bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of delayed consolidation durvalumab and timing of treatment on survival outcomes in patients (pts) with unresectable stage III non-small cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT).
Authors: Stevens Samuel Xavier , Nindra Udit , Shahnam Adel , Bray Victoria Jane , Yip Po Yee , Adam Tamiem , Lee Jenny HJ , Boyer Michael J. , Nagrial Adnan , Kao Steven Chuan-Hao
Published: June 2022

e18809

Background: Consolidation treatment with durvalumab following CRT is now standard of care for pts with unresectable stage III NSCLC. In PACIFIC, durvalumab was administered within 42 days of completing CRT. There has also been recent interest in whether the time-of-day immunotherapy is given impacts on outcomes. In practice, many pts experience delays to consolidation immunotherapy, and the timing of infusions is variable. We investigated the effect of treatment delays and time-of-treatment on survival outcomes in a real-world setting. Materials & Methods: A retrospective observational study was conducted with patients treated with consolidation durvalumab following concurrent platinum-based CRT for unresectable stage III NSCLC in 6 centres across Sydney, Australia between January 2018 and September 2021. The primary outcomes were overall survival (OS) and progression-free survival (PFS) based on RECIST v1.1, from completion of radiotherapy. We collected treatment initiation and completion dates as well the administration time of durvalumab. In the time-of-treatment analysis, pts were stratified into median time of treatment either before or after 12.00pm. Survival was estimated using Kaplan-Meier and Cox-proportional hazard models. Results: 145 pts were included in the study. Median age was 67 years. 62.3% of pts were male, 84.9% were smokers, and 57.5% had adenocarcinoma. The median time between completion of CRT and commencement of durvalumab was 59 days (11-187 days). 71.2% (n = 102) of pts experienced a treatment delay. Over a median follow-up of 18.9 months, median PFS was 33.9 months in pts treated within 42 days of CRT and 25.6 months in pts treated beyond 42 days of CRT (HR 0.97; 95% CI 0.46-2.06; p = 0.815). Median OS was not reached in either group but no difference in OS was observed in the two cohorts (HR 1.07; 95% CI 0.39-2.96; p = 0.88). Median timing of treatment did not affect outcomes for either PFS (HR 1.07; 95% CI 0.50-1.71; p = 0.80) or OS (HR 1.01; 95% CI 0.44-2.31; p = 0.91). Conclusions: No difference in survival outcomes was seen between patients who had received durvalumab 42 days after CRT compared to within 42 days. The median timing of treatment did not appear to impact outcomes in our cohort.
Financial toxicity among patients with breast cancer in a publically funded health care system in Brazil.
Authors: Arevalo Andrea , Nunes Joao Soares , Nakakogue Tabatha , Figueiredo Alexandre Luders , Somensi Eduardo de Souza , Hauki Mariana Cararo , Weffort Marcos Daniel
Published: June 2022

e18818

Background: The concept of financial toxicity (FT) has been used to describe the unanticipated economic damage potentially caused by cancer treatment. Currently, it has been associated with decreased health-related quality of life (QoL), treatment nonadherence and increased risk of mortality. Even in publicly funded environments as Brazilian Unified National Health System, factor such as income loss or out-of-pocket costs could become an issue for cancer care. The aim of this study was to examine the FT related to the breast cancer diagnosis and treatments in a public Brazilian tertiary hospital through Comprehensive Score for Financial Toxicity (COST) instrument. The COST is a 12-item survey scored from 0 to 44, with lower scores reflecting worse financial well-being. Methods: This cross-sectional study was conducted among breast cancer patients in active treatment for at least 6 months attending medical oncology out-patient department. Socio-demographic, clinical characteristics and a simplified assessment of QoL were collected as well as responses to COST questionnaire. Descriptive statistic and analysis of correlations between quantitative variables and scores of QoL and COST were performed. Results: A total of 100 female patients were included with median age of 53 years old. The mean time from initial diagnosis was of 49.6 months and clinical stage IV represented 46% of all cases. Prior to the cancer treatment, 48 (48%) of the patients had their own job as a main source of income. However, after the cancer diagnosis, only 9 (9%) patients keep working, 36 (36%) needed to use savings and 29 (29%) applied for a bank loan. To adjust their finances, 66 (66%) patients reduced spending on leisure. The median COST score was 18.5 (ranged from 4 to 41). According to the age, patients with ≤ 45 years old were at higher risk of suffering FT (p = 0.01). There was also an association between the COST score and QoL since the higher the FT, the lower the QoL (p < 0.001). Conclusions: Patients with breast cancer are at risk of losing their work capacity, become financially dependent of other, and suffering a reduction in QoL as a result of FT. Mostly younger patients are at greater risk of FT. Despite a universal health-model, this study highlights a substantial proportion of patients who experienced FT. Therefore, further studies confirming these findings in larger groups are warranted to develop better strategies and policies to mitigate this form of toxicity.
Outcomes of patients with newly diagnosed acute myeloid leukemia (AML) and hyperleukocytosis.
Authors: Haddad Fadi , Sasaki Koji , Abuasab Tareq , Venugopal Sangeetha , Rivera Daniel , Bazinet Alexandre , Babakhanlou Rodrick , Kim Kunhwa , Senapati Jayastu , Ong Faustine , Desikan Sai Prasad , Short Nicholas James , Pemmaraju Naveen , Borthakur Gautam , Dinardo Courtney Denton , Daver Naval Guastad , Jabbour Elias , Garcia-Manero Guillermo , Ravandi Farhad , Kadia Tapan M.
Published: June 2022

e19029

Background: Hyperleukocytosis in AML is associated with inferior outcomes. Analyzing the factors associated with mortality in AML patients (pts) with a white blood cell count (WBC) ≥100 x 109/L can guide management and improve early mortality. Methods: We reviewed data from 129 pts with newly diagnosed AML presenting at our institution with WBC ≥100. Logistic regression models estimated odds ratios (OR) for 4-week mortality and Cox proportional hazard models estimated hazard ratios (HR) for overall survival (OS). Results: Median age was 65 years (range 23-86). 66% of pts had ECOG performance status (PS) <2. Median WBC was 146 (range 100-687) and 78 pts had clinical leukostasis (CL) including renal failure in 31 pts (24%), new onset hypoxia in 29 pts (23%), headache in 19 pts (15%), chest pain in 9 pts (7%) and neurological symptoms in 3 pts (2%). 29 pts (22%) had poor cytogenetics. FLT3 and RAS pathway mutations were found in 63% and 27% of pts, respectively. Compared with pts without evidence of CL, pts with CL were less likely to have good PS (ECOG PS <2, 58% vs 82%; P = 0.006), had higher 4-week (16% vs 2%; P = 0.015) and 8-week mortality (19% vs 6%; P = 0.038). Cytoreduction consisted of hydroxyurea in 124 pts (96%), cytarabine in 69 pts (54%) and leukapheresis in 31 pts (24%). Pts who underwent leukapheresis were less likely to receive cytarabine compared with pts who did not (35% vs 59%; P = 0.02); and tended to have more CL compared with pts who did not (74% vs 56%; P = 0.09). 30 pts had tumor lysis syndrome (TLS). TLS risk did not increase with WBC and was not associated with the cytoreductive modality used. 11 pts had intracranial hemorrhage (ICH): 9 pts (82%) with WBC ≥150 and 18% with WBC <150 (P = 0.048). No association was observed between the incidence of ICH and the cytoreductive therapy. 4-week and 8-week mortality rates were 10% and 14%, respectively. After a median follow-up of 49.4 months [mos] (95% CI 26.2-72.6), median OS was 14.3 mos (95% CI 7-21.6), with 2-year OS of 40%. Median OS was 12.3 mos (95% CI 7.4-17.2) compared with 29 mos (95% CI 2.1-55.6) in pts with or without CL, respectively (P = 0.007). Median OS was 9.9 mos (95% CI 7.5-12.2) and 21.3 mos (95% CI 10.7-31.8) among those who did or did not undergo leukapheresis, respectively (P=0.003). Median OS was 42 mos (95% CI 14.2-69.8) compared with 8 ms (95% CI 6-10) in pts < or ≥ 65 years. Conclusions: Older age, poor cytogenetics, TLS and DIC were associated with early mortality and inferior OS in pts with hyperleukocytosis. Careful monitoring of those pts with prompt cytoreduction and management of complications may help improve outcomes. [Table: see text]
Body mass index and venetoclax-hypomethylating agent induction therapy for acute myeloid leukemia.
Authors: Weiss Julian J , Le Henry , Agarwal Sonal , Podoltsev Nikolai Alexandrovich , Zeidan Amer Methqal , Shallis Rory
Published: June 2022

e19038

Background: Frontline Ven-HMA dosing is imperfectly estimated with HMA using body surface area (BSA) and Ven not BSA/weight-based. Not much is known if elevated body-mass-index (BMI) reduces drug exposure and impacts clinical outcomes with Ven-HMA. We sought to investigate the effectiveness of Ven-HMA in pts with elevated BMI and hypothesized no negative impact on outcomes. Methods: We retrospectively reviewed the records of pts with AML treated with frontline Ven-HMA from 12/2018-11/2021. The primary outcome was composite response rate (CR/CRi) as defined by 2017 ELN criteria. Pearson’s χ2 tests and Wilcoxon rank tests were used for bivariate analyses. Kaplan-Meier methods were used to calculate OS. Results: We identified 63 pts treated with frontline Ven-HMA, among whom 20 had a normal BMI (<25 kg/m2), 27 were overweight (BMI 25-29 kg/m2), and 16 were obese (BMI>30 kg/m2). Median age was 73 (range 37-89) and there were no differences in baseline patient- and disease-specific factors. The cohort overall was enriched for complex karyotype and TP53-mutated disease (46% and 33%, respectively), but without intergroup differences. Increasing BMI was associated with more HMA naivety and appeared to be associated with more antifungal use during induction (BMI <25: 60%, BMI >30: 88%; p=0.07) with similar rates of moderate/strong CYP3A4 inhibition. Early mortality (within 8-weeks of Ven-HMA), was greater in obese pts, but not significantly so (BMI<25: 20%; BMI>30: 31.3%; p=0.45). CR/CRi rate was similar among groups (BMI<25: 40%; BMI 25-29: 52%; BMI>30: 44%; p=0.71), as was ORR ( p=0.14). A sub-analysis excluding pts with prior HMA did not affect the parity in rate of CR/CRi in normal weight or obese pts (40% vs 44%, p=0.83) (Table). Conclusions: Our study showed that increasing BMI appears to have no negative influence on response to frontline Ven-HMA. However, it remains unclear whether increased BMI affects drug exposure, so dedicated studies are needed.[Table: see text]
Outcomes of clostridioides difficile infection in patients with hematopoietic stem cell transplant.
Authors: Mahfouz Ratib , Mansour Mahmoud , Obeidat Adham E. , Darweesh Mohammad , Batayneh Osama , Ghous Ghulam
Published: June 2022

e19054

Background: Hematopoietic stem cell transplantation (HSCT) recipients are at an increased risk for Clostridioides difficile infections (CDI). Despite it being the main cause of nosocomial enterocolitis in this group of patients, diagnosis of CDI remains challenging and carries significant morbidity and mortality. This is usually due to multiple comorbidities, recurrent antibiotics administration, prolonged immunosuppression, and lengthy hospitalization. This study aims to look more into outcomes and predictors of CDI in HSCT patients in terms of incidence, and mortality. Methods: The United States Nationwide Inpatient Sample was used to extract hospitalization data of patients admitted between 2016 to 2019. Using ICD10 revision codes, we identified adults with a discharge diagnosis of CDI and concomitant HSCT. The control group included non-HSCT patients with CDI. The primary outcome was in-hospital mortality. Secondary outcomes were the length of stay (LOS) and hospital charges. Additionally, predictors for developing CDI and dying from CDI were calculated in HSCT patients. Multivariate logistic regression was used to adjust for relevant variables. Results: An estimated 1,235,465 patients were admitted with CDI during the study period. CDI incidence per 100 discharges was higher among HSCT patients at 4.0% vs. 1.0% in the general population. After adjusting for comorbidities and demographic variables, HSCT was independently associated with increased odds of mortality (adjusted odds ratio [AOR] 1.47 (95%CI 1.20-1.80 and P <0.01). Mean length of stay and hospital charges increased by 1.76 days (95%CI 0.90-2.62, P < 0.01) and $59,023 (95%CI $35,940-$82,105, P < 0.01), respectively, in the HSCT group. In the HSCT group, patients with severe liver disease, malnutrition, and graft vs. host disease showed a significantly higher incidence of CDI. Predictors of mortality of HSCT patients and CDI are outlined in the attached table. Conclusions: HSCT recipients are at an increased risk for CDI compared to general population. LOS, total hospital charge, and mortality rate were significantly higher. The risk of CDI was found to be significantly higher in patients with moderate to severe liver disease, graft vs host disease, and malnutrition. The odds of mortality were found to be the highest in patients older than 65 years and those with congestive heart failure, moderate to severe liver disease, graft vs host disease, or malnutrition.[Table: see text]
Clinical outcomes associated with azacitidine (AZA) monotherapy for treatment-naïve, higher-risk myelodysplastic syndrome (HR-MDS): A systematic literature review and meta-analysis.
Authors: Hasegawa Ken , Wei Andrew H. , Garcia-Manero Guillermo , Daver Naval Guastad , Rajakumaraswamy Nishanthan , Iqbal Shahed , Chan Rebecca J. , Hu Hao , Tse Preston , Yan Jiajun , Zoratti Michael J. , Xie Feng , Sallman David Andrew
Published: June 2022

e19062

Background: AZA is a standard of care for patients who have HR-MDS. Given the limited availability of large datasets describing outcomes in the current treatment paradigm of HR-MDS, this analysis aimed to aggregate clinical outcomes associated with AZA monotherapy for treatment-naïve HR-MDS. Methods: CENTRAL, EMBASE, and MEDLINE were searched to identify interventional, prospective, and retrospective observational studies in treatment-naïve HR-MDS (defined as intermediate-2 or high risk by IPSS or intermediate to very high risk by IPSS-R) using AZA monotherapy. Inclusion of observational studies was limited to those with n >20 in the AZA arm. Responses according to IWG 2000 or IWG 2006 including complete remission (CR) rate, overall response rate (ORR; defined as CR, marrow CR [mCR], partial response, and hematologic improvement), overall survival (OS), duration of response (DOR), and time to response (TTR) were extracted. Response rates were synthesized using random-effects models; median of medians was used for OS, DOR, and TTR. Results: Of 3250 abstracts identified, 34 publications describing 16 studies met inclusion criteria: 5 randomized controlled trials (RCTs), 3 prospective studies, and 8 retrospective studies. None of the response endpoints were reported in all studies (see Table). The pooled ORR ranged from 44% to 55% across RCTs, prospective, and retrospective studies. The pooled CR rates, reported in 2 RCTs (n=55), 1 prospective study (n=27), and 3 retrospective studies (n=509), were 14%, 11%, and 16%, respectively. The pooled CR rate across all studies (n=591) was 16% (95% CI: 13%, 19%). Pooled median OS (mOS) was 16.7 months (mo) in the 3 RCTs (n=161), 16.5 mo in a single prospective study (n=34), and 14.4 mo in the 5 retrospective studies (n=1472). Pooled mOS across all studies (n=1667) was 16.4 mo (95% CI: 12.0, 17.3). The pooled median DOR was 10.1 mo (95% CI: 9.1, 11.0), and the median TTR was 4.6 mo (95% CI: 3.0, 9.0). Conclusions: These findings provide evidence that benefit from AZA monotherapy in treatment-naïve HR-MDS patients is limited. Opportunity exists for novel therapies to increase response rates, improve the duration of responses, and prolong survival. [Table: see text]
A real-world experience of combined treatment with romidepsin and azacitidine in patients with peripheral T-cell lymphoma.
Authors: Kalac Matko , Tam Constantine Si Lun , Goldfinger Mendel , Xiao Zhengrui , Rajeeve Sridevi , Montanari Francesca , Kanakry Jennifer Ann , O'Connor Owen , Marchi Enrica
Published: June 2022

e19550

Background: Patients with peripheral T-cell lymphoma (PTCL) lack good treatment options, particularly in the relapsed and refractory setting. Our work suggested that epigenetic therapies can be safe and effective for patients with PTCL, particularly those with T-cell lymphomas with a follicular helper (TFH) phenotype. It is thought that recurrent mutations in epigenetic factors, including Ten-Eleven Translocation-2 (TET2), DNA methyl transferase-3A (DNMT3A) and isocitrate dehydrogenase-2 (IDH2) may contribute to PTLC vulnerability to epigenetic drugs. Methods: Objective of this study was to evaluate the merits of romidepsin plus subcutaneous azacitidine in patients with PTCL when administered in a ‘real-world’ scenario. We retrospectively identified 17 PTCL patients world-wide that were treated with azacitidine and romidepsin outside of a clinical trial based upon queries regarding off study use. The study was reviewed and approved by each Medical Center Institutional Review Board. Their pretreatment characteristics are shown in Table. Results: Eleven patients had angioimmunoblastic lymphoma (AITL), 2 had adult T-cell leukemia/lymphoma (ATLL), 2 had TFH PTCL, 1 had PTCL-NOS and 1 had composite lymphoma (TFH PTCL with diffuse large B cell lymphoma). Ten patients had next generation sequencing performed. Most common mutations found were those of TET2 (7 pts), RHOA (4pts), IDH2 (3pts) and DNMT3A (1 pt). One ATLL patient had mutations in TRAF3, FAT1 and MED12. Among these 17 patients, overall response rate (ORR) was 76% and the complete response rate (CR) was 52%. Median number of cycles was 4 (range 1-12). Treatment was well tolerated but notable adverse effects included nausea, fatigue, rash, neutropenia and thrombocytopenia. One patient experienced febrile neutropenia while another had pulmonary infiltrates (differential diagnosis included drug toxicity versus infection). In 4 patients, azacitidine and romidepsin were used to achieve remission prior to allogeneic transplant (range of cycles 1-3), with all 4 patients were in CR at their last disease assessment. Conclusions: Subcutaneous azacitidine and romidepsin administered in a ‘real-world’ situation is highly effective in patients with relapsed PTCL with tolerable toxicity, and can be used to successfully bridge patients to stem cell transplant.[Table: see text]
Insurance-based disparities in Waldenstrom Macroglobulinemia: An NCDB analysis.
Authors: Chohan Karan , Abeykoon Jithma P. , Ansell Stephen M. , Gertz Morie A. , Kapoor Prashant , Paulus Aneel , Ailawadhi Sikander , Reeder Craig B. , Witzig Thomas E. , Habermann Thomas Matthew , Lacy Martha , Kyle Robert A. , Go Ronald S. , Paludo Jonas
Published: June 2022

e19562

Background: Considerable healthcare resource utilization and financial burden have been associated with the treatment of Waldenstrom Macroglobulinemia (WM); however, the impact of health insurance status on patient outcomes has not been explored. We aimed to assess the insurance-based outcome relationship in WM using the National Cancer Database (NCDB). Methods: We analyzed patient-level data obtained from the NCDB, a database representing more than 70% of newly diagnosed cancer cases nationwide. All newly diagnosed WM cases (n = 8540) between 2004 to 2017 were identified. Only patients who underwent treatment were included. Insurance status was recorded by assessing the primary payer at the time of diagnosis. Due to Medicare eligibility criteria, age-based (< 65 and ≥65 years) stratified analysis was conducted. Cox proportional hazards model was utilized to analyze survival. Time-to-event analysis was conducted based on date-of-diagnosis using the Kaplan-Meier method and log-rank test. Results: Analysis was conducted on 3878 patients after meeting inclusion criteria, with a median follow-up time of 54.6 months. Among patients < 65 years (n = 1249; median age: 58 years; male: 62.4%), those with non-private insurance had inferior survival on multivariate analysis (Table) after adjusting for patient demographics, comorbidities, income, education, treatment center characteristics, and treatment start time. Significant overall survival (OS) differences were seen in those < 65 years (log-rank p < 0.001), with 5-year OS highest among patients with private insurance 91.2%, compared to Medicaid 79.8%, uninsured 77.4%, and Medicare 70.2%. In patients < 65 years, compared to private insurance, uninsured patients were more likely to be of Black race, reside in lower income areas, and be treated at non-academic centers (all p < 0.05). Both Medicaid and Medicare patients < 65 years were more likely to have a higher Charlson-Deyo comorbidity index (> 1) and live in areas of lower educational attainment and household income compared to private insurance (all p < 0.05). In patients ≥65 years (n = 2629; median age: 75 years; 60.6% males), no insurance-based OS (log-rank p = 0.096) differences were seen. Conclusions: Based on our study, significant insurance-based disparities exist in WM, where patients < 65 years old who are uninsured, or non-privately insured are at a higher risk of mortality. While the root cause of these differences is not fully elucidated, efforts should focus on ensuring that all patients have equal access to care regardless of primary payer status.[Table: see text]
The association between minimal residual disease status and survival outcomes in transplant-ineligible newly diagnosed multiple myeloma (TIE-NDMM) patients: Systematic review.
Authors: Shah Zunairah , Khan Israr , Selene Insija Ilyas , Waqar Syed Hamza Bin , Khanam Razwana , Abid Qurrat-ul-ain , Tahir Nayha , Sathe Sanjivani , Laek Babray , Chattaraj Asmi , Roksana Zinath , Badu Irisha , Anwer Faiz
Published: June 2022

e20009

Background: Despite expanding therapeutic armamentarium of multiple myeloma (MM), it remains an incurable disease. Therefore, there is a need to assess the impact of deeper hematological responses to better gauge treatments in clinical trials and routine practice. The presence of minimal residual disease (MRD), is becoming crucial and a new standard in monitoring remission status. Clinical evidence shows that MRD status after treatment is an independent prognostic factor for MM. This review summarizes current data on MRD status and its role in predicting progression-free survival (PFS) and overall survival (OS) outcomes. Methods: We performed a literature search on four databases (PubMed, Embase, Cochrane, and Web of Science) following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines. We screened 1307 studies using the Mesh terms “Multiple Myeloma and Minimal Residual disease.” After excluding review, duplicate, and non-relevant articles, 7 studies were included. Results: The association between MRD status and outcomes, including survival in TIE-NDMM patients was assessed in 7 studies, including 1083 patients. MRD status was determined using different techniques, such as flow cytometry and clonoSEQ. Different regimens were used in all studies. PFS was reported in all studies. Compared with MRD positive status, achieving MRD negativity improved PFS to 58 months versus 28.65 months as per cumulative analysis. The cumulative OS reported in 2 studies (n=196) was 95.85% in MRD-negative patients compared to 55.65% in MRD positive patients. Conclusions: Further clinical data focusing on post-treatment assessment of MRD will be useful in clinical decision-making and could be practice changing. MRD status may serve as surrogate end-points for PFS and OS in ongoing and future clinical trials. Achieving durable MRD negativity with PFS improvement might also increase the time between treatment relapses for MM and might help switch to a lesser aggressive regimen, chemotherapy-free period, avoiding drug toxicity. [Table: see text]
Comprehensive profiling of the molecular characteristics of both primary tumor and local metastases tumor in Chinese lung cancers.
Authors: Guo Nannan , Jing Zhongying
Published: June 2022

e20517

Background: Metastasis tumor is the leading cause of lung cancer-related deaths, including local metastasis and distant metastasis. Despite its crucial clinical significance, local metastasis of lung cancer is still largely uncharacterized in terms of underlying molecular mechanisms. Here, we performed TSO500 (Illumina, San Diego, CA, USA) sequencing with 19 matched lung cancer primary and local metastatic samples to comprehensively profiling of lung cancer molecular characteristics. Methods: 19 lung cancer patients with paired primary tumor and local metastatic samples were enrolled, including 16 matched primary-lymph node samples and 3 primary-pleura samples. We compared molecular characteristics, including SNV and TMB, of matched samples. Molecular alterations identified were classified into shared (mutations in both primary and metastases) and private (mutations only in primary or metastases) groups. Thus, share mutation statistical analysis, pathway level enrichment and mutational signature was also done. Results: Comprehensively analysis of matched samples showed that mutational concordance between primary tumor and local metastases is lower. The average rate of concordance of primary-lymph node and primary-pleura was 40.6%±28.4%, 39.0%±33.9% respectively. Obviously, no difference in TMB between local metastases and primary tumor was found, average of primary vs lymph node and primary vs pleura was 7.5 vs 6.5, 6.9 vs 4.2 respectively. Significantly, we found that smoking lung cancer patients have higher TMB compared to non-smokers(p < 0.01), regardless primary tumor or metastatic lymph nodes. Conclusions: Lung cancer has higher inter-tumor heterogeneity with proportion of shared mutations less than 50%. Meanwhile, smoking lung cancer has higher TMB in both primary tumor and metastatic lymph nodes compared to non-smokers.
Study of antitumor activity of 2-quinoline-2-yl-derivative 1,3-tropolone in PDX models of lung cancer.
Authors: Lukbanova Ekaterina A. , Dzhenkova Elena A. , Komarova Ekaterina Fedorovna , Engibaryan Marina A. , Volkova Viktoriya L. , Bauzhadze Mamuka V. , Ulianova Yulia V. , Pustovaya Irina V. , Goncharova Elena G. , Maldonado Mary L. , Chertova Natalia A. , Cherkes Maria A. , Gvaramiya Astanda K. , Khodakova D. V. , Shevchenko Nataliya , Goncharova Anna S.
Published: June 2022

e20523

Background: The purpose of the study was to reveal the antitumor effect of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone in subcutaneous PDX models of human non-small cell lung cancer (NSCLC). Methods: The studied tropolone was synthesized using a method of expanding the o-quinone cycle. Acute tropolone toxicity was evaluated by the survival and changes in the health status of female Balb/c Nude mice. Antitumor tropolone effects were studied in subcutaneous patient-derived xenograft (PDX) models of human squamous cell lung cancer in Balb/c Nude mice. The average volumes of tumor nodes and tumor growth inhibition (TGI%) rate were taken into account. Biochemical blood tests and histological analysis of the tumor material were performed in recipient mice. Results: An analysis of acute tropolone toxicity did not reveal the lethal dose. The maximal TGI, 73.5% for females and 74.4% for males, was observed on day 36 of the experiment in group 5 which received 2.75 mg/g tropolone. The average tumor volumes in females of this group were 431.3 mm3 on day 33 of the experiment, in males – 428.9 mm3 on day 30, and then the tumor volumes declined. Biochemical blood tests and histological analysis of the tumor material in recipient mice confirmed the tendency demonstrated during the analysis of the TGI dynamics, which in turn was the result of the dose-dependent antitumor effect of the studied tropolone. Conclusions: The research demonstrated the antitumor activity of 2-(6,8-dimethyl-5-nitro-4-chloroquinoline-2-yl)-5,6,7-trichloro-1,3-tropolone against subcutaneous PDX models of human NSCLC. The revealed tendencies can be used to search for effective modes of the compound application in clinical practice.
Lymph node dissections and survival in sublobar resection of non-small cell lung cancer ≤ 20 mm.
Authors: Takamori Shinkichi , Komiya Takefumi , Powell Emily
Published: June 2022

e20583

Background: A recent Japanese phase III randomized trial of lobectomy versus segmentectomy for small-sized (≤ 20 mm) peripheral non-small cell lung cancer (NSCLC) (JCOG 0802) showed that patients who had undergone segmentectomy had a significantly longer overall survival (OS) in comparison with those who had lobectomy. More attention is needed regarding the required extent of thoracic lymphadenectomy in patients with small-sized NSCLC who undergo sublobar resection. Methods: The National Cancer Database was queried for patients with clinically node-negative NSCLC ≤ 20 mm who had undergone sublobar resection between 2004 and 2017. OS of NSCLC patients by the number of lymph node dissections (LNDs) was analyzed using Log-rank tests and Cox proportional hazards model. The cut-off value of the LNDs was set to 10 according to the Commission on Cancer’s recommendation. Results: This study included 4,379 segmentectomy and 23,138 wedge resection cases. The sequential improvement in the HRs by the number of LNDs was evident, and the HR was the lowest if the number of LNDs exceeded 10. Patients with ≤ 9 LNDs had a significantly shorter OS than those with ≥ 10 LNDs (hazard ratio [HR]: 1.50, 95% confidence interval [CI]: 1.40–1.61, P < 0.0001). Multivariable analysis revealed that performing ≤ 9 LNDs was an independent factor for predicting OS (HR for death: 1.34, 95% CI: 1.24–1.44, P < 0.0001). These results remained significant in subgroup analyses by the type of sublobar resection (segmentectomy, wedge resection). Conclusions: Performing ≥ 10 LNDs has a prognostic role in patients with small-sized NSCLC even if the resection is sublobar.
Characteristics of patients with EGFR-mutant non-small cell lung cancer (NSCLC) at a diverse metropolitan cancer center.
Authors: Chen Lanyi Nora , Schluger Benjamin , Lagos Galina , Henick Brian S. , Herzberg Benjamin , Mathew Matthen , Shu Catherine A.
Published: June 2022

e20593

Background: Epidermal growth factor receptor-mutated [ EGFR(+)] NSCLC has historically been associated with young, non-smoking patients, especially those of Asian descent. Our medical center serves a diverse population within New York City and includes patients from neighborhoods that are predominantly Hispanic/Latino. We therefore sought to describe the population of patients with EGFR(+) NSCLC treated at our cancer center. Methods: We used our single institution lung cancer database to identify 2092 patients diagnosed with NSCLC between 2013-2019; of these, 375 had EGFR(+) disease. We collected retrospective data on patient demographics and disease outcomes. The chi-square test and t-tests were performed to compare between subgroups of patients. Results: Between 2013-2019, 17.9% of patients diagnosed with NSCLC at our center had an identified EGFR mutation. Incidence of EGFR mutations was higher in Asian NSCLC patients (46.7%) compared to Black (13.1%), white (16.8%), and Hispanic (16.0%) NSCLC patients. Within the 375 patients diagnosed with EGFR(+) NSCLC, however, the distribution was 62.1% white (233 patients), 13.6% Asian (51 patients), 11.2% Hispanic (42 patients), 8.3% Black (31 patients), and 4.8% unknown/other race (18 patients). Over half (57.7%) of patients with EGFR(+) NSCLC had a history of smoking, and most (68.9%) were female. Median age at diagnosis was 71 years. Frequency of tyrosine kinase inhibitor (TKI)-sensitive mutations (L858R and exon 19 deletion) was 85.7% in Hispanic patients, 91.7% in Asian patients, 76.4% in white patients, and 71.0% in Black patients. Significantly more Hispanic EGFR(+) patients were diagnosed at Stage IV (65.4%) compared to 40.4% of Asian patients, 36.7% of Black patients, and 25.7% of white patients (p < 0.02 for all comparisons). Among patients diagnosed with Stage IV disease, Hispanic patients had worse average survival compared to non-Hispanic patients (19.4 months vs. 27.9 months, p = 0.01). Conclusions: EGFR-mutant NSCLC is thought to be especially common among patients who are younger, Asian, and/or never smokers. Our population of EGFR(+) NSCLC, however, encompasses a racially diverse group of patients, most of whom were older at the time of diagnosis and many of whom had a history of smoking. This population of patients, most of whom harbor a TKI-sensitive mutation, supports the use of routine mutational testing that is agnostic to patient demographics. Our data also suggest that Hispanic patients in particular are diagnosed with more advanced disease and have shorter survival; the reasons for such disparities within the EGFR(+) NSCLC population warrant further study.
Phase I study of entinostat (Ent), atezolizumab (A), carboplatin (C), and etoposide (E) in previously untreated extensive-stage small cell lung cancer (ES-SCLC), ETCTN 10399.
Authors: Gentzler Ryan D. , Piekarz Richard , Villaruz Liza C , Rhee John C. , Lai Wei-Chu Victoria , Horton Bethany , Mock Joseph , Hanley Michael , Rudek Michelle A. , Phelps Mitch A. , Carducci Michael Anthony , Rudin Charles M.
Published: June 2022

e20606

Background: A-CE has demonstrated improved overall survival in ES-SCLC, but there are currently no approved therapies targeting genomic alterations in SCLC. Mutations in acetyltransferases CREBBP and EP300 occur at a frequency of 15% and 13%, respectively, in SCLC, and PDX models with CREBBP mutations were demonstrated to be susceptible to targeting with HDAC inhibitors. Ent, a class I selective HDAC inhibitor, has also demonstrated clinical activity in a combination with pembrolizumab in patients with NSCLC and uveal melanoma with minimal hematologic toxicity at RP2D of 5 mg PO weekly. We conducted a phase I trial to evaluate the combination of Ent with A-CE for ES-SCLC, NCI ETCTN 10399. Methods: Patients (pts) with treatment-naïve ES-SCLC, stable or treated brain metastases, ECOG ≤2 were enrolled and treated on up to 4 dose levels of Ent. Allocation to cohorts was determined using Bayesian optimal interval (BOIN) design targeting a MTD with a DLT rate of 20%. Dose levels (DL) included Ent 2 mg, 3 mg, or 5 mg PO weekly on day (d) 1 in addition to 4 cycles of A-CE (A 1200 mg, C AUC 5, E 100 mg/m2 d 1-3) followed E+A for 1 year. Pre-treatment tissue and plasma collected for WES. Results: 3 pts were enrolled and treated at DL1 with Ent 2 mg. Pts were age 69-83, 2 male, 1 female, 2 were ECOG 1, 1 was ECOG 0, and 1 with prior SRS radiation for brain metastases. 2 of 3 experienced DLTs during cycle 1: (1) Grade (Gr) 4 febrile neutropenia after 2 doses of Ent and (1) Gr 5 sepsis after 1 dose of Ent. BOIN design required stopping accrual to dose level 1 and the trial was closed to further accrual. The pt without DLT experienced grade 3 thrombocytopenia after 2 doses of Ent, but recovered after holding cycle 1, day 15 Ent. This patient experienced Gr 3 neutropenia during cycle 2. The most common adverse events were anemia (3), neutropenia (3), thrombocytopenia (2), leukopenia (2), hypocalcemia (2). Of these, most were Gr 3-4: anemia (1), neutropenia (3), thrombocytopenia (2), leukopenia (1), hypocalcemia (1). Conclusions: The combination of low dose Ent 2 mg PO weekly + AC-E is unsafe and resulted in early onset and severe neutropenia, thrombocytopenia in the first 1-2 weeks and ≥Gr 3 neutropenia and thrombocytopenia prior to completing 2 cycles of treatment for all pts. There is no role for further exploration of entinostat with carboplatin, etoposide, and atezolizumab. Clinical trial information: NCT04631029.
Analysis of survival and prognostic factors of thymic neuroendocrine tumors.
Authors: Mao Yinggang , Ma Yihui , Li Xiangke , Yang Minjie , Song Lijie
Published: June 2022

e20622

Background: To investigate the clinical characteristics of thymic neuroendocrine tumors and the relationship between treatment and survival prognosis. Methods: 69 patients, including 54 males and 15 females, who were diagnosed with NETT by puncture or surgical pathology in the First Affiliated Hospital of Zhengzhou University from September 2011 to October 2021 were retrospectively analyzed for initial symptoms, Pathological type, lesion size, treatment and prognosis of survival. Results: The median age of the 69 patients was 53 years old (28-83 years old), the median maximum diameter of the primary lesion was 6.85 cm (1.1-14.9 cm), and the clinical manifestations were not specific. The most common initial symptom was chest tightness and chest pain for 20 cases, 19 cases with hidden disease, found during physical examination. The manifestations of local invasion and metastasis included cough (6 cases), neck and face swelling (9 cases), retrosternal discomfort (3 cases), and low back pain (4 cases). There were 6 cases with systemic manifestations (anorexia, fatigue and fever). Only one case showed ectopic ACTH syndrome. The pathological types included 46 cases of well-differentiated neuroendocrine tumors (5 cases of typical carcinoid tumors, 41 cases of atypical carcinoid tumors), 23 cases of poorly differentiated neuroendocrine tumors (13 cases of small cell carcinomas, 3 cases of large cell neuroendocrine carcinomas, and high-grade neuroendocrine carcinomas). 7 cases of endocrine carcinoma). Masaoka-Koga staging: 2 cases of stage I, 10 cases of stage II, 20 cases of stage III, and 37 cases of stage IV. Thirty patients received surgical treatment, and 19 received postoperative adjuvant therapy. Long-term follow-up results showed a median overall survival time of 49.5 months. Univariate analysis showed that surgery could improve PFS (P = 0.009), while postoperative comprehensive treatment had no effect on PFS (P = 0.724). Pathological grade (P < 0.001), Masaoka-Koga stage (P = 0.004), and surgery (P = 0.014) were associated with OS. Multivariate analysis showed that pathological grade was an independent factor affecting OS (HR: 7.133; 95%CI: 2.183-23.306; P = 0.001). Conclusions: Thymic neuroendocrine tumor is a rare malignant tumor, and pathological grade is an independent risk factor for prognosis. Surgery can improve the patient's PFS.
Genomic characterization of immune checkpoint inhibitor resistance genes and hyperprogression related genes in advanced lung cancer.
Authors: Chen Shengjia , Zhu Kai , Zhong Qiaofeng , Jiang Kan , Wang Zhizheng , Mu Tianhao
Published: June 2022

e21042

Background: Immune checkpoint inhibitors have been widely used in the treatment of advanced lung cancer, but immunotherapy still shows poor efficacy or leads to hyperprogression in some patients. Some studies demonstrated that EGFR mutations, ALK fusion, interferon pathway gene mutation, and Wnt signal pathway mutation might reduce the efficacy of immunotherapy and lead to tumor hyperprogression. The aim of this study was to determine the frequency of gene variations associated with immunotherapy resistance or hyperprogression in patients with advanced lung cancer. Methods: The tumor tissues or blood samples of 129 patients with advanced lung cancer were collected. The tumor tissues were sequenced by targated next-generation sequencing (55 genes, Illumina novaseq 6000), MSI (PCR), and PD-L1 detection (IHC). Blood cfdna was extracted and sequenced by targeted next-generation sequencing (55 genes, Illumina novaseq 6000). Results: A total of 129 patients with advanced lung cancer were included in the study, including 126 patients with non-small cell lung cancer and 3 patients with small cell lung cancer. Tissue was available for testing in 113 patients, blood samples were collected from 106 patients, and cerebrospinal fluid samples were collected from 1 patient. Among 85 samples tested for MSI, there were 81 cases of MSS (95.3%), 3 cases of MSI-L(3.5%), and 1 case of MSI-H (1.2%). PD-L1 expression was detected in 60 samples. 23 samples (38.3%) had PD-L1 expression < 1%, 31 samples (51.7%) had PD-L1 expression greater than 1% but less than 49%, and 6 samples (10%) had PD-L1 expression > 50%. Among the genes related to immunotherapy, the mutations of genes related to cell growth or cell cycle regulation (EGFR, ALK, CDKN2A, CCND1) accounted for 86 (66.7%), 12 (9.3%), 15 (11.6%), 8 (6.2%), respectively. The mutation of antigen presentation related gene (B2M) accounted for 2 (1.6%). The mutations of interferon signaling pathway related genes (JAK1, JAK2, JAK3, IFNGR1, PIAS4 and SOCS1) accounted for 6 (4.7%), 7 (5.4%), 3 (2.3%), 3 (2.3%), 1 (0.8%) and 1 (0.8%), respectively. Wnt signaling pathway related genes (APC, AXIN1, CTNNB1) accounted for 8 (6.2%), 2 (1.6%) and 4 (3.1%). Mutations in tumor suppressor genes (PTEN, STK11, KEAP1, PTPN2) accounted for 4 (3.1%), 8 (6.2%), 6 (4.7%) and 3 (2.3%). Mutations in other genes (APLNR, DNMT3A, MDM2, MDM4) accounted for 3 (2.3%), 1 (0.8%), 7 (5.4%) and 1 (0.8%). Conclusions: Our study shows that in patients with advanced lung cancer, there are multiple gene variants related to drug resistance or hyperprogression of immune checkpoint inhibitors, suggesting that this may be the reason for the difference in immunotherapy efficacy in patients. It is necessary to further study the efficacy of immunotherapy in patients with different gene mutations and the combination of immune checkpoint inhibitors for patients with different pathway mutations.
Correlation of clinical outcomes with programmed death ligand-1 expression on liquid biopsy.
Authors: Jayananda Sriraksha , Muzaffar Mahvish , Namireddy Praveen , Sharma Nitika , Meyer David , Walker Paul R.
Published: June 2022

e21050

Background: Programmed death ligand-1 (PD-L1) expression is predictive of immunotherapy benefit. However, tissue PD-L1 protein immunohistochemical testing can be fraught with tissue acquisition and heterogeneity limitations. PD-L1 expression by RNA sequencing can be performed by both tissue and plasma with tissue PD-L1 protein correlations. What has not been well characterized is the correlation of plasma cell free circulating tumor RNA (cfRNA) PD-L1 and clinical outcomes with immunotherapy. Plasma cfRNA PD-L1 expression was evaluated and correlated with immunotherapy benefit in advanced non-small cell lung cancers (NSCLC). Methods: Patients with advanced NSCLC undergoing plasma next-generation sequencing including plasma cfRNA.PD-L1 testing in a Clinical Laboratory Improvement Amendments (CLIA) and College of American pathologists (CAP) accredited laboratory were retrospectively identified and evaluated at a single institution. Plasma PD-L1 positive patients underwent a de-identified chart abstraction to identify those patients with advanced NSCLC treated with front line immunotherapy regimens and those who received cytotoxic chemotherapy alone. Results: Sixteen patients with plasma PD-L1 expression treated with front-line immunotherapy regimens including single-agent immune checkpoint inhibitors, and combinatorial chemo-immune or chemo-immune-bevacizumab regimens were assessed for overall survival (OS). Eleven patients with plasma PD-L1 expression who received chemotherapy were used as a non-immunotherapy OS comparison. Median OS for the immunotherapy treated patients was thirteen months with a thirty percent three year landmark OS versus four months median OS and a ten percent three-year landmark OS for those treated with chemotherapy alone. Comparative log-rank test p-value 0.0091 and a hazard ratio of 0.36 (95%-CI 0.13-0.99). Conclusions: Plasma cfRNA PD-L1 expression is predictive of a statistically significant survival benefit from immunotherapy treatment compared to chemotherapy in the first line treatment of advanced NSCLC. The three year landmark OS of thirty percent parallels tissue PD-L1 directed immunotherapy-based treatment outcomes. The clinical utility of plasma cfRNA PD-L1 to overcome tissue acquisition and PD-L1 protein heterogeneity limitations and to study the dynamic nature of PD-L1 expression with non-immune cancer treatments and potential immunotherapy response monitoring are undergoing ongoing research.
DYNC2H1 Mutation as an indicator stratified patients benefit from Immune Checkpoint Inhibitors in NSCLC.
Authors: Li Chunxiang , Zhao Lele , Yu Yangyang , Xiao Mingzhe , Qi Chuang
Published: June 2022

e21052

Background: Immune checkpoint inhibitors (ICIs), targeting the programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1) or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) have demonstrated impressive anti-tumor efficacy in multiple tumors, particularly non-small cell lung cancer (NSCLC). However, only a minority of patients could clinically benefit from the ICIs. Therefore, it is of vital clinical significance to explore underlying predictive biomarkers to identify to identify these most potentially ICIs-benefitable patients. Dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) encodes a large cytoplasmic dynein protein that involved in intraflagellar transport. However, its role in lung cancer immunotherapy remains unknown. Here we aimed to explore the association between DYNC2H1 and ICIs. Methods: 165 NSCLC patients from three public immunotherapy cohorts (Hellmann 2018, Miao 2018, and Rizvi 2015 cohort) were included to analyze the association between DYNC2H1 gene mutation and efficacy of ICI therapy. Genomic, survival and mRNA data of NSCLC patients from the Cancer Genome Atlas (TCGA) database was used to explore the potential mechanisms of anti-tumor immunity. Results: NSCLC patients with DYNC2H1 mutation were significantly associated with better PFS (HR = 0.3; 95% CI, 0.14-0.64; P= 0.001), objective response rate (ORR, 65.0% vs 27.6%; P = 0.003) and durable clinical benefit (DCB, 75.0% vs 43.4%; P = 0.031) after ICIs therapy, compared with those with wide-type DYNC2H1. DYNC2H1 mutation were associated with increased TMB ( P < 0.001). In the multivariable Cox proportional hazards regression model adjusted by smoking status, PD-L1 expression and TMB, the association between DYNC2H1 mutation and PFS remained significant (HR = 0.32; 95% CI, 0.14-0.73; P = 0.007). In contrast, no association between DYNC2H1 mutation and OS (LUAD: P = 0.97 ; LUSC: P = 0.34) or PFS (LUAD: P = 0.54; LUSC: P = 0.39) was observed in TCGA datasets, suggesting that DYNC2H1 mutation may be a predictive but not a prognostic factor in ICI treatment for NSCLC patients. Based on CIBERSORT-inferred tumor infiltrating lymphocytes from TCGA, DYNC2H1 mutation was significantly associated with higher CD8+ T cell. Moreover, DYNC2H1 mutation was associated with increased TMB ( P < 0.001) and neoantigen load ( P < 0.001) in TCGA. Conclusions: Our results demonstrated that DYNC2H1 mutation is an underlying classifier that could stratify patients with NSCLC for ICIs. The role of DYNC2H1 in immunotherapy is needed to be further studied.