bluuebunny/crossref_metadata_2025 huggingface dataset:
Examining the impact of frequent versus infrequent screenings for breast cancer on employer costs.
Authors: Nair Kavita V. , Ghushchyan Vahram , Thompson Lisa A , O'Bryant Cindy L. , Allen Richard Read , McQueen Robert Brett
Published: March 2020

e16550

Background: Studies have shown an effective way to reduce breast cancer mortality is through early detection with periodic mammographic screening. Screening can increase the likelihood that cancer is detected at an earlier stage when treatment can be more effective and less expensively. Employers may be motivated to improve screening efforts if it results in improved survival and lower healthcare costs. We estimated differences in breast cancer and all cause related costs for women between 40-65 years who received regular screenings compared to those who did not. Methods: Data obtained from the LifeLink™ Health Plan Claims Database (2000 – 2010). ICD-9 codes (174.xx and 233.xx) were used to identify women between 40-65 with a diagnosis for breast cancer, who had an mammogram in the 6 months prior to diagnosis (baseline period) and had a minimum of 12 months following the diagnosis. Two cohorts were created. Those with at least one additional mammogram in the 12 months prior to the start of the baseline period (frequent mammogram group) and those with no additional mammograms (infrequent group). Both groups were followed for a minimum of 12 months and a maximum of 10 years. Adjusted differences in breast cancer and all cause costs were examined controlling for age, chronic condition index, number of mammograms in the baseline period, region and years of follow up using generalized linear models. Results: Mean age was 54 in the frequent (n=1582) and 56 in the infrequent (n=1379) group. Infrequent group had 29.7% of women between 40-49 years compared to 23.6% in the frequent group. Majority of the frequent group (85%) had one additional mammogram in the 12 months preceding the baseline period while 15% had > 2 mammograms. Infrequent group incurred on average $5715 higher breast cancer costs in year one compared to the frequent group (p <0.001). All cause costs in year one were also $6222 higher in the infrequent group (p<0.001). Similar trends were seen in years 2-5 for breast cancer and years 2-3 for all cause costs. Differences were consistent for each year of age from 40-65. Conclusions: Our findings suggest that efforts to improve screening rates can affect employer costs for treating breast cancer between 1-5 years following diagnosis.
Immune compromization and disparities in cancer type among sexual minority men.
Authors: Kamen Charles , Gerry Arianna Aldridge , Andrykowski Michael A. , Palesh Oxana
Published: March 2020

e16564

Background: Self-identified gay men are at higher risk for contracting HIV and other sexually transmitted infections than their heterosexual counterparts. Gay men are also at higher risk for reporting a lifetime history of cancer diagnoses. While certain types of cancers, specifically Kaposi sarcoma and non-Hodgkin lymphoma, are more common among gay and sexual minority men, it is yet unclear to what extent this disparity is due to immune compromization or comorbid infection with HIV. Methods: The current study utilized data from 173 gay and 5544 heterosexual men collected as part of the Behavioral Risk Factor Surveillance System survey conducted in 2009 in California. Items assessed lifetime history of cancer diagnosis, type of cancer, sexual minority status, and presence of a weakened immune system resulting from diseases such as HIV/AIDS. Chi-square tests were used to examine differences in rates and types of cancer diagnoses by sexual minority status. Logistic regression was then used to examine risk for reporting a lifetime history of cancer based on sexual minority status and accounting for a weakened immune system. Results: In this sample, rates of cancer diagnoses differed significantly between gay and heterosexual men, with gay men more likely to report diagnoses of cancer (χ2 = 4.53, p < 0.05, OR = 1.53). In addition, types of cancer diagnoses reported differed significantly between gay and heterosexual men, with gay men more likely to report diagnoses of oral cancer (1.2% vs. 0.1%; χ2 = 23.31, p < 0.001); testicular cancer (1.2% vs. 0.1%; χ2 = 9.84, p < 0.01); and “other” cancers (1.7% vs. 0.3%; χ2 = 9.11, p < 0.01). Notably, this disparity in cancer diagnoses persisted even when controlling for a weakened immune system (χ2 = 3.95, p < 0.05; OR = 1.80, 95% CI = 1.03 to 3.15). Conclusions: Immune system compromization accounts for some of the disparity noted between gay and heterosexual men in rates of cancer diagnoses; however, other risk factors may be implicated. Cancer screening rates for gay men should be increased, and screening physicians should specifically assess for risk factors in gay men.
Somatostain receptor (SSTR)-targeted therapy in pulmonary large-cell neuroendocrine carcinoma (LCNEC) patients with intermediate proliferation rate (PR).
Authors: Biran Haim , Perelman Marina , Bar Jair , Zwas Tzila S.
Published: March 2020

e17509

Background: LCNEC is classified as a high-grade (HG) foregut-derived neuroendocrine tumor (NET), exceeded only by small-cell lung carcinoma (SCLC) in terms of aggressiveness. It is a recent disease entity, only two decades old, and uncommon: 2%-3% of all lung cancer cases. Therefore, therapy guidelines are still evolving. Methods: A single institution observational study, consecutive series. Histopathology diagnosis conformed to WHO criteria for thoracic tumors (Travis et al, IARC Press, 2004). Immunohistochemistry included proliferation Ki67 index evaluation. SSTRs' affinity was assessed either by 111 In octreotate SPECT, or by Ga68 DOTA-NOC octreotate PET CT total body scans. Results: We have treated nine metastatic LCNEC patients over the last four years. Seven were scanned for presence of somatostatin receptors; 4 were positive. Three of the four had Ki67 staining ranging 10-20% (intermediate PR, IPR), one had 80% (high PR). All four have received octreotide LAR as a therapy component. In two cases octreotide was given upfront and conferred PFS of 18 and 8 months and, in the former- regression of hepatic lesions. The other patient also received 177 Lutetium radionuclide therapy (PRRT) upon progression, resulting in uptake normalization at an hepatic mass and stabilization of other lesions. The 3rd patient had started with induction chemotherapy and then maintained imaging-confirmed stable disease and normal function, during octreotide treatment, for three years. The fourth, HG patient, survived only 8 months. Three of the 9 patients are alive with disease on treatment, surviving 25+, 57+ and one, with 50% proliferation index and a negative DOTANOC scan, has survived 16+ months, with no targeted therapy. Conclusions: This small series illustrates the diagnostic value and therapeutic implication of SSTR scans, combined with Ki67 assessment, aiming at therapy selection for IPR subgroup, receptor positive, pulmonary LCNEC patients who can benefit from octreotide targeted therapy.
Clinical significance of the EML4-ALK fusion gene and association with EGFR and KRASgene mutation in 208 Chinese patients with non-small cell lung cancer.
Authors: Chen JUN , Liu Hongyu , Yang Tong , Wei Sen , Zhou Qinghua
Published: March 2020

e17514

Background: EML4-ALK fusion gene is a potentially relevant oncogenic event in lung cancer, which represents a new subgroup of non-small cell lung cancer (NSCLC) patients who respond positively to ALK inhibitors. The characteristics of EML4-ALK fusion gene in Chinese Patients with NSCLC are poorly understood. In this study, we aimed to analyze the prevalence of EML4-ALK fusion gene and their correlation to epidermal growth factor receptor (EGFR) status, KRAS mutation, and clinico-pathological data in Chinese patients with NSCLC. Methods: Genes were detected by nested RT-PCR and confirmed by sequencing. Results: 208 cases of NSCLC were evaluated. There were 24.5% (51/208 cases of mutations in EGFR at exons 18-21, and EGFR mutations occur predominantly (92%) in exons 19 and 21. In concordance with previous reports, these mutations are identified at high frequencies in females (47.5%, 29/61 vs 15.0%, 22/147 in males; P = 0.000); never-smokers (42.3%, 33/78 vs 13.9%, 18/130 in smokers; P = 0.000), and adenocarcinoma patients (44.2%, 42/95 vs 8.0%, 9/113 in non-adenocarcinoma patients; P = 0.000). There were only 6 cases (6/208, 2.88%) of KRAS mutations in our study group. We identified 7 patients who harbored the EML4-ALK fusion gene (3.37%, 7/208) which all confirmed by DNA sequencing. Of these 7 patients, 2 cases displayed the EML4-ALK variant 1 (28.6%), 1 case exhibited variant 2 (14.3%) and 4 cases carried variant 3 (57.1%). All of the positive cases corresponded to female patients (11.5%, 7/61). Six of the positive cases were non-smokers (7.69%, 6/78). The incidence of EML4-ALK translocation in female non-smoking adenocarcinoma patients is as high as 15.2% (5/33). No EGFR/KRAS mutations were detected among EML4-ALK positive patients. The meta-analysis demonstrated that EML4-ALK translocation was 4.71% (125/2652) in unselected patients with NSCLC, and was also predominant in female patients with adenocarcinoma. Conclusions: EML4-ALK translocations are infrequent in the entire NSCLC patient population, but are frequent in the NSCLC patient subgroup of female, nonsmokers, and adenocarcinoma patients.
Hybrid scheme with carboplatin and etoposide intravenous (iv) and oral in patients with small cell lung cancer: Should we treat in a different way based on the age?
Authors: Ruiz-Valdepeñas Andrea , Palka Magda , Ibeas Patricia , Doger de Speville Bernard Gaston , Almagro Elena , Perez Callejo David , Huelves Miriam , Lopez-Gonzalez Ana , Maximiano Constanza , Mendez Miriam , Nuevo Gema , Provencio-Pulla Mariano
Published: March 2020

e17515

Background: The increase in longevity due to a better quality of life in old people makes possible the chemotherapy treatment in the most of patients with Small Cell Lung Cancer. The aim of this research is to evaluate if there are differences in overall survival according to the age (comparing older and younger than 65 years old), in patients treated with the same scheme of chemotherapy. Methods: Patients diagnosed with small cell lung cancer between years 2003 and 2010 and treated in our hospital by the scheme carboplatin 300mg/m2 IV on day 1, with etoposid 100mg/m2 per day (iv on day 1 and oral days two to five), were retrospective reviewed to evaluate the overall survival by group of age (older and younger than 65 years old). Results: 96 patients diagnosed of small cell lung cancer were treated in our hospital between 2003 and 2010 with the aforementioned scheme of chemotherapy. 70 of them were on extended stage, and 26 had limited stage; 54 were until 65 years old (56.25%) and 42 were older (43.75%). In extended disease, the elder than 65 presented an overall survival rate one year after the diagnosis of 38.3% (SE 9.3%) and at 18 months 10.2% (SE 6.3%), with a median overall survival of 10 months (Range 1 to 22 months). The younger than sixty five had an overall survival at 12 months of 23.8% (SE 6.6%), and at 18 moths of 5.4 (3.7%), non significant (p:0.437). Their median overall survival was 8.23 months, with a range of <1month to 24 months. In the group with limited stage, the sample older than 65 had a probability of overall survival 1 year after the diagnosis of 46,2% (Standard error (SE), 13.8%), and 23.1% (SE 11.7%) at 18 months, versus a 48.6% (SE 14,8%) at 12 months and 19.4% (SE 12.2%) in younger (p:0.708). The median overall survival in elder than 65 with Limited stage was 11.5 months (6 to 81 months), and for the younger 15 months (range 4 to 25 months). Conclusions: The hybrid scheme carboplatin 300mg/m2 IV on day 1, with etoposid 100mg/m2 per day (iv on day 1 and oral days 2 to 5), provides an acceptable overall survival, without significant differences comparing older and younger than 65 years old, both in limited and extended stage.
Phase II study of perioperative chemotherapy with cisplatin (C) and pemetrexed (P) in non-small cell lung cancer (NSCLC).
Authors: Farooq Aamer , Dy Grace K. , Demmy Todd L. , Bogner Paul , Nowadly Cynthia , Tan Wei , Chen Hongbin , Yendamuri Saikrishna S. , Nwogu Chukwumere E. , Bushunow Peter Walter , Adjei Alex A. , Ramnath Nithya
Published: March 2020

e17535

Background: Pathological complete response (pCR) with neoadjuvant chemotherapy is associated with improved survival in many solid tumors. We evaluated efficacy and tolerability of neoadjuvant plus adjuvant C+P in this phase II trial. Methods: We recruited patients (pts) with clinical stage IB-IIIA (TNM 7th ed) NSCLC, ECOG performance status (PS) 0-1 in this single-arm phase II trial using two-stage design with 90% power to detect pCR rate of >10% (vs null hypothesis of <2%). Pre-treatment mediastinal biopsy was required. Protocol was amended in 2009 to exclude squamous histology. Pts received 3 cycles of C 75mg/m2 + P 500mg/m2 (day 1 every 21 days) followed by surgical resection. Two cycles were delivered adjuvantly within 60-80 days after surgery. The primary end point was pCR. Secondary endpoints were objective response rate (ORR), overall survival (OS), disease-free survival (DFS), and adverse events (AEs). Results: 38 pts were enrolled with median age of 62 yrs, 19 males: 19 females. 74% (N=28) had ECOG PS 0. Preoperatively, 26% (N=10) had squamous histology, 29% (N=11) had biopsy-proven N2 involvement. Median of 4 cycles were administered. ORR was 29% (11 pts with PR). 4 pts did not undergo surgery (3 had disease progression; one became hypoxic during intubation in the OR). Resection status was R2 in 9% (3 of 34 pts), remaining pts had R0 resection. 6 pts had documented N2 clearance; median DFS (mDFS) and OS (mOS) of these pts have not reached (NR) vs 15 and 24 months respectively, in pts with persistent N2 disease. CTC grade 3+ nonhematologic AEs (<10%) include arterial thrombosis, bronchopleural fistula, empyema, hyperglycemia, fatigue and tinnitus. There was no pCR seen and thus accrual to 2nd stage was not pursued. There was no correlation between DFS or OS with ORR or pre-operative stage. There was statistically signification association between DFS with histology (favoring squamous, p=0.03) and post-op stage (p=0.024). The table shows mDFS and mOS in months according to pre-op stage. Conclusions: While the primary endpoint was not met, this regimen is active and well-tolerated perioperatively in NSCLC pts. [Table: see text]
Gene-expression profile of primary non-small cell lung cancer associated with brain metastasis: A prospective study.
Authors: Arrieta Oscar , Saavedra-Perez David , Ortega Alette , Rangel Claudia , Aviles-Salas Alejandro , Zavala Diego G , Mercado Gabriela , De La Garza Jaime G.
Published: March 2020

e18028

Background: Brain metastases (BM) occur in 30-50% of non-small cell lung cancer (NSCLC) patients and confer worse prognosis and quality of life. Better selection of in-risk patients through an accurate biomarker could improve the benefit of prophylactic therapies. The aim of this prospective study was to determine a gene-expression profile (GEP) of primary tumor (PT) associated with BM in patients with advanced NSCLC. Methods: From January 2009 to June 2011, patients with stage IV of NSCLC were evaluated. PT core biopsy was performed prior to any treatment and snap-frozen. Samples with tumor cellularity > 70% and RNA integrity number > 8 were chosen for RNA isolation. A cDNA microarray platform representing 33,297 genes was used to obtain GEPs. All patients received standard chemotherapy. BM were confirmed by magnetic resonance imaging. Non- and supervised hierarchical clustering methods were employed to identify GEPs. Results: A total of 29 patients were enrolled, 79.4% (23/29) were adenocarcinomas, and 20.6% have other histology. BM were present in 15 (51.7%) patients, 14 at diagnosis and 1 was developed at 5 months of follow-up. Clinical characteristics were similar for patients with and without BM. At non- and supervised analyses, 35 genes up and down regulated were evidenced in BM group. From these, 11 transcripts with proteomic functions previously associated with metastasis processes were identified. Conclusions: Our work provides valuable biological information for development of predictive biomarkers for metastatic brain tumors from primary NSCLC. External validation of our gene-expression signature in a different set of patients is warranted. [Table: see text]
Effects of entinostat onresistance to cetuximab and EGFR TKIs in non-small cell lung cancer.
Authors: Witta Samir E. , Chan Dan , Girard Luc , Zheng Di , Franekova Veronica , Peyton Michael , Zhang Zhi-Yong , Kline Zoe , Minna John D. , Bunn Paul A. , Hirsch Fred R.
Published: March 2020

e18077

Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor (EGFR) is active in patients with NSCLC. Gate keeper mutations in EGFR, such as T790M and activation of alternative driven pathways such as Met amplification are known mechanisms of acquired resistance to EGFR TKI. Here we evaluated the effects of the class I histone deacetylase inhibitors (HDACi), entinostat with cetuximab or EGFR TKIs in NSCLC cell lines with 3 potential mechanisms of intrinsic and acquired EGFR inhibitor resistance: RAS mutation according to E-cadherin expression, T790M EGFR mutation, and amplified MET. Methods: In vivo efficacy of entinostat alone or in combination with cetuximab or gefitinib was tested in athymic nude mice bearing RAS mutant, E-cadherin positive (A549) and E-cadherin negative (NCI-H460) NSCLC xenograft tumors. NSCLC cell lines were treated with various dilutions of cetuximab, entinostat or erlotinib. The NCI-H1975 and NCI-H1993 cell lines harboring the EGFR-L858R/T790M mutation and MET amplification, respectively, were treated with the combination of entinostat and erlotinib. Cell growth was analyzed by the MTT assay. Expression of e-cadherin was evaluated using affymetix microarrays. Results: When entinostat (E; 5mg/kg) was combined with cetuximab (C; 25mg/kg) in nude mice bearing the E-cadherin positive A549 xenograft, tumor growth inhibition was higher than each drug alone in (C: 65%; E: 70%; E+C: 88%; p=0.001) or what is detected in the E-cadherin negative H460 xenografts (C: 3%, E: 64%, E+C: 75%). Synergistic effects were detected when entinostat was combined with erlotinib in the NCI-H1975 or NCI-H1993 cell lines (combination index, CI<1). Conclusions: Entinostat enhances the effect of Cetuximab in vivo in Ras mutant, E-cadherin positive NSCLC cell lines, or erlotinib in cell lines harboring the EGFR mutation T790M or amplified MET. The combination of entinostat and EGFR inhibitors could provide the rational for developing clinical trials in patients with NSCLC with tumors resistant to EGFR inhibitors.
EGFR status and daily dose: Effect on tumor growth inhibition in cancer patients treated with dacomitinib (PF-00299804).
Authors: Ruiz-Garcia Ana , Janne Pasi A. , Park Keunchil , Yamamoto Nobuyuki , Giri Nagdeep , Bello Carlo , O'Connell Joseph P.
Published: March 2020

e18093

Background: Dacomitinib (D) is a highly selective, irreversible small molecule pan-human epidermal growth factor (EGFR/HER) inhibitor. The effect of mean D daily dose (exposure) on tumor growth dynamics was analyzed using a longitudinal exposure-response tumor growth inhibition model. Methods: Estimated parameters included tumor shrinkage rate (KD), which changes over time as resistance to therapy develops according to an exponential decay function where λ = slope of the dynamic shrinkage rate change; and tumor growth rate constant (KL). eDose, the effect of mean D daily dose changes on tumor shrinkage rate, was tested in the base model to establish the best relationship between tumor shrinkage and drug exposure. Model parameters were estimated using a population (pop) approach. Pop pharmacodynamic analyses included data from 4 clinical trials (3 phase I and 1 phase II) of D (15–45 mg QD) in patients (pts) with advanced solid tumors. Multiple tumor size (SLD) measurements were collected from each pt. Data analysis used nonlinear mixed effects modeling (NONMEM, v 7.1.2). After visual inspection of relationships between covariates (weight, age, creatinine clearance, bilirubin, ALT, baseline ECOG PS, race, sex, EGFR status) and individual parameter estimates of KD; subpopulation analysis was carried out in pts with confirmed EGFR status (mutation [mu] or wild type [WT]) to quantify the potential effect of EGFR status on KD. Results: SLD values over time were collected from 200 pts (47% male). For a typical pt, KL = 0.63 year-1; KD = 1.6 year-1; developed therapy resistance over time (λ) = 13.7 year-1; and eDose = 0.45. Drug-specific parameters affecting tumor shrinkage (KD, λ, eDose) and the disease-specific KL were well estimated with low relative standard errors. Visual inspection of relationships between covariates and individual parameter estimates showed a higher shrinkage rate (KD) for pts with EGFR mu vs those with WT EGFR. Conclusions: D mean daily dose affected tumor growth dynamics. Tumor shrinkage rate at an averaged daily dose below 45 mg QD was lower vs 45 mg QD. EGFR status was a significant covariate affecting tumor shrinkage rate (83% less shrinkage in pts with EGFR WT vs. pts with EGFR mut).
TGFb expression as predictor of outcome in EGFR wild type (WT) metastatic non-small cell lung cancer (NSCLC) patients (PTS) treated with EGFR tyrosine kinase inhibitors (TKIs).
Authors: Finocchiaro Giovanna , Toschi Luca , Gianoncelli Letizia , Canal Barbara , Rubino Luca , Lo Russo Chiara , Giordano Laura , Destro Anna , Garassino Isabella , Siracusano Licia , Cavina Raffaele , Roncalli Massimo , Carbone Antonino , Santoro Armando
Published: March 2020

e18104

Background: Gefitinib and erlotinib have shown to be highly effective in pts harboring EGFR mutations, while the majority of EGFR wt pts does not respond to treatment.Preclinical data suggested that TGFb and HGF could affect response to TKIs. Aim of the present study is to investigate molecular predictors for primary resistance to TKIs in metastatic NSCLC pts. Methods: This retrospective study included 120 metastatic NSCLC patients treated with gefitinib (68/56.7%) or erlotinib (52/43.3%) in first line (20/16.7%) or after prior chemotherapy (100/83.4%) with at least one measurable lesion and availability of paraffin-embedded tumour tissue from primary cancer. Analyses included presence of mutations in EGFR and KRAS genes, assessment of ALK rearrangement by fluorescence in situ hybridization (FISH) and protein expression of HGF and TGFb by immunohistochemistry (IHC). Pts were grouped in IHC+ and IHC- according to staining intensity. Results: In the whole study cohort response rate (RR) was 9.2%, median progression free survival (PFS) 2.5 months, and overall survival (OS) 7.8 months. EGFR mutations were observed in 9.2% of pts and were significantly associated with better pts outcome. KRAS was mutated in 23.3% of pts without any correlation with clinical end points. ALK translocations were observed in 5 pts (4.2%), and none responded to treatment. IHC was successfully performed for HGF and TGFb in 95 and 75 pts respectively. No difference was seen in HGF+ (9/9.5%) vs HGF- pts in terms of RR, PFS and OS. TGFb+ pts (41/54.7%) had a significantly shorter OS than TGFb- pts (6.7 vs 10.3 months, p=0.020) although no difference in terms of RR and PFS was observed. When restricting survival analysis to EGFR wt/KRAS wt pts (n=80) TGFb+ subjects had a significantly worse PFS (1.9 vs 2.9 months, HR 2.16, CI 95% 1.18;3.95, p=0.013) and OS (5.3 vs 8.8 months, HR 2.07, CI 95% 1.10;3.91, p=0.025) when compared with the TGFb- group. Conclusions: Overexpression of TGFb is associated with a poor outcome in EGFR and KRAS wt pts treated with gefitinb or erlotinib. Prospective validation of the role of TGFb as a mediator of intrinsic resistance to EGFR TKIs in NSCLC is warranted.
Impact of local and systemic treatment on survival and on brain relapse of patients with localized or metastatic non-small cell lung cancer who develop brain metastasis.
Authors: Florescu Marie , Blais Normand , Tehfe Mustapha , Begin Marie Josee
Published: March 2020

e18120

Background: Up to 20% of patients with localized NSCLC develop brain metastasis, and twice more with metastatic NSCLC. We analyze retrospectively 216 unselected consecutive patients diagnosed with stage I to IV NSCLC treated at Notre-Dame Hospital from 2006 to 2010. Methods: Patients who developed their brain metastasis within 6 months of the NSCLC diagnostic were considered to have synchronous brain metastasis although those who developed more than 6 months later were designated metachronous. We compared the survival Kaplan-Meyer plots with log-rank tests in between each group category: synchronous brain metastasis with localized NSCLC (Sync Loc), synchronous brain metastasis with metastatic NSCLC (Sync Meta), metachronous brain metastasis in patients with localized NSCLC (Mec Loc) and metachronous brain metastasis in patients with already metastatic extracranial NSCLC (Mec Meta). Results: Comparing the 38 patients of Sync Loc with the 95 patients of Sync Meta, we found a not statistical significant difference in median survival with 15.4 months (Sync Loc) vs 6.8 months (Sync Meta) (p=0.18), but a similar 2 years survival 20.4% (Sync Loc) vs 15.7% (Sync Meta). Despite, only 27% of patients of Sync Loc received systemic treatment compared with 43% of patients Sync Meta, the two groups had no statistically significant difference in the median brain-relapse free survival with 18.5 months vs 14.1 months (p=0.335). The metachronous brain metastasis group had a significant difference in the median overall survival with 32.1months for the 61 patients Mec Loc and 18.1months for the 24 patients Mec Meta. Interestingly, stage I NSCLC patients with metachronous metastasis have a 2 year overall survival of 81.6%, stage II of 64.2% and stage III of 49.2%, similar to patients with no brain metastasis. Conclusions: Patients with localized NSCLC diagnosed with synchronous brain metastasis have probably already a metastatic disseminated disease with the same outcome than patients with NSCLC with extracranial metastatic disease. However, patients with metachronous brain metastasis and treated localized NSCLC have a very good prognostic.
Improving outcomes in mantle cell lymphoma patients treated with R-CHOP using autologous transplant.
Authors: McQuade Jennifer , Ahmadi Tahamtan , Porter David L. , Frey Noelle V. , Goldstein Steven C. , Loren Alison W. , Svoboda Jakub , Stadtmauer Edward Allen , Schuster Stephen J. , Nasta Sunita
Published: March 2020

e18540

Background: Mantle cell lymphoma (MCL) is a small B cell lymphoma, incurable with standard chemo-immunotherapy. There is no standard upfront therapy, although Phase II trials have shown a survival benefit to dose-intensified regimens in selected patients. However, many patients are not candidates for these regimens secondary to age or comorbidites. These patients are often treated with R-CHOP with consideration for consolidation with ASCT. Methods: We conducted a retrospective cohort analysis to describe and compare the survival experiences of MCL patients at the University of Pennsylvania treated in the first-line setting with R-CHOP (N=32) with or without autologous stem cell transplant (ASCT). The primary study endpoint was PFS as assessed by chart review and confirmed by SSDI database. Results: Median follow up for all pts was 2.5 years. The median age was 62.5, and 80% (n=30) were stage IV at diagnosis. 16 patients underwent consolidative ASCT. Comparing patients treated with R-CHOP vs R-CHOP +ASCT, there were no statistical differences in terms of age, ECOG PS, LDH, WBC, beta-2microglobulin, BM or GI involvement, bulky disease or blastoid variant at baseline. The response rate for all patients was 96.9% and 87.5% of patients achieved CR. Median PFS for all patients was 2.8 years: R-CHOP alone 1.9 years vs. R-CHOP+ ASCT 3.9 years (P=0.02, HR 3.44, 95%CI: 1.2-9.5). Conclusions: Outcomes are poor for MCL patients treated with R-CHOP with continuous recurrence despite excellent initial response. Our data suggest an improved PFS in patients with advanced MCL when R-CHOP is consolidated with ASCT in first remission as compared to R-CHOP alone. Prospective RCTs are needed to determine the optimum treatment for patients who are not candidates for dose-intensive therapy.
A phase I/II trial of melphalan (MEL) combined with panobinostat (PAN) for patients with relapsed or refractory (R/R) multiple myeloma (MM).
Authors: Yellin Ori , Berenson James R. , Boccia Ralph V. , Cohn Allen Lee , Berard Paul , Ghazal Hassan , Jamshed Saad , Kingsley Edwin , Harb Wael A. , Noga Stephen J. , Nassir Youram , Swift Regina A. , Vescio Robert A.
Published: March 2020

e18558

Background: PAN, a potent histone deacetylase inhibitor, significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity of standard chemotherapy. Studies with our SCID-hu MM models show an increased inhibition of MM cell growth when PAN was combined with MEL compared to treatment with either drug alone. These preclinical studies provided the rationale for evaluating the combination of oral MEL with oral PAN for the treatment of MM patients with R/R disease. Methods: This was a Phase 1/2, open-label, dose‑escalation study to treat R/R MM patients initially using oral PAN every Monday, Wednesday and Fridayin combination with oral MEL (0.05 mg/kg) on days 1-5 of a 28‑day cycle. Results: Thirty-seven patients were enrolled into the Phase 1 portion of this study. The median number of prior regimens received were 4 (range, 1-17) with 22 patients previously treated with MEL. Following amendments to dose and schedule because of toxicity including cytopenias and fatigue, PAN and MEL were both administered only on days 1, 3 and 5 of a 28-day cycle. The maximum tolerated dose for this combination was defined as PAN at 20 mg and MEL at 0.05 mg/kg both administered on only days 1, 3 and 5. Overall, 4 patients (11%) showed objective responses to this combination with 1 complete (3%) and 3 partial (8%) responses and only occurred among patients receiving PAN throughout the cycle. An additional 18 (49%) patients had stable disease while 15 (41%) progressed while on study. Eighteen patients experienced grade 3 or 4 adverse events (AEs) with 6 of these meeting the definition of a dose-limiting toxicity. These AEs included reversible thrombocytopenia (n=11), reversible neutropenia (n=10), reversible worsening anemia (n=3), and one case each of a forearm rash, fatigue/weakness, pneumonia, hypokalemia and hyponatremia. Three more patients who are not yet evaluable have been enrolled into the Phase 2 portion to complete the planned 40 patients on the trial. Conclusions: The combination of intermittent PAN & low-dose oral MEL shows modest activity in heavily pretreated patients with R/R MM. Continuous doses of PAN with MEL yielded better efficacy but this treatment schedule was not tolerable.
Chemotherapy for patients with brain metastases from melanoma.
Authors: Naskhletashvili David R. , Gorbunova Vera A. , Bychkov Mark B. , Bekyashev Ali H. , Karahan Vladislav B. , Aloshin Vladimir A. , Michina Zoya P. , Moskvina Ekaterina A.
Published: March 2020

e19012

Background: There have not been standards of chemo- and chemo-radiotherapy for treatment for patients with brain metastases. The patients (pts) with brain metastases (BM) from melanoma have poor prognoses. The main goal of this trial is to assess the efficacy of nitrosoureas (CCNU or FCNU), temozolomide (TMZ) as monotherapy, TMZ combined with whole brain irradiation (WBI), or combined chemotherapy of TMZ and cisplatin in pts with BM from melanoma. Methods: 78 pts were included in this study. 21 pts were treated with WBI (3Gy/30Gy) and concomitant TMZ therapy (75 mg/m2/day orally on days 1-14), 19 pts were treated with TMZ (150 mg/m2/day orally on days 1-5, every 4 weeks) as monotherapy, 17 pts pts were treated with nitrosoureas (CCNU or FCNU), 21 pts were treated with combined chemotherapy of TMZ (150/mg/m2/day orally on days 1-5, every 4 weeks) + cisplatin (20/mg/m2/day intravenous on days 1-5, every 4 weeks). The main aims of this study were objective response (OR) – complete response (CR) + partial response (PR) in the brain and in the extracranial sites (ES), median of survival (mOS), 1-year and 2-year survival. Results: Observations were as follows: in the TMZ + WBI treated pts, 4 OR (19,0%) in 21 pts group in the brain and 1 OR (6,7%) in 15 pts group in ES. The mOS was 6.0 months, 1-year survival was 23,8%. In the TMZ monotherapy treated pts there were 5 OR (26,3%) in 19 pts group in the brain and no OR in 13 pts group in ES. The mOS was 6 months, 1-year survival was 21,1%. In the nitrisoureas treated pts we achieved 2 OR (11,8%) in 17 pts group in the brain and 1 OR (9,1%) in 11 pts group in ES. The mOS was 5 months, 1-year survival was 17,6%. In the TMZ + cisplatin treated pts there were 7 OR (33.3%) in 21 pts group in the brain and 7 OR (35,0%) in 20 pts group in ES. The mOS was 8 months, 1-year survival was 33,3%. 2-year survival (19,0%) was achieved only in TMZ and cisplatin group. Conclusions: Previous results of our study showed promising higher efficacy of TMZ and cisplatin, especially in OR in ES (p<0.05) and in 2-year survival (p<0.05), in comparison with TMZ alone, nitrosoureas or TMZ with whole brain irradiation in patients with metastatic melanoma with BM. Control of extracranial lesions is important factor for patients with BM. Further investigation is to be expected.
Intra-lesional administrations of TG1042 (adenovirus expressing interferon-γ) combined with adoptive TIL transfer in patients with metastatic melanoma.
Authors: Khammari Amir , Limacher Jean-Marc , NGuyen Jean-Michel , Quereux Gaelle , Brocard Anabelle , Peuvrel Lucie , Knol Anne-Chantal , Saiagh Soraya , Bataille Vincent , Dreno Brigitte
Published: March 2020

e19019

Background: Several tumour factors limit the efficacy of spontaneous immune responses. By changing the tumour environment through immune-stimulation, responses could be more efficient. Methods: This is a phase I/II open, monocentric study with a sample size of 12 patients. The main inclusion criteria were: age 18 to 75, melanoma stage IIIc/IV with cutaneous and visceral metastases except brain metastases. Patients received intra-lesional injections TG1042 combined with tumor infiltrating lymphocytes (TILs) infusions and interleukine-2 (IL2) sub-cutaneous injections. TILs were infused on days 1 and 29 followed by IL2 injections (6M UI daily) for 10 days. TG1042 was injected at the dose of 5x1010 viral particles per lesion (in up to 6 lesions) every two weeks from day -15 to month 2 and then every month up to month 11 or progression. The main objectives were to evaluate the clinical response and safety. Results: Twelve patients stage IVa-c AJCC have been included. Three patients progressed rapidly before starting any treatment and for 2 others TILs were not obtained due to insufficient tumor tissue. Minor erythema at the TG1042 injection site as well as minor to moderate flu-like symptoms linked to IL2 injections was observed. No grade 3 or 4 treatment related adverse events were reported. Among the 7 patients evaluable for tumor response (RECIST rules), 2 partial and 2 complete responses were observed. Distant responses were also observed for 2 patients. Immunohistochemical analysis on biopsies from an injected lesion of 3 patients before and after 3 months of treatment showed an increase of CD8 T lymphocytes in 2 patients with clinical response associated with an increase of IFN-γ and STAT 1 expression. Conclusions: Results of this study demonstrate that TILs-based adoptive cell therapy combined with intra-lesional immunostimulation induced by TG1042 is feasible, safe and can induce a disease control in a majority of patients. Stimulation of innate immunity by adenovirus expressing interferon gamma seems able to reverse the tolerance state within the tumour environment, thus making TILs able to exercise their cytotoxic activity against melanoma.
Role of palliative care department in modifying ICU admissions for patients with advanced cancer: A study.
Authors: ROY Rakesh -
Published: March 2020

e19517

Background: Admission of cancer patients are on the rise in the Intensive Care Unit due to advancement in healthcare facilities. But limited number of ICU beds, health resources and lack of structured Palliative Care services are a matter of concern. Methods: A retrospective study was conducted in an Indian tertiary cancer centre from Jan – Jun 2010 to find out total number and cause of ICU admission of advanced cancer patients when a Palliative Care Department did not exist. Information source were case files and interviews after appropriate consent. Exclusion criteria - age < 18 years, post operative care, complications arising from a major surgery, established oncological emergencies, patients with curative intent. With a 24 hr Palliative Care department under operation from Aug 2010 - another similar study was performed from Jan – Jun 2011. Results: Jan – Jun 2010: Total admissions 542. 297 patients matched the exclusion criteria. Of the remaining 245 patients (45.2%) considered for the study 35 patients (14.2%) died. 11 patients (4.4%) were put on ventilator. Average occupancy of bed 5 days. Commonest cause was respiratory distress. Review of the case notes revealed 54 patients (22%) were admitted due to lack of Palliative Care service. Study was repeated from Jan – Jun 2011 after the initiation of a Palliative care Department from Aug 2010. Out of 487 patients, 195 patients (40%) were considered for study. 18 (9.2%) died. 6 patients (3%) were put on ventilator. The average duration of stay was 4 days. Components of Palliative Care like good communication, early consent from patients as to where they wish to die, do not resuscitate policy for some patients in the background of ethical issues, 24 hour Palliative care service, emergency helpline, home based care, good psychological counselling etc were identified as the key reasons for reduced admissions. Conclusions: Effective round the clock Palliative care service can increase ICU bed turnover, reduce misery of the patients and their family members, save resources, giving patients with longer survival chances a hope to live longer.
Prospective study of chemotherapy-induced clostridium difficile infection in lung cancer patients.
Authors: Toi Yukihiro , Sugawara Shunichi , Kobayashi Takao , Kawashima Yousuke , Koizumi Tatsuhiko , Okazaki Keito , Takahara Masatoshi , Kuda Tomoya , Tanaka Akiko , Ishimoto Osamu , Honda Yoshihiro
Published: March 2020

e19521

Background: Diarrhea after antibiotic treatment is primarily ascribed to the development of mucosal lesion for which Clostridium difficile infection (CDI) is held responsible. Evidence on CDI in patients on chemotherapy without antibiotic treatment prior to chemotherapy is on the rise. However there have been few reports describing diarrhea in relation to regimens of chemotherapy. The aim of our study was to find out whether the incidence of CDI in patients on cancer chemotherapy increases even in the absence of prior antibiotic treatment. Methods: From March 2010 through September 2011, we investigated the presence of Clostridium difficile (C.difficile) and its toxin in any patients undergoing diarrhea while receiving cytotoxic anticancer agents or epidermal growth factor receptor tyrosine kinase inhibitors. Whenever Grade2 or worse diarrhea defined by the Common Terminology Criteria for Adverse Events version4 occurred, we examined their stool samples for anaerobic culture and simultaneously tested for toxins A and B. A case of CDI is defined by the presence of symptoms (usually diarrhea) and either a stool test positive for C.difficile toxins or toxigenic C.difficile according to criteria of the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America. Results: A total of 345 consecutive patients (492 in terms of chemotherapy -regimens) were enrolled in this study. 36 of 492 regimens (7.3%) showed Grade2 or worse diarrhea. CDIs without prior antibiotic exposure were confirmed in as many as 8 out of these 36 regimens (22.2%). CDI was more frequently observed in patients of the regimens including S-1 or irinotecan than other anticancer drugs. Conclusions: CDI may remain undetected among patients who had diarrhea defined as above unless due attention is paid to this possibility. It is highly recommended to perform tests for the detection of C.difficile toxins so that necessary measures can be instituted without delay in the treatment of diarrhea of patients on chemotherapy. Further analysis for drugs specificity and prevention against CDI is necessary.
Paulinia cupana (Guaraná) purified dry extract (PC-18) for chemotherapy related fatigue in patients solid tumors.
Authors: Del Giglio Adriana Braz , Lerner Tatiana Goberstein , Lera Andrea Thaumaturgo , Paiva Henrique Soares , Carelli Bruno , Azevedo Renata Guise Soares , Goldman Cecilia , Schindler Fernanda , Pianowski Luiz F , Latorre Claudia Grandino , Santi Patricia , Cruz Felipe Melo , Cubero Daniel Iracema , Del Giglio Auro
Published: March 2020

e19552

Background: Paulinia cupana (guaraná) is an amazonic plant with stimulant proprieties which was shown previously to be effective for chemotherapy related fatigue in patients with breast cancer in a randomized double blind placebo controlled trial conducted by our group (J Altern Complement Med. 2011;17(6):505-12). Purpose: Extend our study to patients with different tumor types receiving various regimens of chemotherapy, treated with a purified dry extract of Paulinia cupana (PC-18). Methods: We included patients with solid tumors older than 18 years of age who were scheduled to receive systemic chemotherapy. We excluded patients with fibromyalgia and uncontrolled hypothyroidism, depression, anemia, hypertension or cardiac disease. We evaluated basal fatigue with the BFI questionnaire before chemotherapy, and included only patients who had an increase in their BFI score after one week. PC-18 was given at 50 mg PO bid, starting after one week of chemotherapy. We employed the FACIT-F, BFI, Chalder, HADS and PSQI questionnaires to evaluate fatigue, anxiety, depression and sleep quality at one week and after 4 weeks of chemotherapy. Results: 36 patients with a mean age of 54 years, 61 % female, 28% with breast, 22% colorectal, 8.3% lung , 8.3% head/neck, 5.6% ovarian and 27% of other carcinomas were included. Fatigue scores improved significantly when we compared scores of the BFI (mean difference = 19.39; 95%CI 12.4 – 26.37, p < 0.0001), FACIT-F (mean difference = -11.51; 95%CI -19.25 - -3.76, p = 0.0049) and Chalder (mean difference = 4.571; 95% CI 1.86 – 7.28, p = 0.0018) questionnaires. HADS subscales scores of anxiety (p = 0.025) and depression (p = 0.0095) also improved significantly after 3 weeks of PC-18 therapy. PSQI scores did not change significantly (p = 0.26) after 3 weeks of PC-18 treatment. Conclusions: We conclude that Paulinia cupana (Guaraná) PC-18 extract is active for treatment of chemotherapy related fatigue in patients with a variety of solid tumors and also improves their anxiety and depression scores without worsening the quality of their sleep.
Randomized trial effect of an oral nutritional supplement with eicosapentaenoic acid on nutritional and inflammatory parameters, response and toxicity to chemotherapy, quality of life, and survival in treatment-naive patients with advanced non-small lung cancer.
Authors: Sanchez-Lara Karla , Turcott Jenny , Juarez Eva , de la Torre Martha , Villanueva Geraldine , Green Dan , Arrieta Oscar
Published: March 2020

e19594

Background: Nutritional interventions have shown increased of energy intake but the effect of improvement in health related quality of life (HRQL) in non small cell lung cancer (NSCLC) patients is controversial. Eicosapentaenoic acid has been proposed to have anti-inflammatory, anticachectic and possibly could have antitumoral effects. Methods: Patients with advanced NSCLC naive to treatment were included and randomly assigned to receive diet and oral nutritional supplement enriched with EPA or only isocaloric diet. All patients received paclitaxel and cisplatin-carboplatin treatment. Weight, body composition measured with bioelectrical impedance analysis, dietary ingestion, inflammatory parameters and HRQL were assessed at baseline and after 1st and 2nd cycle. Response to chemotherapy and survival were evaluated. Results: Ninety-two patients were analyzed, (46 EPA, 46 control group). No basal differences between groups were found. Experimental group present significantly increased albumin levels, energy, proteins, lipids and carbohydrate intake, and reduced serum CPR, TNF-α and Neutrophyls/Lymphocytes index. Patients in experimental group presented minor prevalence of weight loss and increased 1.6 kg of lean body mass (LBM) compared with controls. In HRQL, experimental group presented an improvement in global and physical scale and anorexia, and regarding toxicity, fatigue and neuropathy diminished. There was no difference in response rate, progression free survival and overall survival between groups. Conclusions: EPA enriched supplementation provided a therapeutic advantage by increasing LBM and nutrients intake, improving HRQL, and reduce several toxicity parameters in NSCLC patients under chemotherapy. The study was registered with ClinicalTrials.gov, number NCT01048970.
Resection of esophageal gastrointestinal stromal tumors.
Authors: Trifanov Vladimir , Kit Oleg I , Vladimirova Liubov Yu , Trifanov Dmitriy , Kasatkin Vadim
Published: March 2020

e20503

Background: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of gastrointestinal tract. GISTs account for 0,1% to 0,3% of all tumors in the gastrointestinal tract. Two thirds of these tumors arise from the stomach, 25% arise from the small intestine and less than 5% arise from esophagus. Use of tyrosine kinase inhibitors has revolutionized therapy for GISTs but complete resection remains the treatment of choice. Methods: We report our experience (from 2005 to 2011) with five patients who underwent resection of esophageal GIST. Reviewed consensus management guidelines and performed a literature review for reported cases. Results: All five patients underwent surgery intervention at our institute. Four patients had no metastasis and they underwent tumor enucleation. Due to submucosal location only one of them was diagnosed with GIST by endoscopic biopsy before surgery. One patient had a giant liver metastasis invading totally all segments of right lobe of liver. He underwent transhiatal extirpation simultaneously combined with extended right-sided hemihepatectomy. That patient suffered from total dysphagia, 15 kg weight loss, gastrointestinal bleeding and a big lump in his right hypochondrium. After laparotomy we diagnosed big metastatic nodule invading the whole right lobe of liver 25 cm in diameter. After diaphragmotomy we diagnosed tumor of the lower third of esophagus. Consequently, we performed extended right-sided hemihepatectomy and transhiatal esophagus extirpation. Two months later esophageal plastics by means of ileocaecal segment of colon was performed. The pathological diagnosis was confirmed in all five cases by microscopic examination (KIT+; CD17+, mitotic rate). In adjuvant regime imatinib (400 mg/body/day) was administered for a year for all five patients. The patients are alive now, they were followed up every six months with CT for two years. Fortunately, no new tumors were observed during this period of time. Conclusions: Esophagectomy is the treatment of choice for esophageal GISTs but requires attention to operative details that emphasize complete en block excision of surrounding tissue and metastatic nodules.