breakthrough Infections and Survival Outcomes.

Due to the devastating COVID-19 pandemic, a preventive tool in the form of vaccination was introduced. Thoracic cancer patients had one of the highest rates of morbidity and mortality due to COVID-19 disease, but the lack of data about the safety and effectiveness of vaccines in this population triggered studies like ours to explore these parameters in a cancer population. Out of 98 patients with thoracic malignancies vaccinated per protocol, 60-75% experienced some adverse events (AE) after their first or second vaccination, most of them were mild and did not interfere with their daily activities. Out of 17 severe AEs reported, all but one were resolved shortly after vaccination. No significant differences were noted considering AE occurrence between different cancer therapies received after the first or second vaccination dose, p = 0.767 and p = 0.441, respectively. There were 37 breakthrough infections either after the first (1), second (13) or third (23) vaccine dose. One patient died as a direct consequence of COVID-19 infection and respiratory failure, and another after disease progression with simultaneous severe infection. Eight patients had moderate disease courses, received antiviral therapies and survived without consequences. Vaccination did not affect the time to disease progression or death from underlying cancer.

Unexpected and Rare Sites of Metastasis in Oncologic Patients.

Case studies of rare oncologic metastases are an important source of clinical data for health care professionals and researchers. While infrequent, the knowledge base and clinical recommendations derived from such cases aid in advancements in the field. As such, we aim to add five cases to the growing body of literature. The first two male patients, aged 69 and 73, were diagnosed with colon adenocarcinoma, suspected to be a second primary prostate carcinoma, following positron emission tomography-computer tomography (PET-CT). This suspicion was ruled out by prostatectomy and histopathological investigations, which instead found adenocarcinoma of colonic origin. The next two male patients, ages 63 and 68, were diagnosed, respectively, with metastatic pancreatic adenocarcinoma with cardiac metastases and metastatic melanoma with distant metastases to the pancreas. The final patient was a 73-year-old male diagnosed with metastatic breast cancer after a radiological investigation of suspected renal cell carcinoma.

Response Rate of the Third and Fourth Doses of the BNT162b2 Vaccine Administered to Cancer Patients Undergoing Active Anti-Neoplastic Treatments.

The BNT162b2 vaccine is globally used for preventing morbidity and mortality related to COVID-19. Cancer patients have had priority for receiving the vaccine due to their diminished immunity. This study reports the response rate of administering the third and fourth vaccine doses to cancer patients receiving active anti-neoplastic treatment. A total of 142 patients received two doses of the mRNA-based BNT162b2 COVID-19 vaccine, while 76 and 25 patients received three and four doses, respectively. The efficacy of the humoral response following two vaccine doses was diminished in cancer patients, especially in the group of patients receiving chemotherapy. In a multivariate analysis, patients who received three and four BNT162b2 vaccine doses were more likely to have antibody titers in the upper tertile compared to patients who received two doses of the vaccine (odds ratio (OR) 7.62 (95% CI 1.38-42.12), p = 0.02 and 17.15 (95% CI 5.01-58.7), p < 0.01, respectively). Unlike the response after two doses, the third and fourth BNT162b2 vaccine booster doses had an increased efficacy of 95-100% in cancer patients while undergoing active treatment. This result could be explained by different mechanisms including the development of memory B cells.

Multi-Center Real-World Outcomes of Nivolumab Plus Ipilimumab and Chemotherapy in Patients with Metastatic Non-Small-Cell Lung Cancer.

Immune checkpoint inhibitors have become the standard of care in the treatment of metastatic non-small-cell lung cancer (NSCLC). The combination of nivolumab plus ipilimumab and chemotherapy has been shown to improve outcomes in terms of overall survival (OS) and progression-free survival (PFS). The aim of this study was to evaluate the outcomes of metastatic NSCLC treated in routine practice on the treatment regimen of the CheckMate 9LA protocol. Medical records of 58 patients treated at Soroka and Bnai Zion Medical Centers between May 2020 and February 2022 were analyzed. All patients were treated with a regimen of platinum-based chemotherapy combined with immunotherapy of nivolumab every three weeks and ipilimumab every 6 weeks. The patients received 2-3 cycles of chemotherapy according to the physician's choice: platinum-based cisplatin or carboplatin with either pemetrexed or paclitaxel. The median PFS was 10.2 months, longer than that of the 9LA trial (6.7 months). Adenocarcinoma patients exhibited a higher median OS of 13.7 (range 5-33) months than squamous cell carcinoma (SCC) patients at 12.3 (5-20) months and PFS of 10.3 (4-33) months, while squamous cell carcinoma patients had a PFS of 9.2 (4-18) months. Patients whose programmed death ligand-1 (PD-L1) tumor expression level was ≥1% showed a higher median OS than those with PD-L1 expression of less than 1%. Treatment-related adverse events (TRAEs) were reported in 93.1% of patients, mostly grade 1 in severity. The first-line treatment of metastatic NSCLC patients in combination with nivolumab plus ipilimumab and chemotherapy can be given safely in routine clinical practice, with results comparable to those achieved in clinical trials of the regimen.

Real-World Experience in Treatment of Patients with Non-Small-Cell Lung Cancer with BRAF or cMET Exon 14 Skipping Mutations.

BRAF and cMET exon 14 skipping are rare mutations of NSCLC. The treatment sequence in these cases for the first and second line is not clear. An international registry was created for patients with advanced NSCLC harboring BRAF or cMET exon 14 skipping mutations, diagnosed from January 2017 to June 2022. Clinicopathological and molecular data and treatment patterns were recorded. Data on 58 patients, from eight centers across five countries, were included in the final analysis. We found that 40 patients had the cMET exon 14 skipping mutation and 18 had the BRAF V600E mutation. In total, 53 and 28 patients received first- and second-line treatments, respectively, among which 52.8% received targeted therapy (TT) in the first line and 53.5% in the second line. The overall response rate (ORR) and disease control rate (DCR) for first-line treatment with TT vs. other treatment such as immune checkpoint inhibitors ± chemotherapy (IO ± CT) were 55.6% vs. 21.7% (p = 0.0084) and 66.7% vs. 39.1% (p = 0.04), respectively. The type of treatment in first-line TT vs. other affected time to treatment discontinuation (TTD) was 11.6 m vs. 4.6 m (p= 0.006). The overall survival for the whole group was 15.4 m and was not statistically affected by the type of treatment (19.2 m vs. 13.5 m; p = 0.83).

Bnai-Zion Medical Center Healthcare Workers' Levels of Professional Burnout during the COVID-19 Pandemic.

Objectives: Unprecedented challenges in hospital care were imposed in response to the COVID-19 pandemic due to the highly contagious disease. Healthcare services adjusted for working with additional personal protection equipment and hygiene measures while attending to a large number of critically ill patients. In this study, we aimed to determine burnout rates and preferred interventions among healthcare staff, including nurses and physicians, at Bnai-Zion Medical Center during the COVID-19 pandemic. Methods: The Copenhagen Burnout Inventory questionnaire was administered to 185 cross-sectional volunteer participants from the nursing and medical staff between June and August 2020, when Israel experienced its second surge of COVID-19. Results: We found a statistically significant correlation between work-related and personal burnout. COVID-19 ward staff had greater burnout levels than the rest of our institution's personnel. Most highly burned-out healthcare workers were interested in intervention therapy. Conclusions: Dealing with burnout is imperative to improve the well-being of our hospital staff and ensure the best possible performance. Nursing management should consider first-line responders' stressful conditions to be alleviated through support programs.

Factors Predicting Type I Gastric Neuroendocrine Neoplasia Recurrence: A Single-Center Study.

Type I gastric neuroendocrine neoplasms (gNENs) are associated with atrophic gastritis and have a high recurrence rate, which means frequent endoscopies are required. The objective of this study was to identify factors predicting the local recurrence of type I gNENs. The clinical course and the pathological and biochemical data of patients with type I gNENs treated at Bnai Zion Medical Center between 2006 and 2022 were analyzed retrospectively. Twenty-seven type I gNENs were evaluated. The follow-up period was 41 months (range: 11-288 months). Recurrence of the tumor occurred in 13/27 (48%) patients after 35 months (median (M), interquartile range (IQR): 21-67.5). Serum gastrin levels were significantly higher in patients with recurrent disease versus patients with non-recurrent disease (788 vs. 394 ng/L; p = 0.047), while the Ki-67 index was significantly lower in patients with recurrent disease versus patients with non-recurrent disease (1% vs. 3.5%; p = 0.035). Tumor size, mitotic count, and serum chromogranin A levels did not correlate with recurrence. The present study emphasizes the role of gastrin in the pathogenesis of gNEN recurrence and highlights the debate regarding the ability of the Ki-67 index to predict the clinical course of this disease.

Molecular Epidemiology and Treatment Patterns of Patients With EGFR Exon 20-Mutant NSCLC in the Precision Oncology Era: The European EXOTIC Registry.

Introduction: Real-world evidence regarding molecular epidemiology and management patterns of patients with EGFR exon-20 mutated, advanced NSCLC outside the context of clinical trials is lacking. Methods: We created a European registry for patients with advanced EGFR exon 20-mutant NSCLC diagnosed from January 2019 to December 2021. Patients enrolled in clinical trials were excluded. Clinicopathologic and molecular epidemiology data were collected, and treatment patterns were recorded. Clinical end points according to treatment assignment were assessed using Kaplan-Meier curves and Cox regression models. Results: Data on 175 patients from 33 centers across nine countries were included in the final analysis. Median age was 64.0 (range: 29.7-87.8) years. Main features included female sex (56.3%), never or past smokers (76.0%), adenocarcinoma (95.4%), and tropism for bone (47.4%) and brain (32.0%) metastases. Mean programmed death-ligand 1 tumor proportional score was 15.8% (range: 0%-95%) and mean tumor mutational burden was 7.06 (range: 0-18.8) mutations per megabase. Exon 20 was detected in the tissue (90.7%), plasma (8.7%), or both (0.6%), using mostly targeted next-generation sequencing (64.0%) or polymerase chain reaction (26.0%). Mutations were mainly insertions (59.3%), followed by duplications (28.1%), deletions-insertions (7.7%), and the T790M (4.5%). Insertions and duplications were located mainly in the near loop (codons 767-771, 83.1%) and the far loop (codons 771-775, 13%) and only in 3.9% within the C helix (codons 761-766). Main co-alterations included mutations in TP53 (61.8%) and MET amplifications (9.4%). Treatment on mutation identification included chemotherapy (CT) (33.8%), CT-immunotherapy (IO) (18.2%), osimertinib (22.1%), poziotinib (9.1%), mobocertinib (6.5%), mono-IO (3.9%), and amivantamab (1.3%). Disease control rates were 66.2% with CT plus or minus IO, 55.8% with osimertinib, 64.8% with poziotinib, and 76.9% with mobocertinib. Corresponding median overall survival was 19.7, 15.9, 9.2, and 22.4 months, respectively. In multivariate analysis, type of treatment (new targeted agents versus CT ± IO) affected progression-free survival (p = 0.051) and overall survival (p = 0.03). Conclusions: EXOTIC represents the largest academic real-world evidence data set on EGFR exon 20-mutant NSCLC in Europe. Indirectly compared, treatment with new exon 20-targeting agents is likely to confer survival benefit than CT plus or minus IO.

Acupuncture and integrative oncology for taxane-induced peripheral neuropathy: a randomized multicentered study.

OBJECTIVE: To compare the effectiveness of acupuncture alone or with additional integrative oncology modalities for taxane-induced peripheral neuropathy-related symptoms in patients with gynecological and breast cancer. METHODS: The study was a prospective evaluation of patients undergoing twice-weekly treatments with either acupuncture alone (single-modality, group A) or with additional manual-movement and mind-body therapies (multimodality, group B), for 6 weeks. Symptom severity was assessed at baseline, 6 weeks, and 9 weeks using the Functional Assessment of Cancer Therapy-Taxane (FACT-Tax) tool; and von Frey perception thresholds. Additional symptoms were also assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the Measure Yourself Concerns and Wellbeing (MYCaW) study tool. RESULTS: For the 120 participants (60 in each study arm), baseline to 6-week scores were similar in both groups for improved FACT-Tax physical wellbeing and scores for hand numbness/tingling; EORTC physical functioning and global health status; and MYCaW scores. FACT-Tax taxane subscales and scores for foot numbness/tingling improved only in group A (p=0.038), while emotional wellbeing FACT-Tax (p=0.02) and EORTC pain (p=0.005) improved only in group B. Group B showed greater improvement for FACT-Tax neuropathy-related concerns than group A at 24 hours (p=0.043) and 7 days (p=0.009) after the first treatment. CONCLUSION: Acupuncture alone or with additional integrative oncology modalities may help reduce neuropathy-related symptoms. The single-modality group demonstrated greater improvement for foot numbness/tingling, and the multimodality group demonstrated improvement for pain and improved emotional wellbeing and neuropathy-related concerns in the first week of treatment. TRIAL REGISTRATION NUMBER: NCT03290976.

The Correlation between Proliferative Immunohistochemical Markers and Papillary Thyroid Carcinoma Aggressiveness.

Background and Objectives: Papillary thyroid carcinoma (PTC) is one of the most common malignancies of the endocrine system. In order to improve the ability to predict tumor behavior, several studies have been conducted to search for surrogate prognostic immunohistochemical tumor markers. Objective: To evaluate the correlation between the intensity of different immunohistochemical marker staining in PTC and the risk for extrathyroidal extension and metastases. Materials and Methods: The study comprised patients who underwent hemi- or total thyroidectomy. Thyroid tissues were immunohistochemically stained for different tumor proliferative markers: Minichromosome maintenance proteins 2 (MCM2), Ki-67 labeling index, E-Cadherin, Neuropilin-1 and Metallothionein. The correlation between the intensity of each marker staining and the final diagnosis (benign neoplasm and PTC) and the correlation between the intensity of each staining and tumor extrathyroidal extension and metastases were evaluated. Results: The study included 66 patients. Staining for Metallothionein, E-Cadherin and MCM2 significantly differed between benign neoplasm (n = 22) and thyroid-confined PTC (n = 21) (p = 0.002, 0.004 and 0.005, respectively), between benign neoplasm and PTC with extrathyroidal extension (n = 11) (p = 0.001, 0.006 and 0.01, respectively), and between benign neoplasm and PTC with metastases (n = 12) (p = 0.01, <0.001 and 0.037, respectively). No staining correlated with extrathyroidal extension. The intensity of E-Cadherin staining was significantly lower in PTC with metastases than thyroid confined PTC and PTC with extrathyroidal extension (p = 0.028 and 0.021, respectively). Conclusions: Immunohistochemical staining for Metallothionein, E-Cadherin and MCM2 significantly distinguished between benign thyroid tumor and PTC. E-Cadherin staining significantly and inversely correlated with the presence of metastases.

Acupuncture in the Treatment of Panitumumab Skin Toxicity: A Case Report.

BACKGROUND: Inflammatory skin rash resulting from treatment with epidermal growth factor receptor inhibitors may cause physical and mental disabling to patients treated for their oncologic condition and may, in some cases, lead to the cessation of biological treatment. CASE REPORT: In this case report, acupuncture treatment was provided to a patient with metastatic colorectal carcinoma who developed skin toxicity from panitumumab including rash, itching, and skin inflammation. Itching, infection, and inflammation symptoms improved significantly following acupuncture, subsequently relapsed following treatment cessation, and improved once again following reintroduction of acupuncture. CONCLUSION: Acupuncture may be effective in alleviating panitumumab-related skin inflammatory symptoms.

Impact of acupuncture and integrative therapies on chemotherapy-induced peripheral neuropathy: A multicentered, randomized controlled trial.

BACKGROUND: To explore the impact of acupuncture with other complementary and integrative medicine (CIM) modalities on chemotherapy-induced peripheral neuropathy (CIPN) and quality of life (QoL) in oncology patients. METHODS: In this prospective, pragmatic, and patient-preference study, patients with CIPN were treated with acupuncture and CIM therapies (intervention group) or standard care alone (controls) for 6 weeks. Patients in the intervention arm were randomized to twice-weekly acupuncture-only (group A) or acupuncture with additional manual-movement or mind-body CIM therapies (group B). Severity of CIPN was assessed at baseline and at 6 weeks using the Functional Assessment of Cancer Therapy-Taxane (FACT-Tax) tool. Other QoL-related outcomes were assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC); and the Measure Yourself Concerns and Well-being questionnaire. Von Frey measurements examined perception thresholds. RESULTS: Of 168 participants, 136 underwent the study intervention (group A, 69; group B, 67), with 32 controls. Baseline-to-6-week assessment scores improved significantly in the intervention arm (vs controls) on FACT-Tax (p = .038) and emotional well-being (p = .04) scores; FACT-TAX scores for hand numbness/tingling (p = .007) and discomfort (p < .0001); and EORTC physical functioning (p = .045). Intervention groups A and B showed improved FACT-Tax physical well-being (p < .001), FACT-TAX total score (p < .001), FACT-TAX feet discomfort (p = .003), and EORTC pain (p = .017) scores. CONCLUSIONS: Acupuncture, with or without CIM modalities, can relieve CIPN-related symptoms during oncology treatment. This is most pronounced for hand numbness, tingling, pain, discomfort, and for physical functioning.

Crizotinib in MET Exon 14-Mutated or MET-Amplified in Advanced Disease Non-Small Cell Lung Cancer: A Retrospective, Single Institution Experience.

Introduction: Non-small cell lung cancer (NSCLC) accounts for most lung cancers and is a leading cause of cancer-related deaths in the USA. Alterations in c-MET, a tyrosine kinase receptor, have been involved in many cases of NSCLC progression and metastasis. Crizotinib and other tyrosine kinase inhibitors (TKIs) have been used in NSCLC treatment with limited success. Methods: In this retrospective observational study, we analyzed data from patients diagnosed with lung cancer at Soroka University Medical Center between January 2015 and January 2020. We investigated patient characteristics, including disease-associated mutation type and median survival in response to different TKI treatments. Results: A total of 780 patients with lung cancer were included in the study, 134 of whom had small cell lung cancer and 646 had NSCLC. Of the NSCLC patients, 403 were diagnosed with advanced or metastatic disease, and 374 underwent molecular testing. We identified 16 patients with either c-MET mutations or amplifications who were treated with crizotinib. Of these patients, 7 expressed a c-MET exon 14 skipping mutation while the remaining 9 patients expressed c-MET amplification. Among the patients with a c-MET exon 14 skip mutation, the overall survival was 22.8 months and the median progression-free survival (PFS) on crizotinib treatment was 12.4 months. Of the patients with c-MET amplification, the median overall survival was 5.4 months and the median PFS with crizotinib treatment was 2.6 months. Discussion and Conclusions: We analyzed the data of a series of cases describing patients diagnosed with different stages of NSCLC, having either a c-MET exon 14 skipping mutation or an amplification mutation, and treated with various TKIs, including crizotinib. We investigated the characteristics of these patient groups in accordance with mutation types and compared median survival between patient groups. Crizotinib was found to be an optimal treatment for NSCLC harboring c-MET exon 14 skipping mutations.

The Impact of Comprehensive Genomic Profiling (CGP) on the Decision-Making Process in the Treatment of ALK-Rearranged Advanced Non-Small Cell Lung Cancer (aNSCLC) After Failure of 2nd/3rd-Generation ALK Tyrosine Kinase Inhibitors (TKIs).

Background: The use of CGP in guiding treatment decisions in aNSCLC with acquired resistance to ALK TKIs is questionable. Methods: We prospectively assessed the impact of CGP on the decision-making process in ALK-rearranged aNSCLC patients following progression on 2nd/3rd-generation ALK TKIs. Physician's choice of the most recommended next-line systemic treatment (NLST) was captured before and after receival of CGP results; the percentage of cases in which the NLST recommendation has changed was assessed along with the CGP turnaround time (TAT). Patients were divided into groups: patients in whom the NLST was initiated after (group 1) and before (group 2) receival of the CGP results. Time-to-treatment discontinuation (TTD) and overall survival (OS) with NLST were compared between the groups. Results: In 20 eligible patients (median [m]age 63 years [range, 40-89], females 75%, adenocarcinoma 100%, failure of alectinib 90%, FoundationOne Liquid CDx 80%), CGP has altered NLST recommendation in 30% of cases. CGP findings were as follows: ALK mutations 30% (l1171X 10%, G1202R, L1196M, G1269A, G1202R+l1171N+E1210K 5% each), CDKN2A/B mutation/loss 10%, c-met amplification 5%. CGP mTAT was 2.9 weeks [IQR, 2.4-4.4]. mTTD was 11.3 months (95% CI, 2.1-not reached [NR]) and 5.4 months (95% CI, 2.0-NR) in groups 1 and 2, respectively (p-0.34). mOS was 13.2 months (95% CI, 2.9-NR) and 13.0 months (95% CI, 6.0-NR) in groups 1 and 2, respectively (p-0.86). Conclusion: CGP has a significant impact on the decision-making process in ALK-rearranged aNSCLC following progression on 2nd/3rd-generation ALK TKIs.

FGFR Fusions as an Acquired Resistance Mechanism Following Treatment with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR TKIs) and a Suggested Novel Target in Advanced Non-Small Cell Lung Cancer (aNSCLC).

BACKGROUND: FGFR1/2/3 fusions have been reported infrequently in aNSCLC, including as a rare, acquired resistance mechanism following treatment with EGFR TKIs. Data regarding their prevalence and therapeutic implications are limited. METHODS: The Guardant Health (GH) electronic database (ED) was evaluated for cases of aNSCLC and FGFR2/3 fusions; FGFR2/3 fusion prevalence with and without a co-existing EGFR mutation was assessed. The ED of Tel-Aviv Sourasky Medical Center (TASMC, June 2020-June 2021) was evaluated for cases of aNSCLC and de novo FGFR1/2/3 fusions. Patients with EGFR mutant aNSCLC progressing on EGFR TKIs and developing an FGFR1/2/3 fusion were selected from the ED of Davidoff Cancer Center (DCC) and Oncology Department, Bnei-Zion hospital (BZ) (April 2014-April 2021). Clinicopathological characteristics, systemic therapies, and outcomes were assessed. RESULTS: In the GH ED (n = 57,445), the prevalence of FGFR2 and FGFR3 fusions were 0.02% and 0.26%, respectively. FGFR3-TACC3 fusion predominated (91.5%). In 23.8% of cases, FGFR2/3 fusions co-existed with EGFR sensitizing mutations (exon 19 del, 64.1%; L858R, 33.3%, L861Q, 2.6%). Among samples with concurrent FGFR fusions and EGFR sensitizing mutations, 41.0% also included EGFR resistant mutations. In TASMC (n = 161), 1 case of de novo FGFR3-TACC3 fusion was detected (prevalence, 0.62%). Of three patients from DCC and BZ with FGFR3-TACC3 fusions following progression on EGFR TKIs, two received EGFR TKI plus erdafitinib, an FGFR TKI, with clinical benefit duration of 13.0 and 6.0 months, respectively. CONCLUSIONS: Over 23% of FGFR2/3 fusions in aNSCLC may be associated with acquired resistance following treatment with EGFR TKIs. In this clinical scenario, a combination of EGFR TKIs and FGFR TKIs represents a promising treatment strategy.

Real-World Journey of Unresectable Stage III NSCLC Patients: Current Dilemmas for Disease Staging and Treatment.

Daily-practice challenges in oncology have been intensified by the approval of immune checkpoint inhibitors (ICI). We aimed to outline current therapy policies and management of locally advanced unresectable stage III non-small-cell lung cancer (NSCLC) in different countries. One thoracic oncologist from each of the following countries-Belgium, Croatia, Greece, Israel, the Netherlands, Norway, Poland, Portugal, Romania, Slovenia, and Switzerland-participated in an electronic survey. Descriptive statistics were conducted with categorical variables reported as frequencies and continuous variables as median and interquartile range (IQR) (StataSE-v15). EBUS (endobronchial ultrasound bronchoscopy) was used either upfront or for N2 confirmation. Resectability is still a source of disagreement; thus, decisions vary within each multidisciplinary team. Overall, 66% of stage III patients [IQR 60-75] undergo chemoradiation therapy (CRT); concurrent CRT (cCRT) accounts for most cases (~70%). Performance status is universally used for cCRT eligibility. Induction chemotherapy is fairly weighted based on radiotherapy (RT) availability. Mean time to evaluation after RT completion is less than a month; ICI consolidation is started within six weeks. Durvamulab expenditures are reimbursed in all countries, yet some limiting criteria exist (PD-L1 ≥ 1%, cCRT). No clear guidance on therapies at Durvamulab progression exist; experts agree that it depends on progression timing. Given the high heterogeneity in real-world practices, standardized evidence-based decisions and healthcare provision in NSCLC are needed.