tbuckley/cabot-search huggingface dataset:
Phase II trial of miniDOX (reduced-dose docetaxel/oxaliplatin/capecitabine) in “suboptimal” patients with advanced gastric cancer (AGC): TTD 08-02.
Authors: Fernando Rivera, Bartomeu Massuti, Matilde Salcedo, Javier Sastre, Joaquina Martínez-Galán, Manuel Valladares-Ayerbes, Raquel Serrano, Marisa Garcia De Paredes, Josep Tabernero, M. Carmen Galan, Jose Luis Manzano Mozo, Eduardo Diaz Rubio, Veronica Conde, Margarita Reboredo, Silvia Vazquez, Laura Layos Romero, Francisco Javier Ramos Pascual, Enrique Aranda
Journal: Journal of Clinical Oncology (2013)

87 Background: Chemotherapy has improved overall survival (OS) in patients (p) with AGC and docetaxel (D), oxaliplatin (O) and capecitabine (X), have shown consistent activity in this setting. We defined "Suboptimal" p as those with PS ECOG-2 and/or weight loss 10-25% and/or age ≥70 years. This population is usually underrepresented in AGC clinical trials. Methods: We explored in 43 previously untreated "suboptimal" AGC p the "miniDOX" regimen (D: 40 mg/m2 iv, d1; O: 80 mg/m2 iv d1; C: 625 mg/m2 po bid, d1 to 21, every 21d; after 6 courses only C was maintained). D and O dose were allowed to be increased to 45 and 90 mg/m2 respectively (dose level +1) and to 50 and 100 mg/m2 (level +2) if less than grade 2 toxicity after the first 2 courses. One p that did not received any dose of chemotherapy, was included in the ITT efficacy analysis but not in the safety analysis. Primary endpoint was Response Rate (RR), Toxicity, Progression Free Survival (PFS) and OS were secondary objectives. Results: p characteristics: PS ECOG-2:12 p, Weigh loss 10-25%:23 p; median age 73.3 years (40-87); 32 males; locally advanced:8 p/metastatic:35 p; Primary site:Gastric 32 p/ EGJ 11; In 19 p the dose of D and O were increased to level +1 and in 8 of them to level +2. Worst toxicity per p (Grade 3-4): neutropenia: 5 p (3 of them with febrile neutropenia); pulmonary embolism (PE):4 p (3 of them suffered sudden death and the PE was suspected but not confirmed); diarrhea:9 p; paronychia:2 p; CVA:1 p; renal failure:1 p (this p suffered infection/bacteriemia without neutropenia and died); hand-foot syndrome:4 p and asthenia:5 p. Response: CR:1 p, PR:23 p (RR: 56%), SD:12 p, Progression:3 p, No determined:4 p; With a median follow-up of 27 months, 36 p have died (toxicity:4 p, progressive disease:32 p). Median and 1 year actuarial PFS and OS are 5.5 months/19% and 13.3 months/54% respectively. Conclusions: Although relevant the toxicity of miniDOX has been found, its activity is encouraging in "suboptimal" pts with AGC and this combination should be further investigated in this setting. Clinical trial information: NCT00733616.
EMBR-31. DEVELOPMENT OF INJECTABLE POLYSACCHARIDE HYDROGEL TO ENHANCE DRUG PENETRATION IN PEDIATRIC BRAIN TUMORS
Authors: Jenny Patel, Elizabeth Barker
Journal: Neuro-Oncology (2021)

Abstract Improving unacceptable low response rates and reducing acute and long-term morbidities remain significant challenges in pediatric neuro-oncology. Chemotherapy is an effective primary or adjuvant treatment for pediatric disease, but current administration approaches hinder the pharmacological activity exerted by chemotherapy treatments. Barriers in the route of drug administration and in the tumor microenvironment limit anticancer drugs from penetrating tissue efficiently and reaching all cancer cells. Strategies have been proposed to overcome these barriers with hope of leading to sustained and elongated drug exposure in solid tumors. However, few methods have been explored to design drug delivery systems to circumvent these barriers with potential to enhance drug penetration and reduce adverse systemic side effects in treating pediatric brain tumors. In this study, we validate an injectable polysaccharide hydrogel capable of releasing drugs locally at tumor site, sustaining drug concentration, and eliciting tumor response. We synthesized a hydrogel with dimethyl sulfoxide (DMSO) incorporating amylopectin, a polysaccharide found in starch, loaded with doxorubicin. We determined the structure of doxorubicin is not altered when released from the hydrogel through characterization of drug-loaded and unloaded hydrogels, suggesting drug is encapsulated in the hydrogel network and is able to maintain structure to induce mechanism of action. We tested sustained release of drug and therapeutic efficacy in vitro with DAOY, a medulloblastoma cell line. Our approach demonstrates that local drug delivery presents potential to enhance drug penetration in pediatric brain tumors by sustaining drug concentration at tumor site for an extended period of time. Local drug delivery systems have been investigated for decades but few have been investigated for treatment of pediatric brain tumors. For researchers, physicians, and clinicians, this research can lead to a greater effort to improve current outcomes of conventional drug treatment and provide an opportunity to address current challenges in pediatric oncology.
Aggressive T‐cell lymphomas: 2021 Updates on diagnosis, risk stratification and management
Authors: Jasmine M. Zain, Paul Hanona
Journal: American Journal of Hematology (2021)

Aggressive T-cell lymphomas continue to have a poor prognosis. There are over 27 different subtypes of peripheral T-cell lymphoma (PTCL), and we are now beginning to understand the differences between the various subtypes beyond histologic variations.Gene expression profiling (GEP) can help in diagnosis and prognostication of various subtypes including PTCL-nos and anaplastic large cell lymphoma (ALCL). In addition, mutational analysis is now being incorporated in clinical trials of novel agents to evaluate various biomarkers of response to allow better therapeutic choices for patients.There are many targeted agents currently in various stages of clinical trials for PTCL that take advantage of the differential expression of specific proteins or receptors in PTCL tumors. This includes the CD30 directed antibody drug conjugate brentuximab vedotin. Other notable targets are CD25, CCR4, inhibition of PI3kinase - m TOR and JAK/STAT pathways. The ALK inhibitors are promising for ALK expressing tumors.Allogeneic stem cell transplant continues to be the curative therapy for most aggressive subtypes of PTCL. The use of checkpoint inhibitors in the treatment of PTCL is still controversial. The most promising results have been seen in cases of extranodal natural killer cell/T-cell (ENK/T) lymphomas and cutaneous T-cell lymphomas (CTCL). Bispecific antibody based treatments as well as CAR-T cell based therapies are in clinical trials.
Survival benefit of nephrectomy prior to immunotherapy-based combinations in patients with metastatic renal cell carcinoma: An FDA pooled analysis.
Authors: Jaleh Fallah, Haley Gittleman, Chana Weinstock, Erik Bloomquist, Elaine Chang, Daniel L. Suzman, Sundeep Agrawal, Amna Ibrahim, Shenghui Tang, Richard Pazdur, Julia A. Beaver, Laleh Amiri-Kordestani
Journal: Journal of Clinical Oncology (2021)

4516 Background: Immunotherapy-based combination therapies (IO-X) are standard of care for metastatic RCC (mRCC) in the frontline setting. Limited data is available on the role of cytoreductive nephrectomy prior to IO-X in patients (pts) with mRCC (Bakouny, et al. GU ASCO 2020). We assessed the correlation between nephrectomy prior to IO-X and overall survival (OS) in pts with de novo mRCC. Methods: We pooled data from trials submitted for FDA review of a checkpoint inhibitor combination as first-line treatment for pts with mRCC. We only included trials with available data for stage at initial diagnosis (dx) to identify pts with stage IV disease at initial dx and to exclude those with nephrectomy in the non-metastatic setting. Kaplan-Meier method was used to estimate median OS in pts with de novo mRCC with and without nephrectomy prior to IO-X. Results: Five trials met inclusion criteria, all of which evaluated IO in combination with a kinase inhibitor. Data for stage at initial dx was available in 1708 pts who received IO-X. The majority of pts were male (72%) and White (80%). Among the 849 pts (50%) with stage IV RCC at initial dx, 523 pts (62%) had nephrectomy prior to IO-X. All pts had clear cell histology; Sarcomatoid differentiation was present in tumor pathology of 25% and 10% of pts with and without prior nephrectomy, respectively. Proportion of pts with favorable, intermediate and poor risk disease was 10%, 70% and 20%, respectively. OS appeared better in those with stage IV disease at dx who had prior nephrectomy compared to pts without nephrectomy (Hazard ratio (HR) = 0.53, 95% CI: 0.42, 0.68), even after adjusting for age and prognostic risk group (HR = 0.59, 95% CI: 0.46, 0.75) (see table). Conclusions: In this retrospective exploratory analysis, nephrectomy prior to IO-X in pts with new dx of stage IV RCC appeared to be associated with improved OS, even when controlling for age and prognostic risk group. The decision for nephrectomy is affected by factors such as medical comorbidities which could not be completely controlled. Results should be considered hypothesis generating.[Table: see text]
CheckMate 8KX: Phase 1/2 multitumor preliminary analyses of a subcutaneous formulation of nivolumab (± rHuPH20).
Authors: Sara Lonardi, Iwona Lugowska, Christopher G. C. A. Jackson, Anne O'Donnell, Rastilav Bahleda, Marcelo Garrido, Loes Latten-Jansen, Matias Chacon, Habte Aragaw Yimer, Trixia Camacho, Srivani Konduri, Urvi Aras, Kinjal Sanghavi, Heather Vezina, Sonia Dolfi, Federica Alessi, R Donald Harvey, José Trigo, Aitana Calvo
Journal: Journal of Clinical Oncology (2021)

2575 Background: Immunotherapy has transformed cancer survival expectations. Nivolumab (NIVO), a programmed death-1 inhibitor, is approved for intravenous (IV) administration across multiple cancers. BMS is developing a subcutaneous (SC) NIVO formulation with a permeation enhancer, recombinant human hyaluronidase PH20 enzyme (rHuPH20), to allow for more rapid delivery and the potential to decrease treatment burden. We report the first data on pharmacokinetics (PK), pharmacodynamics, safety, and immunogenicity for SC NIVO + rHuPH20. Methods: CheckMate 8KX is a phase 1/2 study in checkpoint inhibitor-naïve patients (pts) who were ≥ 18 years of age, ECOG PS 0–1, with metastatic/unresectable solid tumors and measurable disease. The primary objective was to describe SC NIVO PK; secondary objectives were safety and immunogenicity. Additional analyses compared exposures to historical IV NIVO (Zhao X, et al. J Clin Oncol 2020;31:302–309). In cycle 1, pts in Part A received SC NIVO 720 mg + rHuPH20, and pts in Part B received SC NIVO 720 mg, SC NIVO 960 mg + rHuPH20, or SC NIVO 960 mg. For cycles 2+, pts in Parts A and B received IV NIVO 480 mg every 4 weeks (Q4W). Pts still on study switched to Part C, SC NIVO 1200 mg + rHuPH20 until end of therapy. In Part D, pts received de novo SC NIVO 1200 mg + rHuPH20 Q4W. Results: Patient characteristics varied by age, weight, tumor type, and prior treatment. NIVO exposures increased with increasing SC dose (Table). For 960 mg and 1200 mg NIVO + rHuPH20, Cavg and Ctau were above geometric mean exposures for IV NIVO 3 mg/kg every 2 weeks (Q2W), and Cmax was below IV NIVO 10 mg/kg Q2W. In Part C (n = 28), 13 (46.4%) pts experienced any-grade TRAEs with no new/worsening grade 3+ TRAEs or TRAEs leading to discontinuation/death; 7 (25.0%) reported grade 1 local site reactions. In Part D (n = 36), 27 (75.0%) pts experienced any-grade TRAEs, 4 (11.1%) grade 3/4 TRAEs, 2 (5.6%) serious grade 3/4 TRAEs with 1 leading to discontinuation, and no treatment-related deaths; 10 (27.8%) reported grade 1 local site reactions. Anti-NIVO antibodies (Ab) were observed with SC NIVO but not associated with altered PK/safety, or neutralizing Ab. Exploratory biomarker data found increased CD8+ tumor-infiltrating lymphocytes and PD-L1 tumor expression in post-treatment biopsies, similar to IV NIVO. Conclusions: Exposures associated with SC NIVO + rHuPH20 doses investigated in CheckMate 8KX were well tolerated, with a safety profile consistent with IV NIVO. Data support evaluation of SC NIVO + rHuPH20 in a phase 3 study. Clinical trial information: NCT03656718. [Table: see text]
Genetic instabilities as potential biomarkers for pregnancy-associated breast cancer.
Authors: B.B.M. Berendine Suelmann, Cathy B. Moelans, Aniek Rademaker, Carsten Bakhuis, Carmen Dooijeweert, Paul J. van Diest, Elsken Van Der Wall
Journal: Journal of Clinical Oncology (2021)

e12559 Background: Pregnancy associated breast cancer (PABC), defined as breast cancer diagnosed during or within one year after pregnancy, occurs approximately once in every 3,000 pregnancies and accounts for up to 6.9% of all breast cancers in women ≤ 45 years. Compared to age-matched non-PABC patients, PABC is generally characterized by a particularly aggressive histopathologic profile (more ER-, PR- and HER2 negative tumors and tumors of higher grade) with a higher mortality rate. Whether these cancers arise before or during pregnancy, and whether their genetic profile differs from non-PABC tumors, is currently unknown. This study assesses the genetic background of PABC by detection of specific DNA copy number alterations (CNA). Methods: We assembled 29 triple-negative PABC patients from the Dutch nationwide pathology database (PALGA). From their formalin-fixed and paraffin embedded (FFPE) tumor tissue blocks, DNA was extracted. Multiplex Ligation-Dependent probe Amplification (MLPA) analysis was performed for detection of CNAs in 20 oncogenes and 2 tumor suppressor genes using the P078-D2 kit (MRC Holland). Individual gene copy number loss (MLPA ratio &lt; 0.7), gain (ratio 1.3-2.0) and amplification (ratio &gt; 2.0) was determined and unsupervised hierarchical cluster analysis was performed to identify differences in copy number (CN) patterns between PABC patients. Chi square statistics were used to interrogate associations with clinicopathologic characteristics. Log-Rank test was used to compare Kaplan Meier survival curves between CN subgroups. Results: Triple negative PABC tumors showed frequent copy number loss on chromosome 17q ( CPD, MED1, TOP2A, MAPT, PPM1D) and 8p ( ZNF703 and ADAM9), as well as frequent copy number gain/amplification of MYC (8q) and CCND1 (11q). Cluster analysis identified 2 clusters of PABC patients based on their tumor copy number patterns: a CN-neutral cluster and a CN-high cluster, the latter demonstrating significantly lower chromosome 17 copy numbers than the former (for PPM1D, ERBB2, CPD, MED1, TOP2A, CDC6 and MAPT). Patients with CN-neutral tumors more often showed lymph node metastases (p = 0.028), were of significantly higher stage (p = 0.031), and demonstrated a worse overall survival (p = 0.036) compared with PABC patients harboring CN-high tumors. Conclusions: We demonstrate different tumor CN patterns within a small group of triple negative PABC-patients, associated with distinct aggressiveness. This will form the basis for further in-depth genetic profiling within a larger Dutch PABC cohort, rendering insight in the disease progression and contributing to the development of more targeted and personalized treatments.
The timeliness of lung cancer care: A systematic review of systematic/scoping reviews on risk factors and interventions.
Authors: Jianrong Zhang, Jasmeen Oberoi, Napin Karnchanachari, Paige Druce, Maarten J. IJzerman, Jon D. Emery
Journal: Journal of Clinical Oncology (2021)

e18575 Background: Lung cancer is the leading cause of cancer death worldwide, and over half of lung cancer cases are diagnosed with advanced stage, indicating an urgent need to improve the timeliness of lung cancer services. In this systematic review of systematic and scoping reviews, we summarize the current evidence of risk factors and interventions on diagnostic and treatment intervals. Methods: Eligible articles were published systematic or scoping reviews and meta-analyses that used systematic searching to investigate risk factors for longer time intervals or interventions aimed to reduce time intervals in original studies on lung cancer, based on at least one interval involving the date of diagnosis as the start or end point. Articles were searched via PubMed, Embase, Web of Science, and the Cochrane Library; the date range of the search was from database inception to 6 August 2020 (PROSPERO identifier: CRD42020203530). Results: A total of 16 systematic/scoping reviews published in 2002-2020 were included (10 on risk factors and 9 on interventions). According to these reviews, we found that risk factors had intersected impacts on the increase of diagnostic and treatment intervals. However, these factors could be summarized based on tumor, patient, healthcare provider and healthcare system levels as: (tumor level) adenocarcinoma, small size; (patient level) living in a rural area, lower education level, lower-income level, longer travel distance, non-specific symptom, non-white race (in the USA), fear and lack of knowledge about lung cancer; (healthcare provider level) low index of suspicion, multiple consultations for diagnosis, missed diagnosis; (healthcare system level) long waiting time for hospitalization, health system’s incapacity to treat all patients, high cost, inaccessibility or lack of diagnostic tools/investigations, poor organization and management of health services. To reduce time intervals, these reviews indicated that effective interventions include multidisciplinary teams or clinics, lung-specific clinics, nurse navigation or other care coordination program. In these reviews, we found that the types of time intervals used in original studies were poorly reported. Conclusions: Therisk factors identified from the current reviews indicate disparities in timely access to lung cancer services, as well as potential for improvements to reduce waiting time at the patient, healthcare provider and healthcare system levels. To reduce waiting time, effective interventions suggested from the current reviews should be considered for implementation.
The IL-8-CXCR1/2 axis contributes to diabetic kidney disease
Authors: Cristian Loretelli, Francesca Rocchio, Francesca D'Addio, Moufida Ben Nasr, Eduardo Castillo-Leon, Sergio Dellepiane, Andrea Vergani, Ahmed Abdelsalam, Emma Assi, Anna Maestroni, Vera Usuelli, Roberto Bassi, Ida Pastore, Jun Yang, Basset El Essawy, Khalid M. Elased, Gian Paolo Fadini, Elio Ippolito, Andy Joe Seelam, Marcus Pezzolesi, Domenico Corradi, Gian Vincenzo Zuccotti, Maurizio Gallieni, Marcello Allegretti, Monika Anna Niewczas, Paolo Fiorina
Journal: Metabolism (2021)
The lung cancer obesity paradox: An analysis of 432,924 patients.
Authors: Brittany Miles, James David Mackey
Journal: Journal of Clinical Oncology (2021)

10578 Background: The lung cancer obesity paradox is the unexpected inverse relationship between body mass index (BMI) and lung cancer mortality. While there is a growing body of evidence to support the existence of the obesity paradox in lung cancer, little is known about its magnitude and relationship to cancer incidence and its impact on outcomes from surgery, chemotherapy, immunotherapy, and radiation treatment. Methods: To evaluate the impact of obesity on lung cancer incidence, we used TriNetX, a global federated health research network providing access to electronic medical records (diagnoses, procedures, medications, laboratory values, genomic information) from approximately 69 Million patients in 49 large Healthcare Organizations. We evaluated 2 patient cohorts of 216,462 adult smokers aged 18 to 75 that were matched for age, race, gender, and ethnicity. One cohort of patients carried a diagnosis of overweight and obesity (ICD-10 code E66), while the other cohort required exclusion of those diagnoses. Results: We found a statistically significant decrease in lung cancer incidence for patients with obesity (1.407% vs 2.039%, p &lt; 0.0001), in addition to superior overall survival (95.344% vs 92.039%, p &lt; 0.0001). A subset analysis of patients who contracted lung cancer showed a statistically significant benefit in median survival in favor of patients with overweight and obesity (851 vs 602 days, p value 0.0009). Conclusions: These findings support the existence of the obesity paradox in lung cancer, and its positive impact on both lung cancer incidence and outcome.
Prevalence of potential drug-drug interactions among nonmetastatic castration-resistant prostate cancer patients treated with apalutamide and enzalutamide.
Authors: Sreevalsa Appukkuttan, Chunmay Fu, Yuxian Du, Ashley Cha, Jacqueline Parkin, Andrew Gaiser, Jamie Partridge, Sheldon Kong, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2021)

e18690 Background: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are often treated with concurrent medications for the management of comorbid conditions. This increases the risk of drug interactions which may lead to compromised efficacy and safety of nmCRPC therapies. This study aimed to characterize potential drug-drug interactions (pDDIs) with the novel anti-androgen (AA) agents enzalutamide (Enza) and apalutamide (Apa) in a real-world nmCRPC population. Methods: We analyzed Optum Clinformatics Data Mart, a large claims database from January 1, 2017, through March 31, 2020. The study population included adult males with prostate cancer, evidence of castration, &gt;1 pharmacy claim for Apa or Enza (index date defined as drug initiation), and without codes for metastases. Darolutamide, a more recently approved AA, was not included due to lack of data. Concomitant medications were defined as therapy with at least 1 day overlap with Apa and Enza. The top concomitant medications covering 99% of Apa and Enza population were assessed for pDDI using Micromedex, Lexicomp, and Drugs.com compendia. Results: We identified 149 Apa and 319 Enza patients with mean age 77 years across groups. The study population was primarily white (56.3% Apa; 56.7% Enza) and had Medicare insurance (81.0% Apa; 82.2% Enza). Mean Charlson comorbidity index scores were similar for each group (Apa: 2.3 [SD: 4.1]; Enza: 2.4 [SD: 2.4]). Polypharmacy was common in both groups, with the majority taking ≥5 medications (Apa: 79.8%; Enza: 75.9%). Of the co-medications included in this analysis, Micromedex, Lexicomp and Drugs.com flagged 12, 38 and 53 pDDIs for Apa, and 7, 35 and 49 pDDIs for Enza, respectively. A pDDI was identified for 35% Apa and 21% Enza patients using Micromedex and &gt;80% of Apa and Enza patients using other compendia. The pDDIs by severity and risk rating as defined by the respective compendia are shown in Table. Specifically, 4 interactions for Apa and 1 for Enza were rated X (i.e., avoid combination). Conclusions: This study finds a high prevalence of pDDIs among Apa and Enza patients signifying the need for strict monitoring while initiating these therapies. Given the high prevalence of polypharmacy and comorbidities among nmCRPC, these patients may benefit from drugs with lower interaction potential. Future real-world analyses should be conducted to characterize the clinical and economic impact of these pDDIs as well as to assess pDDI for darolutamide. [Table: see text]