tbuckley/cabot-search huggingface dataset:
Characteristics, associations, and outcomes of hemophagocytic lymphohistiocytosis: Retrospective data over a period of 13 years from a university hospital.
Authors: Dinesh Atwal, Derek Middleton, Manojna Konda, Belal Firwana, Naveen Yarlagadda, Pooja Motwani, Muthu Kumaran Veeraputhiran, Appalanaidu Sasapu
Journal: Journal of Clinical Oncology (2018)

e19563 Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare life threatening disorder characterized by exaggerated immune response leading to multi-organ damage. Despite increasing recognition, much of our current knowledge is based on the data from pediatric HLH. Methods: All adult patients diagnosed with HLH, over a period of 13 years at our institution, were identified using retrospective chart review. We identified their baseline characteristics including the underlying triggering condition. Results: A total of 38 patients were identified, mostly males (21, 55%) and Caucasians (74%). Median age was 51 years (range 15 to 78). 28 (74%) had underlying infection, most common was EBV (18.4%). 13 patients (34%) had underlying malignancy with multiple myeloma being the most common malignancy (8%) and 11 (29%) had underlying rheumatologic disorder. 30 patients (79%) fulfilled the HLH-04 criteria. Cytopenias and elevated ferritin (95% each) were the most common criteria fulfilled. 22 were tested for elevated soluble IL-2 receptors, of which 21 tested positive. 5 were tested for NK-cell activity, of which 4 had low/ absent NK-cell activity. 30 patients (79%) received HLH-specific chemotherapy and 28 (74%) received treatment for the underlying trigger as well. The most common chemotherapy regimen was etoposide-dexamethasone. The overall mortality was 47% and 20 patients (53%) achieved remission with 3 (15%) relapses. The patient characteristics are listed in Table 1. Conclusions: HLH remains an enigmatic disorder associated with high mortality. It is increasingly being recognized but more studies are needed in adults to better diagnose and manage this disorder Table 1. Patient Characteristics Characteristic N = 38 Median Age 51 (15-78) Race Caucasian 74% African American 21% Hispanic 5% Underlying Condition Infections 74% Malignancy 34% Rheumatologic disorder 29% HLH-2004 Criteria Fever 92% Splenomegaly 40% Cytopenia 95% Hypertriglyceridemia 53% Hypofibrinogenemia 42% Elevated Ferritin 95% Biopsy 69% Increased IL-2 receptors 85% Low/Absent NK-Cell Activity 11% Fulfilling 5/8 criteria 79% Overall mortality 47% Remission rate 53%
Understanding treatment, utilization, and costs in advanced/metastatic (Adv/Met) gastric or gastroesophageal junction cancer (GC/GEJC): Implications for episodic payment models.
Authors: Ronan Joseph Kelly, Hannah Le, Sze-Jung Wu, Melissa Laurie, Amit D Raval, Qian Shi, Beata Korytowsky
Journal: Journal of Clinical Oncology (2018)

e16035 Background: Few studies have examined the economic burden of adv/met GC/GEJC in the US. This analysis assessed real-world treatment patterns, healthcare resource utilization (HRU), and costs by line of therapy (LOT) to understand the implications for alternative payment models, like the Oncology Care Model (OCM). Methods: Patients (pts) aged ≥18 years with adv/met GC/GEJC from 01Oct2011-30Jun2017 in the HealthCore claims database were selected. Index date was first systemic treatment. Pts with other cancers prior to index date or during the follow-up period, pregnant pts, those with gastrectomy 3 months before index date, and those with < 1 month follow-up were excluded. Costs were calculated per pt per month (PPPM). Additional analyses in alignment with OCM evaluating 6-month and 12-month HRU and costs are in progress. Results: Of 392 treated 1L pts, 41.5%, 10% and 3.6% received 2L, 3L, and 4L+, respectively. Median age was 62 years, and 61% were male. In 1L, most frequent regimens were FOLFOX (22.5%), EOX (13.8%), and ECF (5.1%). In 2L, out of > 30 uniquely observed regimens, the most commonly used were FOLFOX (9.8%), EOX (9.2%) and paclitaxel+ramucirumab (PAC+RAM) (7.4%). No clear standard therapy emerged in 3L and 4L+; use of PAC+RAM (~15%), and FOLFIRI (~7%) was observed. The use of anti-PD1 therapy across all LOTs was 1.5%. The mean total all-cause healthcare cost was $9,717 PPPM allocated as follows: systemic therapy and related services, 33%; hospitalizations/ED, 36%; outpatient services, 28%; and pharmacy, 3%. Frequency of hospitalization was high across all LOTs, with the highest burden in 1L and 4L+ (table). Hospice HRU was below OCM quality metrics recommendations. Conclusions: Fewer than 50% of pts received subsequent therapies following 1L, with no clear standard of care in 3L+ setting. This analysis highlights the burden of managing adv/met GC, suggesting that more effective treatments are needed in this disease setting. All LOTs 1L 2L 3L 4L+ N 392 392 164 39 16 Median treatment duration (months) 7.3 3.8 4.1 4.3 4.9 Hospitalization (%) 69 53 43 46 50 30-day readmission (%) 29 20 15 21 25 ED visits (%) 40 30 23 21 38 Hospice stay (%) 6 3 5 5 19
Safety and tolerability of guadecitabine (SGI-110) plus cisplatin in patients (pts) with platinum-refractory germ cell tumors (GCT): Preliminary results from an open label phase 1b study.
Authors: Neda Hashemi-Sadraei, Lawrence H. Einhorn, Susan Perkins, Michael J Spinella, Fang Fang, Nasser H. Hanna, Kenneth P Nephew, Costantine Albany
Journal: Journal of Clinical Oncology (2018)

e16545 Background: Preclinical data suggests platinum resistant embryonal carcinoma (EC) cell lines are sensitive to hypomethylating agents. Guadecitabine (G), a novel hypomethylating dinucleotide of decitabine, induces complete regression of cisplatin (Cis)-resistant EC xenografts and re-sensitizes refractory EC cells to Cis in vivo. We assessed safety and efficacy of G plus Cis in pts with platinum refractory GCT (rGCT). Methods: This phase 1b trial enrolled pts with rGCT at Indiana University. Pts were treated with G at 30-45 mg/m2 subcutaneous daily for 5 days in dose-escalation cohorts plus Cis 100 mg/m2 on day 8 every 28 days (initially 21-days, amended due to myelosuppression) up to 6 cycles using modified Toxicity Probability Interval (mTPI) design, until progression or intolerable toxicity. Primary objective was safety and toxicity of G plus Cis. Results: As of December 1st 2017, 12 pts (11 male, 1 female) were enrolled, 11 were evaluable. Median age was 29.5 (range, 26-47). Nine had prior high dose chemotherapy (HDCT) with stem cell transplant (SCT). Seven received G plus Cis as 4th or 5th line of therapy. At data cutoff, 2 pts continued to receive study treatment. Median duration of follow-up was 12 mo (range, 1-25). Treatment-related adverse events (TRAEs) in ≥ 50% of pts were neutropenia (83%), thrombocytopenia (67%), fatigue (67%), nausea (58%). Most common grade 3-4 TRAEs were neutropenia (83%), thrombocytopenia (42%), anemia (33%). No grade 5 TRAEs occurred. The maximum tolerated dose was G 30 mg/m2 day 1-5 plus Cis 100 mg/m2 day 8 every 28 days. Two pts achieved complete response (CR) and survived over 12 mo after completing therapy, one of whom had primary mediastinal nonseminomatous GCT and had a rapid progression on all prior 3 lines of therapies, including HDCT with SCT. Conclusions: In this phase 1b study, combination of G plus Cis was well tolerated in pts with rGCT. Enrollment is ongoing. CR’s with survival > 1 year was observed in this heavily pre-treated pt population. Clinical trial information: NCT02429466 Clinical trial information: NCT02429466.
Predictors of urinary diversion choice in patients with bladder cancer in integrated care settings.
Authors: Marilyn L. Kwan, Michael C Leo, Valerie S. Lee, Kim N. Danforth, Sheila Weinmann, Maureen Cecelia O'Keeffe-Rosetti, David Yi, Christopher S. Wendel, Joanna E. Bulkley, Mark C. Hornbrook, Robert S. Krouse, Scott Michael Gilbert, Carmit K. McMullen
Journal: Journal of Clinical Oncology (2017)

4543 Background: Annually over 10,000 people with bladder cancer in the US have cystectomy surgery with urinary diversion (UD). While ileal conduit (IC) is most common, neobladder (NB) and continent pouch (CP) are options to retain urinary continence. Few studies in community settings have examined patient and clinician factors associated with UD choice. Methods: Eligible patients were age ≥21 with a cystectomy and UD for bladder cancer from 1/2010 to 6/2015 in 3 West coast Kaiser Permanente regions. Data were obtained from the EHR and chart review.We useda mixed effects logistic regression model with surgeon as a random effect, and region as a fixed effect, to identify patient factors associated with UD choice (IC vs NB/CP). We also examined whether surgeon factors were associated with UD choice above and beyond patient factors. Results: Among 1063 patients, 80% had an IC. IC patients were older (mean age 72 vs. 62), more likely female (24% vs. 16%), more likely diagnosed with AJCC stage III/IV (41% vs. 28%), and had higher Charlson comorbidity score (median 4 vs. 3) than NB/CP patients. Surgeons accounted for a sizable portion of the variability in UD choice (ICC = .26). The model with patient factors showed good fit (AUC = .93, Hosmer-Lemeshow test p = .22). Including surgeon factors (annual cystectomy volume, specialty training, clinical tenure) did not improve model fit (p = .32). Female sex, eGFR &lt; 45, 4+ comorbidities, and stage III/IV tumors were associated with higher odds of receiving an IC vs. NB/CP (Table). Conclusions: Patient factors predict much of the variability in UD choice. The high ICC indicates that surgeons also contribute to this process, but surgeon factors we examined were not uniquely associated with IC. Future studies should explore more nuanced surgeon factors, such as how UD choice is shaped by personal beliefs about UD and likely outcomes. [Table: see text]
Utility and prognostic value of <sup>18</sup>F-FDG PET/CT scan in patients with newly diagnosed multiple myeloma.
Authors: Mohammed A. Aljama, M Hasib Sidiqi, Shaji Kumar, Taxiarchis Kourelis, Morie A. Gertz, S. Vincent Rajkumar, Wilson I. Gonsalves, Martha Lacy, Francis Buadi, Prashant Kapoor, Angela Dispenzieri, David Dingli, Nelson Leung, John Anthony Lust, Suzanne R. Hayman, Ronald S. Go, Lisa Hwa, Robert A. Kyle, Rahma M. Warsame
Journal: Journal of Clinical Oncology (2018)

8023 Background: Positron emission tomography–Computed tomography (PET/CT) can identify bony lesions, assess disease burden and detect extramedullary disease in patients with newly diagnosed multiple myeloma (MM). Methods: We conducted a retrospective review of patients who had a PET/CT performed within sixty days of diagnosis and prior to commencement of therapy to identify the nature and prognostic impact of PET/CT abnormalities in newly diagnosed MM. Results: Between April 2005 and June 2017, 314 patients were identified and included in the analysis. 235 (75%) patients had focal lesions (FL), 183 (58%) had ≥3 FL, 38 (12%) had extra medullary disease (EMD) and 194 (62%) had documented lytic lesions. Median maximum standardized uptake value (SUVmax) in the entire cohort was 5.9 (range 0-48.3). Presence of ≥3 FL and EMD predicted overall survival (OS); median OS of 58 months for ≥3 FL vs 89 months for < 3 FL (P= 0.009) and median OS 45 months for EMD present vs 71 months for EMD absent (P= 0.025). Compared to those with SUVmax of less than 8.5, those with SUVmax of more than 8.5 had a shorter overall survival, 89.6 versus 57.8 months, respectively (P= 0.022). Conclusions: PET/CT is a valuable tool in assessing disease burden and provides prognostic information in patients with newly diagnosed MM treated with novel agents. Variable Cohort N = 314 < 3 Lesions N = 131 ≥ 3 Lesions N = 183 P value Non-EMD N = 276 EMD N = 38 P value Age years, median (IQR) 65 (58-72) 66 (57-73) 64 (58-71) 0.6 65 (57-71) 66 (61-78) 0.2 Male, % 197 (63) 85 (65) 112 (61) 0.6 173 (63) 23 (64) 1 Median Hemoglobin 12.0 (10.3-13.3) 12.2 (10.7-13.4) 11.8 (9.9-13.2) 0.1 12.0 (10.3-13.3) 11.4 (9.3-13.6) 0.4 Median Calcium 9.6 (9.1-10.2) 9.5 (9.0-10.0) 9.6 (9.1-10.3) 0.1 9.6 (9.1-10.2) 9.5 (9.1-9.9) 0.3 Median Creatinine 1 (0.8-1.2) 1 (0.9-1.3) 1.2 (0.8-1.2) 0.5 1.0 (0.8-1.2) 1.0 (0.9-1.2) 0.5 Median LDH 166 (135-195) 155 (129-184) 170 (137-212) 0.03 161 (134-191) 194 (161-262) Bone marrow plasma cell count 40 (20-61) 40 (20-60) 46 (23-66) 0.2 41 (20-62) 40 (20-60) 0.9 ISS, n (%)* 0.01 0.9 I 56 (32) 30 (45) 26 (24) 50 (32) 6 (29) II 63 (36) 18 (27) 45 (41) 55 (36) 8 (38) III 57 (32) 19 (28) 38 (35) 50 (32) 7 (33) Missing 138 * With available testing
Gut microbiome and immunotherapy response in melanoma patients.
Authors: Brandilyn Peters, Melissa Wilson, Una Moran, Anna C. Pavlick, Allison Izsak, Todd Wechter, Jeffrey S. Weber, Iman Osman, Jiyoung Ahn
Journal: Journal of Clinical Oncology (2018)

9575 Background: Treatment of melanoma with checkpoint blockade immunotherapy brings potential for long-term freedom from progression. However, responses to immunotherapy are heterogeneous, and improving outcomes remains a critical need. We explored whether gut microbiota may modulate response to immunotherapy. Methods: Stool was collected from 26 stage 3-4 melanoma patients at NYU Langone Health, prior to immunotherapy (Ipi, Nivo, Ipi+Nivo, or Pembro). We conducted 16S rRNA gene sequencing on Illumina MiSeq, followed by the QIIME2 Deblur workflow to characterize taxonomic composition. We examined bacterial community α- and β-diversity, and taxon abundance, in relation to time to disease progression, using survival methods and adjusting for age and sex. Results: During follow-up (range: 3-18 months), 12 patients progressed. Higher community diversity was marginally associated with lower risk of progression (Shannon index HR = 0.40; 95% CI = 0.14-1.17; p = 0.09). Overall community composition was also marginally associated with time to progression, according to the non-phylogenetic Jensen-Shannon Divergence (MiRKAT-S p = 0.07 with 1000 permutations), but not according to the phylogenetic weighted UniFrac distance (p = 0.26). Centered log ratio-transformed abundance of several bacterial taxa was related to risk of progression (p < 0.05), though small sample size limited detection of associations after false discovery rate adjustment (all q > 0.44). An operational taxonomic unit (OTU) within Faecalibacterium prausnitzii was associated with significant risk reduction (HR = 0.71; 95% CI = 0.57-0.88; p = 0.002), resulting in significance at higher taxonomic levels (Faecalibacterium genus and F. prausnitzii species, p = 0.02). Additionally, genus Desulfovibrio (HR = 1.24; 95% CI = 1.04-1.49; p = 0.02) and an OTU in Ruminococcus gnavus (HR = 1.49; 95% CI = 1.12-2.00; p = 0.007) were associated with increased progression risk. Conclusions: We observed that gut microbiome is associated with response to immunotherapy, suggestive that microbiome manipulation may improve immunotherapy outcomes. Forthcoming shotgun metagenome and metatranscriptome sequencing of these samples will further elucidate species and functions related to response.
DESMOPAZ pazopanib (PZ) versus IV methotrexate/vinblastine (MV) in adult patients with progressive desmoid tumors (DT) a randomized phase II study from the French Sarcoma Group.
Authors: Maud Toulmonde, Isabelle Laure Ray-Coquard, Marina Pulido, Thierry Andre, Nicolas Isambert, Christine Chevreau, Nicolas Penel, Emmanuelle Bompas, Antoine Thyss, Francois Bertucci, Celeste Lebbe, Julien Domont, Patrick Soulie, Sophie Piperno Neumann, Fabiola Cecchi, Todd A. Hembrough, Florent Petitprez, Carine A. Bellera, Jean-Yves Blay, Antoine Italiano
Journal: Journal of Clinical Oncology (2018)

11501 Background: DT are a group of locally aggressive tumors of fibroblastic origin that can lead to significant morbidity. No randomized trial assessing systemic treatment activity in this rare disease has been reported previously. Methods: DESMOPAZ is a multicenter non-comparative randomized phase II trial based on a two-stage optimal Simon's design assessing safety and efficacy of PZ in DT adult patients (pts). All pts had to have documented progressive disease (PD) according to RECIST 1.1 based on two imaging within a 6-months interval. Pts were randomly assigned to receive PZ 800 mg/day orally continuously, or M (30 mg/m²) + V (5mg/m²) intravenously once a week for 6 months and then every 15 days for 6 months. Treatment was administered until PD (cross-over then permitted), unacceptable toxicity, and for a maximum of 1 year. The primary endpoint was 6-month non-PD rate according to RECIST 1.1. Based on the following hypotheses: P0 = 60%, P1 = 80%, α = 5% and β = 20% and a 2:1 randomization, a total of 43 assessable pts were needed in PZ-arm and 22 pts in MV-Arm. PZ could be regarded as an active drug if at least 31/43 6-month non-PD. Archive FFPE samples of tumor tissue were mandatorily collected at baseline, and an on-treatment tumor biopsy at Cycle 2 was optional. Results: Accrual started in September 2012 in 12 centers of the French Sarcoma Group. As of December 2017, 72 pts (26 males, 46 females) were included: 48 in PZ-arm (46 assessable) and 24 in MV-arm (20 assessable). Median age was 40 years (18-79). The median number of previous lines of treatment was 1 (0-3). After central pathological and radiological review, 38 assessable pts (82.6%) in PZ-arm had tumor shrinkage, resulting in PR in 17 (37%) and SD in 21 (45.7%). In MV-arm, 11 assessable pts (55%) has tumor shrinkage resulting in PR in 5 (25%) and SD in 6 (30%). The 6-month non-PD rate was 86% (95%CI = 72.1-94.7) in PZ-arm (37/43) and 50% (95%CI = 27.2-72.8) in MV-arm (10/20). Conclusions: The primary endpoint of the DESMOPAZ study was reached. PZ has meaningful clinical activity in pts with progressive DT. Safety, quality of life and pharmacodynamics translational data will be presented at the meeting. Clinical trial information: NCT01876082.
Treatment of metastatic human papillomavirus-associated epithelial cancers with adoptive transfer of tumor-infiltrating T cells.
Authors: Sanja Stevanovic, Sarah R. Helman, John R. Wunderlich, Michelle M. Langhan, Stacey L. Doran, Mei Li M. Kwong, Robert P. Somerville, Christopher Austin Klebanoff, Udai Kammula, Richard Mark Sherry, James C. Yang, Steven A. Rosenberg, Christian S. Hinrichs
Journal: Journal of Clinical Oncology (2018)

3004 Background: Adoptive T-cell therapy (ACT) is a promising cancer treatment modality. However, its study in epithelial cancers has been limited. Human papillomavirus (HPV)-associated cancers are difficult to treat epithelial malignancies for which better systemic treatments are needed. We conducted a clinical trial of ACT for the treatment of metastatic HPV-associated cancers. Methods: The clinical trial was a phase II design with two disease cohorts (cervical cancers and non-cervical cancers). Patients were treated with a single infusion of tumor-infiltrating lymphocytes (TIL), which were generated, when possible, from TIL subcultures with HPV-oncoprotein reactivity (HPV-TIL). HPV-TIL infusion was preceded by a lymphocyte-depleting conditioning regimen followed by systemic high-dose aldesleukin. Results: Objective tumor responses occurred in 5/18 (28%) patients in the cervical cancer cohort and 2/11 (18%) patients in the non-cervical cancer cohort. In the cervical cancer cohort, two patients experienced complete responses that are ongoing 53 and 67 months after treatment. Three patients experienced partial responses that were three months in duration. In the non-cervical cancer cohort, partial responses were observed in a patient with anal cancer (four months duration) and a patient with oropharyngeal cancer (five months duration). The latter patient had previously been treated with six systemic anti-cancer agents. Multiple thoracic metastases responded completely after HPV-TIL infusion. A brain metastasis developed five months after treatment and was surgically resected. He is without evidence of disease 51 months after treatment. Conclusions: HPV-TIL can mediate regression of metastatic HPV-associated cervical, oropharyngeal and anal epithelial cancers in some patients. These findings support the study of ACT for HPV-associated cancers and possibly other epithelial malignancies. Clinical trial information: NCT01585428.
Metformin activity in advanced adrenocortical carcinoma: A comparative analysis in human tumors.
Authors: Robert Alan Nagourney, Paula J Bernard, Federico R Francisco, Adam Nagourney, Steven Evans, Eknath A. Deo, Renata Peixoto
Journal: Journal of Clinical Oncology (2018)

e14568 Background: The biguanide metformin is a widely used oral hypoglycemic. One mode of action is the inhibition of mitochondrial complex I and activation of AMP kinase with down-regulation of mTOR. Numerous studies have examined biguanides in human cell lines and animal models revealing potent effects in tumors of the breast, ovary, prostate, colon, stomach and gliomas. We used phenformin to examine biguanide-activity in human tumors. Methods: We applied a phenotypic platform (Ex Vivo Analysis of Programmed Cell Death (EVA/PCD)) (Nagourney, Anticancer Res. 2012) in 382 human tumor primary culture micro-spheroids isolated from patient’s surgical specimens to examine phenformin activity and to compare it with Everolimus (mTOR), BYL 719 (PI3K) AZD 6244 (MEK/ERK). Dose response curves were interpolated to provide LC50 values for comparison by Pearson Moment. Disease-specific LC50 values were compared by modified by Z-score. Results: Phenformin activity favored adrenocortical, gastrointestinal, breast, neuroendocrine, NSCLC and uterine over ovarian and non-Hodgkin’s lymphoma. By Pearson-moment the highest correlation was found for Everolimus (r = 0.287, P < 0.001). The striking Ex Vivo activity for Phenformin observed in a young adrenocortical cancer patient’s study led to the institution of oral Metformin administered BID that led to a durable, CT-scan confirmed, objective response lasting over 9 months, the subject a recent case-report (Peixoto, R et al Rare Tumors, 2018). Conclusions: Metformin is active in human tumors with disease and patient-specific profiles of efficacy. Correlation with Everolimus is consistent with described modes of action. The dramatic response to therapy in a young patient with metastatic adrenocortical cancer offers proof-of-concept for the use of biguanides in therapy and may offer a novel therapy for patients with this rare and highly lethal form of cancer. Phenotypic platforms like EVA/PCD offer insights into cellular cell death events that serve as surrogate markers for clinical response and provide the opportunity to examine operative cellular signaling events in the presence or absence of detectable genomic alterations.