tbuckley/cabot-search huggingface dataset:
Extremely low frequency electromagnetic fields and induced malignant tumors.
Authors: Yulia A. Pogorelova, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Lidia K. Trepitaki, Alla I Shikhliarova, Gennadiy Z. Sergostyants, Tamara G. Ayrapetova, Anna V. Chubaryan, Irina Stasio Tavaryan
Journal: Journal of Clinical Oncology (2016)

e23201 Background: Induced tumors, as well as spontaneous ones, are known to be an adequate model of human tumors and allow revealing pathognomonic characteristics of malignant growth in the lungs and developing methods of experimental therapy. The purpose of the study was to analyze anti-carcinogenic effects of extremely low frequency electromagnetic fields (ELF EMF) on induced malignant tumors growing in lung tissue of rats. Methods: Induced tumors in the lung were reproduced with 3,4-benzopyrene in male outbred rats. The animals were divided into 2 groups: group A – control, without exposure, n = 100; group B – with ELF EMF exposure using magnetotherapeutic device Gradient-2, n = 30. Brain scanning was performed using 0.03 - 0.3 - 3 - 9 Hz frequency, sinusoidal waveform and 300 Hz frequency, square wave. Magnetic induction did not exceed 5 mT, exposure - 8 min. MF source was installed in projection to the hypothalamus of animals. Tumor was verified histologically after hematoxylin and eosin staining. Results: An autopsy revealed 1- and 2-foci tumor growth in both groups, with sizes in the control – 0.5-1.5 cm and in the main group – 0.5-1.0 cm. Histology showed round cell sarcoma in both groups. ELF EMF resulted in maintenance and increase of reserve fiber tortuosity, as well as increase in elastic and reticular fibers in relation to collagen ones. Life span of animals in the control was 16±1.2 weeks, in the main group – increased to 20±1.6 weeks (by 25%). Influencing the brain, ELF EMF triggers neuro-hormonal regulation, increasing general and local (lung tissue) adaptive potential and the level of resistance associated with it which contributes to temporal expression of anti-carcinogenic effect. Conclusions: ELF EMF exposure activates protective mechanisms in tissue structures of the lungs and provides compensatory-adaptive restructuring of the respiratory system and duration of the life support without tumor nodule resorption with unchanged volume and structure.
Exploring effects of MEK inhibition in tumor microenvironment in non-small cell lung cancer (NSCLC) pre-clinical models.
Authors: Tarik Silk, Hyejin Choi, Jiehui Deng, Stephane Pourpe, Kwok-Kin Wong, Taha Merghoub, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2018)

12060 Background: NSCLCs often harbor mutations in the KRAS oncogene and require improved treatment to provide durable disease control. Targeted therapy via MEK inhibition shows promising but temporary control of tumor growth but ultimately fails with a quick rebound of tumor growth. As the RAS-RAF-MEK-ERK pathway is evolutionarily conserved in most cells, MEK inhibition may cause broader effects in the tumor microenvironment. Methods: We examined the effect of novel pulsatile versus standard continuous MEK inhibition on lymphocytes and myeloid cells. KRAS tumor bearing mice were treated with selumetinib and T cells were analyzed for phenotypic changes. Tumor progression and survival with and without the addition of checkpoint blockade therapy was also monitored. In vitro experiments were also conducted with murine bone marrow-derived macrophages subsequently exposed to pulsatile or continuous selumetinib treatment. Results: MEK inhibition in T cells shows significant effects on T cell activation and proliferation. CD8+ T cell phenotypes increased CTLA-4, Ki67 and 4-1BB expression when treated with pulsatile compared to continuous MEK inhibitor, suggesting greater activation and proliferation status. Pulsatile MEK inhibitor therapy with CTLA-4 checkpoint blockade showed improved overall survival compared to continuous treatment in a mouse model of Kras mutant lung cancer. We extended our investigation to other tumor microenvironment components particularly myeloid cells. In vitro experiments revealed that pulsatile versus continuous treatment with the clinical MEK1/2 inhibitor selumetinib differentially effects macrophage viability and pro-inflammatory cytokine production. Conclusions: Pulsatile MEK inhibition improves T cell activation and prolongs survival in combination with anti-CTLA-4, compared with continuous treatment. It also has a modulating effect on myeloid cells compared to the standard continuous dosing. Optimizing MEK inhibition scheduling to target cancer cells and activate immune infiltrates will provide the best therapy for KRAS mutant NSCLC. These data will contribute to informing design immune modulation with targeted therapies in patients.
Efficacy and safety of pazopanib (PAZ) versus sunitinib (SUN) in patients (pts) with locally advanced or metastatic renal cell carcinoma (RCC): A pooled China subgroup analysis from COMPARZ studies.
Authors: Xinan Sheng, Jie Jin, Zhisong He, Yiran Huang, Ai-Ping Zhou, Jinwan Wang, Xiu-Bao Ren, Dingwei Ye, Xu Zhang, Shukui Qin, Fang-Jian Zhou, Yanfang Guo, Jun Guo
Journal: Journal of Clinical Oncology (2018)

e16588 Background: A pooled analysis of treatment-naïve Chinese pts enrolled in the phase 3 COMPARZ studies VEG108844 (randomized, open-label, global study) and VEG113078 (sub-study to VEG108844 conducted in China, Korea and Taiwan) was carried out to compare the efficacy and safety of PAZ with SUN for advanced or metastatic RCC Methods: In both studies, pts were randomized (1:1) to receive PAZ 800 mg once daily continuously or SUN 50 mg once daily in 6-week cycles (4 weeks on/ 2 weeks off). Progression-free survival (PFS) was the primary endpoint. Secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. PFS and ORR assessments were done by the independent review committee (IRC) and local investigators. Results: Of 209 pts (PAZ, 109; SUN, 100), 155 (74%) were male; median age was 57 years (range, 18-79). The median PFS was 13.9 months (mo) for PAZ vs 14.3 mo for SUN by investigator assessment and it was 8.3 mo in both arms by IRC assessment. The PFS HR was 1.17 (investigator) and 0.99 (IRC).The median OS was not reached in PAZ arm and was 29.5 mo in SUN arm. The ORR (complete response + partial response) in the PAZ arm was significantly higher than the SUN arm (investigator: 41% vs 23%, p = 0.005; IRC: 35% vs 20%, p = 0.02). Diarrhea and hair color changes were more frequent adverse events (AEs) in the PAZ arm compared to SUN; and decreased neutrophil, platelet count and thrombocytopenia were more common AEs in SUN arm compared to PAZ. Conclusions: This pooled analysis confirms that the efficacy was similar for PAZ and SUN in the Chinese population in terms of PFS and OS, consistent with the overall population of the COMPARZ study. ORR was higher in the PAZ arm than the SUN arm based on both investigator and IRC assessments. PAZ was generally well tolerated in the Chinese population with locally advanced or metastatic RCC. Clinical trial information: NCT00720941, NCT01147822.Parameter Investigator assessment IRC assessment PAZ SUN PAZ SUN Median PFS, mo 13.9 14.3 8.3 8.3 HR (95% CI) 1.17 (0.792,1.727) 0.99 (0.6760,1.4580) ORR, % 41 23 35 20 Duration of response, mo Not assessed 8.3 21.8 95% CI for difference P value (5.9, 30.7) 0.005 (3.0, 26.8) 0.02
Capecitabine efficacy and safety in patients with locally advanced nasopharyngeal cancer: Retrospective study.
Authors: Reyad Dada, Ehab Mosaad Abdelghany, Jamal Zekri
Journal: Journal of Clinical Oncology (2018)

e18070 Background: Capecitabine, an oral 5-fluorouracil (5FU) derivate, is widely used as replacement for 5FU in many chemotherapy regimens administered in patients with different gastrointestinal tract cancers. However, worldwide experience with capecitabine in neoadjuvant chemotherapy (NAC) regimens in patients with locally advanced nasopharyngeal cancer (LANPC) is limited. Methods: the data of patients with LANCPC receiving capecitabine in combination with cisplatin as NAC prior definitive radio-chemotherapy for LANPC treated between 01/2013-12/2017 was retrospectively analyzed. Treatment consisted 2-4 cycles of NAC with cisplatin 100 mg/m2 on day 1 and capecitabine 850-1000 mg/m2 BID d 1-14 every 3 weeks. Patients with clinical meaningful response after second cycle underwent radiological assessment. In case of significant tumor shrinkage (equal and more than partial remission) in images, NAC was stopped. Thereafter, the patients received radical concurrent radio-chemotherapy (CCRT) (cisplatin 100 mg/m2, q3 weeks during radiation). Clinical and radiological examinations were carried out 2-3 months after the end of radiotherapy and every 3-6 months thereafter. Results: we identified 33 patients of whom 28 patients were fulfilling the inclusion criteria. Of the 20 male and 8 female patients with median age of 45 years, 4 were in stage IV and 1 patient in stage 2, the rest (n = 23) was in stage 3. 16, 7 and 4 patients received 2, 3 and 4 cycles NAC respectively. 1 patients went for CCRT due to PD after 1 cycle NAC. CR, PR, SD and PD rates after NAC were 32,1%, 53.6%, 3.5% and 10.7% respectively. After completion of CCRT 67.9%, 14.2% and 10.7% achieved CR, PR and PD respectively. The response of two patients was undetermined. After median follow-up time of 9 months 39% were progression free (table 1) and 82% were alive (table 2). Median PFS was 17 months. Grade3 mucositis, diarrhea and neutropenia occurred in 10%, 7% and 7% respectively. No grade 4 toxicity was documented. No grade 3/4 anemia or thrombocytopenia was observed. Conclusions: According to our results, replacement of 5FU by capecitabine as partner with cisplatin during NAC in LANPC is effective and safe.
WEE WIN: Window of opportunity study of induction WEE1 inhibition in advanced high-grade serous ovarian cancer.
Authors: Shannon Neville Westin, Susan M. Galbraith, Robert Godin, Mark J. O'Connor, Mark F. Munsell, Katerina Savelieva, Alpa Manchandia Nick, Pamela T. Soliman, Anil Sood, Gordon B. Mills, Robert L. Coleman
Journal: Journal of Clinical Oncology (2016)

TPS5610 Background: High grade serous ovarian cancer (HGSOC) is associated with DNA repair and cell cycle aberrations, such as mutations in p53, which result in G1/S checkpoint deficiencies and high levels of endogenous damage and replication stress. This can lead to dependency on WEE1 kinase, which plays important roles in dealing with replication stress and provides an important G2/M checkpoint, allowing the repair of DNA damage prior to entering mitosis and undergoing cell division. AZD1775 is a highly selective, small-molecule inhibitor of WEE1 being developed for the treatment of advanced solid tumors. Identification and validation of biomarkers that stratify patients (pts) likely to benefit or not from this therapy will be essential to obtain optimal benefit. Further, the clinical effects of different p53 mutation types (loss of function, hot spot, gain of function) on AZD1775 response are unknown. Thus, we are conducting a window of opportunity study to evaluate the molecular effects of AZD1775 on untreated HGSOC. Methods: A total of 30 pts with untreated advanced-stage ovarian, primary peritoneal, or fallopian tube cancer who are surgical candidates, will undergo laparoscopic evaluation with tumor sample collection prior to tumor reductive surgery (TRS). A validated scoring system is utilized to determine ability to resect to no gross residual disease (R0). Pts scored < 8 are eligible and proceed to primary TRS at a later date. Pts scored > 8 are not eligible. After laparoscopic evaluation, pts with a score < 8 will receive AZD1775 (200mg PO 3 days on/4 days off) for 14-28 days prior to TRS. Tissue (tumor primary, omentum, and 2 non-omental peritoneal sites) and plasma collected at laparoscopy (pre-treatment) and TRS (post-treatment) will be interrogated and molecular results correlated to clinical and pathologic endpoints including CA125 levels, mutations in cfDNA, RPPA, tumor volume, and apoptosis. Following TRS, pts receive adjuvant treatment at physician discretion. The opportunities provided by this approach allow collection of untreated tumor and utilization of time between laparoscopic evaluation and TRS to evaluate the clinical and molecular impact of therapeutic agents. Clinical trial information: NCT02659241.
Depth of response post autologous hematopoietic stem cell transplantation (auto-HCT) to predict outcome in high risk multiple myeloma (MM).
Authors: Bei Hu, Koji Sasaki, Qaiser Bashir, Nina Shah, Krina K. Patel, Uday R. Popat, Chitra Hosing, Yago Nieto, Pei Lin, Ruby Delgado, Jeffrey L. Jorgensen, Jatin J. Shah, Elisabet Esteve Manasanch, Donna M. Weber, Sheeba K. Thomas, Robert Z. Orlowski, Richard E. Champlin, Muzaffar H. Qazilbash
Journal: Journal of Clinical Oncology (2016)

8019 Background: Despite major advances in the treatment for MM, patients (pts) with high risk disease (HRD) have significantly worse outcomes. Emerging data supports the importance of the depth of response on the outcome, including negative minimal residual disease (MRD-) status by multiparametric flow cytometry (MFC). Methods: 416 newly diagnosed pts with symptomatic MM received bortezomib-based induction, followed by auto-HCT between 1/1/2005 and 12/31/2013 at our institution. Pts with t(4:14), t(14;16), del 17p, del 1p and/or amplification 1q by cytogenetics or FISH were defined as HRD; all others were standard risk (SRD). MFC was performed on bone marrow to detect MRD before and after auto-HCT in select pts. Primary endpoints were complete remission (CR), MRD status, progression free survival (PFS), and overall survival (OS). Results: Eighty pts (19%) were HRD; 336 (81%) were SRD. 64 (80%) HRD and 260 (77%) SRD pts received maintenance therapy post auto-HCT. After induction, 10 (13%) HRD and 32 (10%) SRD pts were in CR. This increased to 17 (21%) HRD and 98 (29%) SRD pts in CR after auto-HCT. Three to 24 months post maintenance, CR was achieved in 23 (29%) HRD and 141 (42%) SRD pts. 229 pts (50 HRD, 179 SRD) had MRD data post-auto-HCT. Twenty-five (50%) HRD and 121 (68%) SRD pts achieved MRD- status (p = 0.03). After a median follow up of 33.4 months, median PFS in the HRD and SRD group was 24.8 and 45.5 months, respectively (p = 0.0003). Median OS in HRD and SRD group was 68.6 months and not reached, respectively (p < 0.001). MRD- status was associated with longer PFS on univariate analysis (p = 0.003), but longer PFS or OS was not seen on multivariate cox proportional hazards analysis (MVA) with time-dependent covariates. The only two independent factors that were associated with shorter PFS and OS on MVA were HRD disease (HR for PFS = 3.2, p = 0.007; HR for OS = 2.9, p < 0.001) and lack of stringent CR post maintenance (HR for PFS = 8.6, p = 0.04; HR for OS = 4.4, p = 0.03). Conclusions: Even with bortezomib-based induction, upfront auto-HCT, and maintenance in 80% pts, the PFS and OS is significantly shorter in pts with HRD. Achievement of a deeper response post-maintenence therapy is associated with better outcome.
Chemotherapy and radiotherapy in early stage uterine papillary serous and clear-cell carcinoma: A National Cancer Data Base study.
Authors: Julian C. Hong, Jonathan Foote, Laura Jean Havrilesky, Stephanie Gaillard, Junzo P. Chino
Journal: Journal of Clinical Oncology (2016)

5590 Background: Adjuvant chemotherapy (CT) and radiotherapy (RT) are often part of management of early stage uterine papillary serous (UPSC) and clear cell carcinoma (UCC), though their benefit remains unclear. This study uses a national cohort to study the benefit and interaction of lymph node dissection (LND), CT and RT in stage I UPSC and UCC. Methods: The National Cancer Data Base (NCDB) was queried for all women with FIGO 2009 stage I UPSC and UCC diagnosed from 1998 to 2012 who underwent at least total hysterectomy. Overall survival (OS) was estimated for combinations of RT and CT by the Kaplan-Meier method stratified by histology and LND. RT included external beam RT, vaginal brachytherapy (VBT) or both. Multivariate Cox proportional hazards models of OS were generated. Results: UPSC: 5432 women with UPSC were identified. UPSC with LND had longer 5-year OS with CT+RT (83% [95% CI 79-87%]) than CT (79% [75-83%]), RT (72% [68-75%]) or surgery alone (71% [69-74%]) (p < 0.001). Without LND, CT+RT (76% [63-88%]) had longer OS than RT (55% [46-66%]), CT (48% [36-60%]) or hysterectomy alone (53% [48-58%]) (p = 0.02). On multivariate analyses for UPSC with and without LND, age, race, Charlson/Deyo comorbidity, depth of invasion and VBT were independently associated with longer OS. CT was independently associated with OS with LND (HR 0.77, p = 0.01) but not without (HR 1.21, p = 0.92). UCC: 2516 women with UCC were identified. UCC with LND had comparable 5-year OS for CT+RT (83% [76-89%]), CT (81% [74-89%]), RT (76% [72-81%]) or surgery alone (78% [74-81%]) (p = 0.21). Without LND, OS was similar for CT+RT (66% [45-88%]), CT (56% [28-84%]), RT (58% [45-72%]) and hysterectomy alone (47% [38-55%]) (p = 0.47). On multivariate analysis for UCC with LND, age, comorbidity and depth of invasion were independently associated with OS. Without LND, only age independently predicted OS. CT was not independently associated with OS with LND (HR 1.12, p = 0.51) or without (HR 1.07, p = 0.84). VBT was also not associated with OS with LND (HR 1.01, p = 0.97) or without (HR 0.42, p = 0.06). Conclusions: VBT was associated with longer OS in stage I UPSC. CT benefit was limited to those with LND. No adjuvant therapy was associated with OS in stage I UCC.
Carfilzomib (CFZ), carboplatin and etoposide for previously untreated extensive-stage small cell lung cancer (ES-SCLC): Phase 1b results from a phase 1b/2 study.
Authors: Firas Benyamine Badin, Anne C. Chiang, William B. Fisher, Sergey Orlov, Harry D. Harper, Elhamy Eskander, Wael A. Harb, Ebenezer Kio, Priya Kadambi Gopalan, Daniel Ernest Haggstrom, Olga Burdaeva, Anita Zahlten-Kumeli, Sanjay Aggarwal, Mihaela Obreja, Vera Gorbunova
Journal: Journal of Clinical Oncology (2016)

e20092 Background: Studies have suggested proteasome inhibitors can be combined with topoisomerase inhibitors to treat ES-SCLC. CFZ has previously demonstrated activity in relapsed SCLC. Results from a phase 1b are presented to determine the maximum tolerated dose (MTD), safety, and preliminary efficacy of CFZ with carboplatin and etoposide in previously untreated ES-SCLC patients (pts). Methods: This study was a 3+3 P1b dose expansion design where dose-limiting toxicities (DLT) were used to determine MTD and the recommended phase 2 dose (RP2D). Patients received carboplatin IV (target AUC=5 mg/mL/min) on day (D) 1 and etoposide (100 mg/m2) on D1-3 of each 21-D cycle (up to 6 cycles) and CFZ IV on D2, 3, 9, and 10: 20 mg/m2 (D2, 3; cycle 1); 20–56 mg/m2(dose escalation) thereafter. After combined therapy, pts with stable disease (or better) received CFZ monotherapy. Results: A total of 32 pts (median age: 58.5 years) were treated in 5 dosing cohorts. Patients received a median of 6 cycles of CFZ plus chemotherapy (carboplatin and etoposide), with a median treatment duration of 14.3 weeks. Protocol defined MTD was not reached. One DLT (thrombocytopenia) and one on-study death (pulmonary hemorrhage) were observed in the 56 mg/m2 cohort. The 45mg/m2 dose was chosen for dose expansion. Overall, four pts discontinued CFZ due to an adverse event (AE). Twenty-four pts (75%) had a grade ≥3 AE; the most common was neutropenia (n=13). All AEs were consistent with the agents under study. Best overall response rate (ORR) and preliminary PFS are shown in Table 1. Conclusions: The RP2D of CFZ with carboplatin and etoposide is 45mg/m2, with AEs consistent with the profiles of the study agents. Anti-tumor activity was observed with this therapy. Clinical trial information: NCT01987232.Preliminary efficacy (n = 30 evaluable pts). Carfilzomib (mg/m2) Cohort 1 (20/ 20); n=5 Cohort 2 (20/ 27); n=3 Cohort 3 (20/ 36); n=3 Cohort 4 (20/ 45); n=14 Cohort 5 (20/ 56); n=5 Total N=30 ORR; n (%) 3 (60.0) 3 (100.0) 3 (100.0) 5 (35.7) 2 (40.0) 16 (53.3) Median PFS; months, (95% CI) 4.0 6.4 7.0 3.7 4.4 4.4 (3.2, 5.8)
A retrospective study of comorbidities and complications in elderly acute myeloid leukemia (AML) patients in the U.S.
Authors: Neil Dhopeshwarkar, Xuehong Wang, Shahed Iqbal, Maribel Salas
Journal: Journal of Clinical Oncology (2018)

7032 Background: Treatment decisions are often influenced by comorbidity and functional capacity. Comorbidity burden in patients with AML has been shown to increase by age, but there is limited characterization of comorbidities and complications in elderly AML patients, who generally are under-represented in clinical trials. We characterized elderly AML patients in terms of comorbidities and complications. Methods: Patients (≥ 65 years) with a primary diagnosis of AML (SEER ICD-O Recode 35021 and ICD-9 205.0x) were identified from the SEER-Medicare Linked Database (2000-2013) and were followed till end of 2014. AML patients were matched 1:1 to patients without cancer on age, sex, geographic region, and race. A subset of relapsed and/or refractory (R/R) AML patients was identified using a modified previously validated algorithm. Comorbidities were assessed using NCI index scores. Incidence rates were calculated for select complications. Cox Proportional Hazards models were used to assess risks of complications. Results: The median age in AML and matched non-cancer patients (3,911 matched pairs) was 77 years (65-101 years) with 54% being male. AML patients had more comorbidities (52.1 % vs. 48.3% with ≥1 comorbidity) and higher comorbidity scores (NCI scores: 0.97 vs. 0.84, p < 0.01) at baseline (up to 12 months prior diagnosis) compared to non-cancer controls. Among other complications, incidence rates (per 100 person years) of cardiovascular disease (CVD) (54.0 vs. 8.8, p < 0.01), type 2 diabetes (T2D) (25.4 vs. 4.8, p < 0.01), and stroke (17.0 vs. 5.7, p < 0.01) were higher among AML patients. After adjusting for age, sex, region, NCI score, and baseline myelodysplastic syndrome, AML patients had a significantly higher risk of CVD (HR 4.61, 95% CI 4.07-5.21), T2D (HR 3.85, 95% CI 3.35-4.42), and stroke (HR 2.60, 95% CI 2.32-2.92). Similar results were observed in the R/R AML group. Conclusions: Elderly AML patients had higher comorbidities and rates of complications compared to matched non-cancer patients. Clinical decisions should consider the presence of comorbidities and complications. Further research is needed to better understand the association between AML and chronic health outcomes.
Notes from the Field: Acquisition of Delamanid Under a Compassionate Use Program for Extensively Drug-Resistant Tuberculosis — United States, 2017
Authors: Alfred A. Lardizabal, Anum N. Khan, Sapna Bamrah Morris, Neela D. Goswami
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Delamanid, a nitro-imidazole, is a new tuberculosis (TB) drug developed to address some of the adverse reactions and related adherence difficulties associated with currently available mediations for treating drug-resistant TB. A patient with extensively drug-resistant TB was successfully treated in 2017.