tbuckley/cabot-search huggingface dataset:
Clinical factors affecting therapeutic response of conventional chemotherapy with bevacizumab in metastatic colon cancer.
Authors: Rezwan Islam, TramAnh Xuan Phan, Po-Huang Chyou, Mahbubur Rahman, Muhammad Ghulam Kibriya
Journal: Journal of Clinical Oncology (2016)

e15001 Background: Molecularly targeted agent like Bevacizumab (BZ) combining with conventional chemotherapy (CC) showed good clinical outcomes in patients with metastatic colorectal cancer (mCRC). However, it is unclear if any clinico-morphological factor(s) affect the overall survival (OS) &/or progression free survival (PFS) in mCRC who received BZ with/without 5FU-based CC (e.g. FOLFOX). Methods: A retrospective electronic medical record review of all consecutive mCRC patients treated with BZ with/without CC at Marshfield clinics between 2003 and 2009 was undertaken. Total 149 patients (m = 77, f = 72) were eligible. RECIST criteria were used to identify early responder and non-responders. Results: Mean age at diagnosis was 63.5 yrs (SD11) with a median follow up period of 581 days (range:37-2294 days). At the first radiological evaluation following BZ therapy, a complete/partial response (early responders) was observed in 56 patients (m = 31, f = 25). Rest of the patients (m = 46, f = 47) was either stable or showed progressive disease (non-responders). Subsequent follow-up showed disease progression in 50% among early responders and 60% among non-responders [RR 0.67 (95%CI 0.43-1.06)]. The early responders showed slightly better OS than the non-responders but it did not reach statistical significance [median 644 days vs. 505 days, p = 0.07, Wilcoxon Rank Sum test]. Cox regression showed that male sex (RR 0.65, 95%CI 0.43-0.98), patients presenting with surgically removable primary tumor (RR 0.42, 95%CI 0.24–0.72) and resectable metastatic mass (RR 0.32, 95%CI 0.14-0.74), blood in stool (RR 0.63, 95%CI 0.4-0.98) were associated with longer OS. Unexplained weight loss (RR 2.73, 95%CI 1.73-4.29), abdominal pain (RR 1.76, 95%CI 1.1-2.8), accompanying diabetes (RR 1.76, 95%CI 1.09-2.85) and diverticulitis (RR 1.81, 95%CI 1.01-3.24) were associated with poor OS. Conclusions: Consistent with earlier studies we observed better OS among mCRC presenting with surgically removable primary tumor and resectable metastatic mass. This may be the first study to show significant influence of male gender and diabetes on outcome in mCRC treated with BZ. However, larger study is needed to confirm.
Perilesional edema and blood vessel characteristics in brain metastases and implications for treatment with immune therapy.
Authors: Thuy Tran, Lucia Jilaveanu, Amit Mahajan, Sarah B. Goldberg, Don Nguyen, Veronica Chiang, Harriet M. Kluger
Journal: Journal of Clinical Oncology (2018)

9572 Background: Little is known about tumor-associated vasogenic edema in brain metastasis, yet it is the cause of significant morbidity and mortality. Our purpose was to better characterize edema and vessel leakage in humans treated with anti-PD1 and in pre-clinical models. We hypothesized that the etiology of tumor edema is multifactorial and not dependent on tumor volume mass effect alone. Methods: We analyzed tumor and edema volume in 18 non-small cell lung (NSCLC) and 18 melanoma patients with untreated brain metastasis treated with pembrolizumab. Cerebral melanoma tumors were stained with anti-CD34 to determine vessel density and the association with vascular leak. We employed an in vitro model of the blood-brain barrier using short term cultures from melanoma brain and extracranial metastases to determine tight junction resistance. Results: While larger tumors tended to have more edema, the correlation was weak (R2= 0.30). Edema:tumor volume ratios are similar in NSCLC and melanoma brain metastasis and were not associated with response (P> 0.50), progression-free (P= 0.22), or overall survival (P= 0.17). Patients responding to pembrolizumab had concurrent shrinkage of edema volume (R2= 0.81). Vessel density by CD34+ cell staining on brain metastasis samples was not correlated with perilesional edema on imaging. Melanoma brain metastasis cells in culture were able to cause decreases in tight junction resistance in an in vitro system, whereas cell cultures from extracerebral samples did not. Conclusions: Additional factors aside from tumor mass effect cause perilesional edema. Edema itself should not deter physicians from using PD-1 inhibitors; pembrolizumab-sensitive tumors tend to have decreases in both tumor volume and edema on treatment. Factors other than vessel density result in endovascular leak, and should be further studied. Moreover, melanoma cells themselves can cause vessel leakiness in an experimental system void of immune cells, suggesting they secrete properties that affect tight junctions, which might be harnessed for pharmacologic targeting.
Pathologic response to predict survival in patients who underwent surgery after neoadjuvant chemotherapy with bevacizumab for clinical stage II/IIIA non-squamous non-small cell lung cancer.
Authors: Yasuhiro Tsutani, Yuichiro Kai, Masaoki Ito, Takeshi Mimura, Yoshihiro Miyata, Kenji Suzuki, Kazuya Takamochi, Fumihiro Tanaka, Haruhiko Nakayama, Yoshinori Yamashita, Makoto Oda, Masahiro Tsuboi, Morihito Okada
Journal: Journal of Clinical Oncology (2016)

e20023 Background: Pathologic response after neoadjuvant therapy may be a surrogate marker of survival for lung cancer patients. We investigated the prognostic role of pathologic response after neoadjuvant chemotherapy with bevacizumab (BEV) in patients with clinical stage II/IIIA non-squamous non-small cell lung cancer (NSCLC). Methods: In a phase II feasibility study of neoadjuvant chemotherapy with cisplatin (CDDP), pemetrexed (PEM), and BEV followed by surgery for resectable clinical stage II/IIIA non-squamous NSCLC (NAVAL study), the relationships between pathologic response and recurrence-free survival (RFS) or overall survival (OS) were analyzed. Less than 33% residual viable primary tumor after neoadjuvant chemotherapy was defined as pathologic response. None of study patient received postoperative adjuvant chemotherapy. Results: Twenty-five of 30 (83%) study patients underwent surgery after 3 cycles of neoadjuvant CDDP (75 mg/m2) + PEM (500 mg/m2) + BEV (15 mg/kg). Twenty-two (88%) and 3 (12%) patients underwent lobectomy and bilobectomy with systematic lymphadenectomy, respectively. Six (24%) patients were classified as pathologic responders, whereas 19 (76%) as non-responders. Three (12%) patients achieved pathologic complete response. Pathologic responders significantly correlated to RFS with 3-year RFS for pathologic responders of 100% versus 15.8% for non-responders (P = 0.002). Similar trend was observed in OS with 3-year OS for pathologic responders of 100% versus 63.2% for non-responders (P = 0.102). Conclusions: Pathologic response can be a surrogate marker for survival in patients who underwent surgery after neoadjuvant CDDP + PEM + BEV. Additional treatment such as postoperative adjuvant chemotherapy may be needed for pathologic non-responders. Clinical trial information: UMIN000004278.
Hematopoietic stem cell transplant (HSCT) utilization in Hodgkin lymphoma (HL) after treatment failure from a statewide claims database.
Authors: Anem Waheed, Angie Mae Rodday, Anita J. Kumar, Susan K. Parsons
Journal: Journal of Clinical Oncology (2018)

e18739 Background: In the era of novel therapies, the first line and subsequent lines of therapies are rapidly evolving in the treatment of patients with HL in order to optimize disease control and reduce long-term health risks. HSCT is often used following treatment failure, which is associated with cost and morbidity. We define and describe a cohort of patients with HL from 2009-2013 in the Massachusetts All Payer Claims Database (MA APCD) who received HSCT. Methods: We defined a cohort of patients with HL who underwent HSCT from among the 7,613 cases with ICD-9 diagnostic codes for HL. To identify HSCT cases, we developed an iteratively refined algorithm using ICD-9 diagnostic and procedure codes, dates of service, and length of stay. Each potential HSCT case was reviewed by an oncologist prior to final inclusion. Reasons for exclusion were not HL, no HSCT, and remote history of HSCT. Results: Before applying our algorithm, we identified 695 HL patients with any ICD-9 code related to HSCT. Our algorithm reduced this to 178 potential cases of patients with HL who underwent HSCT. After clinical review, 128 (72%) were true cases. Cases were excluded for no HL (n = 28), no HSCT (n = 2), and history of HSCT (n = 20). Of the 128 patients with HL who received HSCT, the median age was 40 years (q1 = 26, q3 = 52) and 50% were female. 80% (N = 102) received autologous HSCT, 6% (N = 8) received allogeneic HSCT, 2% (N = 2) received both, and 13% (N = 16) received HSCT of undetermined type based on the claims data. Conclusions: We successfully developed and refined an algorithm to help identify HSCT among patients with HL within a claims database. While clinical review was required to determine true cases, our algorithm substantially reduced the amount of case reviews required. This algorithm and process can be applied to identify the use of HSCT in other hematological malignancies. Identifying true cases of HSCT from claims databases allows us to better describe patterns for treatment failure in HL, follow younger patients who are not routinely captured in other databases, and estimate cost of care. Future directions of this analysis include following patients across different insurers and estimating cost based on site and payer type.
TCT-690 Incremental Age-related 1-year MACCE after Acute Myocardial Infarction in the drug-eluting stent era (from KAMIR-NIH registry)
Authors: Dae-Won Kim, Dong-Bin Kim, Keepyung Hong, Sung-Mi Kim, Kyun Young Kim, Sung-Ho Her, Hawook Park, Jee Hyuk Kim, Myun Hee Lee, SeongHyeon Bu, Byung-Hee Hwang
Journal: Journal of the American College of Cardiology (2018)
Lung cancer immunotherapy outcomes in Hispanic patients.
Authors: Luis E. Raez, Teresita Munoz-Antonia, W. Douglas Cress, Brian Hunis, Alberto Chiappori, Martin Dietrich, Scott Joseph Antonia, Herman Powery, Paola Izquierdo, Daniel Sumarriva
Journal: Journal of Clinical Oncology (2018)

e18665 Background: Hispanics (H) in the US seem to have a lower age-adjusted mortality resulting from non-small cell lung cancer (NSCLC) compared with Non-Hispanic Whites (NHW). Immunotherapy outcomes in lung cancer are well known for the NHW population, since the studies that drove approval of atezolizumab, nivolumab and pembrolizumab in NSCLC involved predominantly NHW patients (pts). However, studies demonstrate that the prevalence of mutations, such as EGFR, driving NSCLC in H differs from NHW, and thus, there is great interest to see if the immunotherapy outcomes in H populations are similar to NHW. Methods: We reviewed clinical outcomes in 60 pts H pts with NSCLC treated with atezolizumab, nivolumab or pembrolizumab at the Memorial Cancer Institute (MCI) and the Moffitt Cancer Center (Moffitt) both in Florida/US. Immunotherapy was used in most of them as second line and beyond. Results: The study included 37 males and 23 females with a median age of 65 years (range: 38-88y). The overall response rate (ORR) was 13% and the disease control rate (ORR+SD (stable disease)) that shows the clinical benefit was 71%. The progression free survival (PFS) at 6 months (m) and 12m were 85% and 66%, respectively. Median PFS and median overall survival were 15m and 23m, respectively. Conclusions: ORR is 13% in Hispanics treated at MCI and Moffitt; compared to an expected 20% ORR for NHW as reported in the literature. Therefore it appears that Hispanics do not derive benefit from immunotherapy to the extent that NHWs do. This suggests more needs to be done to understand the potential of immunotherapy resistant mechanisms in order to devise more effective strategies for Hispanic patients.
Combining Tumor Microenvironment Modulating Nanoparticles with Doxorubicin to Enhance Chemotherapeutic Efficacy and Boost Antitumor Immunity
Authors: Mohammad Ali Amini, Azhar Z Abbasi, Ping Cai, HoYin Lip, Claudia R Gordijo, Jason Li, Branson Chen, Li Zhang, Andrew M Rauth, Xiao Yu Wu
Journal: JNCI Journal of the National Cancer Institute (2018)

Tumor microenvironment (TME) and associated multiple factors are found to contribute to the failures in cancer therapies, including chemo- and immunotherapy. Here we report a new multimodal strategy that uses a bioreactive multifunctional hybrid polymer-lipid encapsulated manganese dioxide nanoparticle (PLMD NP) system to remodel the TME, suppress drug resistance factors, reverse immunosuppressive conditions, and enhance chemotherapy efficacy. The influence of PLMD NPs on enhancing cellular uptake in EMT6 mouse breast cancer cells and tumor penetration of doxorubicin (DOX) in EMT6 orthotopic breast tumor mouse model was evaluated using confocal microscopy (n = 3–4). Immunohistochemistry was employed to examine the effect of PLMD NPs on downregulating hypoxia-induced drug resistance proteins and anticancer activity of DOX (n = 3–4). The efficacy of the combination therapy with PLMD NPS and DOX was assessed in murine EMT6 (n = 15–23) and 4T1 (n = 7) orthotopic breast tumor mouse models. Rechallenge and splenocyte transfer were performed to validate the stimulation of adaptive tumor immunity in the surviving mice. PLMD NPs enhanced intratumoral penetration and efficacy of DOX, and reduced intratumoral expression of P-glycoprotein, p53, and carbonic anhydrase IX by 74.5%, 38.0%, and 58.8% vs saline control, respectively. Combination treatment with PLMD NPs and DOX increased the number of tumor-infiltrated CD8+ T cells and resulted in up to 60.0% complete tumor regression. Of naïve mice (n = 7) that received splenocytes from the PLMD+DOX–treated surviving mice, 57.1% completely suppressed tumor growth whereas 100% of mice that received splenocytes from DOX-treated mice (n = 3) and the control group (n = 7) showed rapid tumor growth. The clinically suitable PLMD NPs can effectively downregulate TME-associated drug resistance and immunosuppression. The combination therapy with PLMD NPs and DOX is a multimodal and translational treatment approach for enhancing chemotherapeutic efficacy and boosting antitumor immunity.
Immune marker profiling and PD-L1, PD-L2 expression mechanisms across non-small cell lung cancer mutations.
Authors: Maria Toki, Nikita Mani, James William Smithy, Yuting Liu, Mehmet Altan, Brad Wasserman, Rasikh Tuktamyshov, Konstantinos N. Syrigos, David L. Rimm
Journal: Journal of Clinical Oncology (2017)

9076 Background: PD-1/PD-L1 axis inhibitors have been proven effective, especially in patients expressing Programmed Death Ligand 1 (PD-L1). Their clinical efficacy in patients with epidermal growth factor receptor (EGFR) activating mutations is still unclear, while KRAS mutations seem to be associated with high response rates. In this study we investigated the expression of PD-L1, PD-L2 and Tumor Infiltrating Lymphocyte (TIL) status as a function of mutation status in Non-Small Cell Lung Cancer (NSCLC). Methods: We used the AQUA method of quantitative fluorescence (QIF) to compare PD-L1 and PD-L2 expression and to characterize TILs populations and their activation status in over 150 NSCLC patient tumors with known mutation status. EGFR activation was assessed in situ using the proximity ligation assay (PLA) for EGFR and GRB2 and T cell activation was assessed using a novel multiplexed QIF assay including CD3, Granzyme B and Ki67. Results: PD-L1 tumor and stroma expression was significantly lower in EGFR mutant compared to KRAS mutant (p = 0.009) and EGFR/KRAS Wild Type (p &lt; 0.0001) tumors, while they had a higher frequency of PD-L2 expression. Conversely, KRAS mutants had significantly lower PD-L2 tumor and stroma expression but they were also more inflamed with higher CD4+, CD8+ and CD20+ TILs. Subgroup analysis of patients by their TILs activation status revealed that EGFR mutants had a very high frequency of inactive TILs even though lymphocytes were present in the tumor microenvironment. In contrast, in KRAS mutants, when TILs were present, they were almost always active. Finally, we find that PLA-defined activated EGFR correlated with increased PD-L1 expression in EGFR mutants but not in EGFR WT, while TIL activation was associated with higher PD-L1 in EGFR/KRAS WT. Conclusions: Our findings are consistent with the unique biology of EGFR mutant tumors. The high frequency of inactive TILs could explain the low immune therapy response rates in this patient group. Similarly, in this group, the reason PD-L1 expression fails to predict response may be due to expression as a result of constitutive oncogenic signaling rather than immune signaling, which would be associated with high PD-L1 levels and TILs activation.
Response of germline and somatic smoothened (SMO) mutations in non-small cell lung cancer (NSCLC) to hedgehog inhibitor vismodegib.
Authors: Anne S. Tsao, Ignacio Ivan Wistuba, Dianren Xia, Lauren Averett Byers, Lixia Diao, Jing Wang, Vassiliki Papadimitrakopoulou, XiMing Tang, Wei Lu, Humam Kadara, Zeynep H. Gumus, Zhi Tan, Shuxing Zhang, Monique B. Nilsson, John Heymach
Journal: Journal of Clinical Oncology (2017)

9062 Background: Smoothened (SMO) gene somatic mutations activate hedgehog signaling in basal cell cancers (BCC) and medulloblastomas but have not been reported in NSCLC. We detected somatic and germline SMOmutations in NSCLC patients (A-C) and sought to characterize the mutations further. Methods: We performed tumor/blood germline sequencing of SMO mutations, familial germline mutation testing (saliva specimens), somatic mutation analysis of TCGA lung carcinoma datasets, and germline mutation analysis of the TCGA and 3 additional large cohorts (n = 1933). To evaluate the functional significance of SMOP641A, HCC4011 lung cancer cells were transfected with a wild-type SMO or SMOP641A expression vector and a predictive model was created. Results: NSCLC SMOP641A in vitro activated the hedgehog pathway, and vismodegib/cyclopamine inhibited tumor cell growth. Structural modeling suggests that SMO P641A induces conformational changes and disrupts PTCH-SMO interaction leading to constitutive activation. In the NSCLC TCGA databases, somatic SMO mutations occur 1.7%. In the overall TCGA database, germline SMO P641A occurred in 0.11% of cancer patients (multiple cancers) compared with 0% in cancer-free individuals. Patient A (never-smoking SCC) had a 46% RECIST reduction within 6 weeks for 6 months on vismodegib. His 3-generation family pedigree identified germline SMOP641A in one daughter (who developed BCC early). Two additional NSCLC patients (B – germline P641A and C –M525L received vismodegib; B initially stabilized but stopped vismodegib after 14 weeks for toxicity while patient C had no response. Conclusions: SMO mutations are targetable, potentially heritable, oncogenic drivers in NSCLC and other cancers. Tumor genetic profiling should consider including SMO gene, especially in never-smoking lung SCC patients. Additional studies are needed to define the role of germline/somatic SMO alterations in promoting carcinogenesis, interactions with P53 alterations, and the responsiveness of different SMO mutations to hedgehog inhibitors. Currently, the ongoing ECOG-ACRIN MATCH study (NCT02465060) treats SMO/PTCH mutated patients with vismodegib.
Financial distress among older versus younger adults with cancer.
Authors: Thomas Gregory Knight, Allison Mary Deal, Hyman B. Muss, Stacie Dusetzina, Seul Ki Choi, Jeannette T Bensen, Grant Richard Williams
Journal: Journal of Clinical Oncology (2016)

e18268 Background: Financial toxicity (FT) is a growing area of cancer research and interventions for this problem are in development (de Souza et al, Cancer 2014). However, there is a gap in the literature regarding age-related differences in both the characteristics and potential treatment implications of FT. Using patient reported data, this study quantified these age-related differences. Methods: Cancer patients aged ≥ 18 years who completed a survey ≥ 90 days from the date of diagnosis were identified from the Health Registry/Cancer Survivorship Cohort, an institutional database designed to aid in cancer survivorship research. FT was defined as agreement with the phrase "You have to pay for more medical care than you can afford" from the patient satisfaction questionnaire (PSQ-18). Patients were then separated into two groups based upon age ( ≥ 65 years). Demographic characteristics and delays in care were compared using Fisher's exact and Wilcoxon rank sum tests. Results: There were 1,992 patients included, 32.6% were aged ≥ 65 years. Characteristics of the groups were similar, although those aged ≥ 65 were more likely to be male (43.9% vs 34.8%, p < .0001) and Caucasian (89.3% vs 76.3%, p < .0001). Patients < 65 years were much more likely to report financial toxicity (32.2% vs 14.4%, p < .0001). Younger patients were also more likely to be uninsured (7.7% vs 1.4%, p < .0001) and to report difficulties affording: transportation (3.6% vs 1.9%, p = 0.04), taking time off work (4.9% vs 0.3%, p < .0001), travel expenses (4.7% vs 0.5%, p < .0001), and general expenses (11.2% vs 2.5%, p < .0001). Younger patients were more likely to report noncompliance to prescription medications (9.9% vs 2.2%, p < .0001), mental health care (3.4% vs 0.2%, p < .0001), doctor's visits (6.8% vs 1.7%, p < .0001), medical tests (4.0% vs 0.9%, p < .0001), and OTC medications (5.2 % vs 0.9%, p < .0001) as a result of affordability concerns. Conclusions: Patients under the age of 65 reported greater rates of financial distress compared to older adults. Higher rates of insurance, primarily through Medicare, and increased savings likely contribute to this finding, but further research is required.