tbuckley/cabot-search huggingface dataset:
The Individualized Medical Pathways for Advanced Care and Treatment Program (IMPACT): Facilitating access to innovative clinical care.
Authors: Shannon Kieran, Frank Papatheofanis, Paul Billings
Journal: Journal of Clinical Oncology (2014)

e17513 Background: Access to new technology for the diagnosis and treatment of cancer is crucially important to cancer patients. However, commercial and federal payers of health care often wait for FDA approval, randomized control trials of effectiveness and utility, and professional society guideline adoption before covering and reimbursing diagnostic and therapeutic innovations. To assess the impact of technology access on cancer care, we created a unique employee benefit for self-insured employers, providing guided access to advanced cancer assessments, approved treatments, and clinical trials, at no cost to the employee. Methods: Enrollment criteria were established that included a diagnosis of cancer and program availability only to an employee, their spouse or domestic partner, and the employee’s dependent children. HR, Legal and IT teams created necessary consent documents, firewalled the benefit data from employee records, and established HIPAA compliant communications. The benefit program includes eligibility review, program navigation, cancer genetic counseling, a medical expert second opinion service, the creation of diagnostic and therapeutic roadmaps as well as an assessment of compliance with current standards of care and clinical trial matching. Results: We estimated from claims data that among the approximately 10,000 employees, about 100 cases of active cancer could be expected per year. During the first 10 months, 32 employees completed enrollment in the benefit program. Advanced genomic and molecular testing on 15 participants, averaging a cost of $6,014 per participant, revealed significant molecular changes in the somatic and/or germline cells in all cases. Significant findings included somatic mutations enabling personalized cancer therapies. Unexpected findings included germline mutations revealing hereditary cancer syndromes that would not otherwise have been detected through family history analysis. Conclusions: A unique technology benefit for cancer patients was launched at a large, self-insured employer. High program satisfaction and many valuable unexpected results have been produced in the first cohort of beneficiaries.
Treating Disease at the RNA Level with Oligonucleotides
Authors: Arthur A. Levin
Journal: New England Journal of Medicine (2019)

Interview with Dr. Arthur A. Levin on the use of oligonucleotide drugs that regulate RNA. (10:24)Download As research on the structure and function of RNAs has rapidly expanded, so too has the number of oligonucleotide drugs in clinical development that regulate RNA. This article describes several examples and suggests where the field is headed.
Hypoxia, angiogenesis, and metabolism in the hereditary kidney cancers
Authors: John C. Chappell, Laura Beth Payne, W. Kimryn Rathmell
Journal: Journal of Clinical Investigation (2019)

The field of hereditary kidney cancer has begun to mature following the identification of several germline syndromes that define genetic and molecular features of this cancer. Molecular defects within these hereditary syndromes demonstrate consistent deficits in angiogenesis and metabolic signaling, largely driven by altered hypoxia signaling. The classical mutation, loss of function of the von Hippel-Lindau (VHL) tumor suppressor, provides a human pathogenesis model for critical aspects of pseudohypoxia. These features are mimicked in a less common hereditary renal tumor syndrome, known as hereditary leiomyomatosis and renal cell carcinoma. Here, we review renal tumor angiogenesis and metabolism from a HIF-centric perspective, considering alterations in the hypoxic landscape, and molecular deviations resulting from high levels of HIF family members. Mutations underlying HIF deregulation drive multifactorial aberrations in angiogenic signals and metabolism. The mechanisms by which these defects drive tumor growth are still emerging. However, the distinctive patterns of angiogenesis and glycolysis-/glutamine-dependent bioenergetics provide insight into the cellular environment of these cancers. The result is a scenario permissive for aggressive tumorigenesis especially within the proximal renal tubule. These features of tumorigenesis have been highly actionable in kidney cancer treatments, and will likely continue as central tenets of kidney cancer therapeutics.
A phase I study with LTX-315, an immunogenic cell death inducer, in patients with transdermally accessible tumors.
Authors: Paal Brunsvig, Steinar Aamdal, Arne Kolstad, Olav Inge Haaskjold, Robert M. Miller, Oystein Rekdal, Berit Nicolaisen, Wenche Marie Olsen
Journal: Journal of Clinical Oncology (2014)

3067 Background: LTX-315, a chemically modified 9-mer peptide derived from naturally occurring membrane-active host defence peptides, induces the release of potent danger signals (i.e. HMGB1) and tumor-associated antigens from treated tumor cells. Preclinical animal studies have demonstrated that treatment of a single tumor with LTX-315 generated a systemic anti-tumor immune response that eradicated distant lesions and prevented reoccurrence following tumor rechallenge. A phase I dose escalating open label, single centre study was designed to evaluate safety profile and determine recommended dose as measured by assessment of adverse events, laboratory values and tumor necrosis. Immunological responses to the injections were exploratory endpoints. Methods: Patients received weekly ultrasound guided injections of LTX-315 into a single tumor for a maximum of six injections. Cohorts 1 and 2 received 10% of the tumor volume until DLT or ≥ 50% necrosis of target tumor was observed. In cohort 3, a fixed dose of 4 mg was injected. Results: Fourteen patients with lymphomas, malignant melanomas or breast cancer were enrolled. The main safety issue was primarily flushing and transient hypotension related to the dose of study drug and independent of tumor type. Two patients experienced a DLT (hypotension grade 3 and 4). Tumor necrosis was seen in 5 patients. Two of the patients had a reduction in tumor volume ≥ 50%. Tissue necrosis and presence of tumor infiltrating lymphocytes (TILs) was observed in a breast cancer tumor. Conclusions: Based on the safety information it seems as LTX-315 is causing reactions that can be controlled by limiting the dose injected into the tumor; dosages ≤ 4.0 mg are well tolerated. The signs of tumor necrosis, presence of TILs and tumor regression without accompanying severe reactions confirms the rationale and the potential benefit of intratumoral injections with LTX-315. A new intratumoral study with LTX-315 at four European sites is ongoing with detailed characterization of immune response. Clinical trial information: NCT01058616.
Bayesian network meta-analysis, comparison of cardiac events associated with liposomal doxorubicin, epirubicin, and doxorubicin in breast cancer.
Authors: Norihiro Yamaguchi, Takeo Fujii, Shunsuke Aoi, Gabriel N. Hortobagyi, Ronald H. Blum
Journal: Journal of Clinical Oncology (2014)

1056 Background: Anthracyclines have the potential for causing cardiac events (CE). Given minimal evidence based data predicting CE rates, a Bayesian network meta-analysis (NMA), a validated statistical methodology provides direct and indirect comparison among different regimens. Methods: We conducted a systematic review of prospective randomized controlled trials through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Google Scholar comparing non-anthracycline based regimen (Non), doxorubicin (Dox), epirubicin (Epi), and liposomal doxorubicin (LD). We included studies published up to January 1, 2014, adjuvant and metastatic regimens, but not HER2/neu inhibitor containing regimens. Studies were included in the NMA with consensus of two authors. Our outcome measure was cardiac events greater than CTCAE grade 3. Bayesian NMA was conducted to estimate pooled Odds Ratio (OR). Results: Nineteen randomized controlled trials met criteria. We found a trend showing that LD is less cardiotoxic than Dox with an OR of 0.60 and 95% confidence interval (CI) [0.34-1.07]. There was no difference between Epi and LD with an OR of 0.95 and 95%CI [0.39-2.33]. Dox is more cardiotoxic than Non with an OR of 1.57 and 95%CI [0.90-2.72]. Conclusions: Our study showed that LD trended with a lower CE rate compared to Epi and Dox, but the difference did not reach statistical significance. One of the reasons is likely the small number of CE. Based on this analysis and given the low CE rate in the clinical context of the selected trials, the potential for cardiac toxicity need not be a major factor in clinical decision making. Comparison Pooled OR 95% CI LD vs Dox 0.60 0.34-1.07 LD vs Epi 0.95 0.39-2.33 Dox vs Non 1.57 0.90-2.72
Antimyeloma Effect of the Simultaneous Inhibition of MCL-1 (with S63845) and BCL-2 (with Venetoclax) in the Presence of the Microenvironment
Authors: Esperanza M Algarín, Andrea Díaz-Tejedor, Pedro Mogollón, Susana Hernández-García, Luis Corchete, Laura San-Segundo, Montserrat Martín-Sánchez, Lorena González-Méndez, Marie Schoumacher, Sébastien Banquet, Laurence Kraus-Berthier, Ioana Kloos, Ensar Halilovic, Heiko Maacke, Norma C. Gutierrez, Maria-Victoria Mateos, Teresa Paíno, Mercedes Garayoa, Enrique M. Ocio
Journal: Blood (2018)
The activity of ruxolitinib in controlling the disease manifestations and improving the quality of life in systemic mastocytosis.
Authors: Abdulraheem Yacoub
Journal: Journal of Clinical Oncology (2014)

e18025 Background: Systemic mastocytosis (SM) is characterized by proliferation of malignant mast cells (MC), and MC degranulation resulting in chronic and episodic release of cytokines which result in variable, often life-threatening, manifestations. Treatment of SM is challenging and is mostly palliative. Cytoreductive agents have modest success and do not eliminate MC degranulation. Current therapy focuses on symptom management, avoiding MC degranulation. We report a successful approach to treating SM symptoms after cytoreductive therapy in a single patient. Methods: A 30 year old woman was diagnosed with childhood Aggressive SM. KIT mutation analysis showed a rare K509I mutation that is sensitive to imatinib. She was treated with imatinib 100 mg daily and achieved a durable complete response. Nonetheless, she continued to suffer degranulation symptoms including disabling fatigue, flushing, skin erythema and chronic bone pain. The patient was offered therapy with ruxolitinib. Ruxolitinib dose was titrated for response and side effects. Symptoms and quality of life (QOL) were evaluated by EORTC QLQ-C30 (Version 3.0), MPN-SAF, BFI, and PGIC. Results: Grade 1 anemia developed while on 20 mg BID of ruxolitinib and resolved with dose reduction. There was a weight gain of 6.7 kg limited to the first 3 months. There were no unexpected toxicities. There was a marked improvement in bone pain, 50% reduction in analgesics requirement, complete resolution of flushing, erythema, and itching. The patient had marked improvement in QOL, > 80% reduction on her symptoms score, > 50% improvement of her fatigue (BFI) and improvement in PGIC. Conclusions: Despite maximal cytoreduction, microscopic residual disease persists and is responsible for significant morbidity. Ruxolitinib is effective in improving symptoms and QOL in patients with other MPNs. Ruxolitinib therapy in this patient significantly improved symptoms, pain, fatigue, and QOL. This was not associated with unexpected adverse events in combination with imatinib. Prospective clinical trials evaluating the role of ruxolitinib in SM are needed.
Impact of radical treatments in the quality of life for patients with advanced buccal mucosa cancers: A one-year longitutdinal study.
Authors: Sudhir Vasudevan Nair, Shrinivas Narayan Rathod, Santosh Nikam, Tejpal Gupta, Pankaj Chaturvedi, Rajiv Sarin, Jaiprakash Agarwal
Journal: Journal of Clinical Oncology (2014)

e17034 Background: Quality of life (QOL) is a major issue in Head Neck cancers (HNC). Till date QOL issues in buccal mucosa cancers as a separate entity has not been reported separately. This study reports QOL patterns in radically treated buccal mucosa cancers. Methods: Newly diagnosed 199 cases of HNC patients from undergoing clinical trials at Advanced Centre for Treatment, research and education in cancer (ACTREC), India treated with surgery followed by adjuvant treatment were included and studied. QOL was assessed with European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the EORTC QLQ-H&N35 questionnaires before treatment and at 3, 6, 9 and 12 months. Mean QOL scores for each domain were evaluated longitudinally using ANOVA. Results: Median age of presentation was 48 years (range 26-72 years) with Male: Female ratio as 165 (83%): 34 (17%). Pathological T stage distribution T1:T2:T3:T4 was 7(3.5%): 30(15%): 9(4.5%): 153(77%) and Nodal distribution was N0: N1:N2:N3 was 95(48%): 31(15.5%): 71 (36%): 1(0.5%) respectively. Adjuvant radiation was received by 166 (83%) and 132 (66%) received adjuvant chemotherapy. Majority of population had advanced disease at presentation. Global QOL score mean was 46 at presentation and with treatment it improved considerably and was statistically significant over all the time points. Similarly, insomnia, pain and pain killer requirement also showed statistically significant improvement over all the time points. Physical functioning scores had a statistically significant deterioration at 3 months; but was followed by a gradual recovery. Other major domains showed a transient non significant deterioration in scores at 3 months followed by recovery to pretreatment levels by 6 months. Conclusions: Quality of life burden is considerable in advanced buccal mucosa cancers. Standard radical treatment improved majority of QOL parameters and none of QOL domains was worsening with treatment. Contrary to the expectation of a post treatment transient deterioration, Global quality of life, pain, insomnia had a continuous significant improvement with treatment.
Cost-minimization analysis of tbo-filgrastim and filgrastim.
Authors: Gisoo Barnes, Ashutosh Pathak, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2014)

e17550 Background: Tbo-filgrastim (Granix) and filgrastim (Neupogen) are commercially available, short-acting granulocyte colony-stimulating factors with comparable efficacy and tolerability for the reduction of the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive chemotherapy at a ≥ 20% risk of febrile neutropenia. We performed a cost-minimization analysis to estimate the patient-level costs and annual incremental costs/savings for tbo-filgrastim compared with filgrastim in the United States (US). Methods: A Microsoft Excel model was utilized that allows users to customize the model to best reflect their health plan characteristics. Based on the projected number of patients that may be treated with tbo-filgrastim following its introduction to the market vs filgrastim, the potential annual costs/savings for a larger patient population was estimated. Annual wholesale acquisition cost (WAC) was calculated based on 10 doses/package, 1 dose/day for 10 days/chemotherapy cycle for an average of 6 cycles/year of myelosuppressive chemotherapy eligible for growth factor support. Results: Estimated WAC/package costs for tbo-filgrastim (estimated potential cost), filgrastim prefilled syringes (PFS), and filgrastim vials (costs from RedBook online) were $3,825.00, $4,939.20, and $4,658.80, respectively. Tier 3 formulary status was assumed, with a copay of $51.00 and projected administration costs of $25.86 (2013 Medicare Physician Fee Schedule payment rates). The aggregated filgrastim cost/patient was calculated using a weighted average assuming 40% utilization of PFS and 60% of vials based on utilization data. An annual cost difference of $5,055 per US patient for filgrastim minus tbo-filgrastim was estimated. Annual savings assuming 1000 US patients treated with tbo-filgrastim vs filgrastim was estimated at >$5 million. Conclusions: This cost-minimization analysis suggests that tbo-filgrastim provides greater cost savings than filgrastim to reduce the duration of severe neutropenia in US patients with nonmyeloid malignancies treated with myelosuppressive chemotherapy.
Reappraisal of conventional risk stratification for local recurrence based on clinical outcomes in 285 resected phyllodes tumors of the breast.
Authors: Cha Kyong Yom, Wonshik Han, Sung-Won Kim, Dong-Young Noh
Journal: Journal of Clinical Oncology (2014)

e22217 Background: A second resection has been recommended, to ensure a surgical margin of ≥ 1 cm for the effective treatment of phyllodes tumor of breast (PTB), but the outcomes of an extensive series of cases casts this clinical approach in doubt. To identify the local recurrence risk factors of PTB and determine future optimal surgical treatment according to verified risks. Methods: All cases given a diagnosis of PTB and resected between 1989 and 2008 were retrospectively evaluated. Clinicopathologic data and clinical outcomes were analyzed and stratified according to the risks for local recurrence (LR). Results: All 285 cases occurred and 200 (70.2%) categorized as benign, 51 (17.9%) as borderline, and 34 (11.9) as malignant. Median follow-up was 6.7 years and during follow-up, there were 20 LRs. All benign PTBs recurred as benign PTB lesions. Mitosis (p = 0.007) and tumor size (p = 0.029) were independent prognostic factors for LR in multivariate analysis. Neither margin status (p = 0.836) nor type of surgery (p = 0.627) had any significance for LR. In the risk stratification for LR, PTBs sized 2 - 5cm with ≥ 10 mitoses / 10 HPF had the highest LR rate (60%) compared with all other groups (p< 0.001). Conclusions: OnlyPTB with 2-5 cm and frequent mitoses, is it recommended to follow to ascertain a wide excision and clear margin of 1 cm, it necessary by means of a 2nd surgery could be considered to avoid the risk of LR in this distinct group. Clinical trial information: KCT0000945.Local recurrence rate according to grouping by tumor size and mitosis. Mitosis 0~9/10HPF ≥ 10/10HPF Tumor size Group 1 Group 2 ≤ 2cm N = 61 LRR = 1.6% (1/61) N = 1 LRR = 0.0% (0/1) Group 3 Group 4 2cm < and ≤ 5cm N = 115 LRR = 8.7% (10/115) N = 5 LRR = 60.0% (3/5) Group 5 Group 6 > 5cm N = 33 LRR = 3.0% (1/33) N = 15 LRR = 0.0% (0/15)
Impact of state-specific Medicaid policies on timely receipt of breast cancer surgery.
Authors: Michael T. Halpern, Susan G. Haber, Heather A. Beil
Journal: Journal of Clinical Oncology (2014)

6500 Background: Reports have demonstrated barriers in access to and quality of care for Medicaid enrollees, including enrollees with cancer. State-specific Medicaid eligibility policies and low reimbursements for medical care services provided to enrollees with cancer may hinder receipt of high-quality cancer treatment. This study examined how eligibility and reimbursement policies affect timely receipt of breast cancer surgery among Medicaid enrollees diagnosed with breast cancer. Methods: The study utilized 2006-2008 Medicaid data for all women 21-64 years of age diagnosed with breast cancer and enrolled in fee-for-service Medicaid for at least 4 months. We examined the association of state-specific Medicaid breast surgery reimbursements, Medicaid income eligibility requirements, and frequency of Medicaid eligibility renewal on time from diagnosis to receipt of breast cancer surgery. Analyses used multivariate logistic regressions controlling for correlation between beneficiaries within a state. Results: We identified 10,968 Medicaid enrollees with breast cancer. Lower reimbursements for breast cancer surgery were associated with greater delays for breast conserving surgery, mastectomy, and all breast cancer surgery combined. Shorter time periods for Medicaid eligibility renewal were also associated with greater surgery delays. Income eligibility thresholds did not affect delays. Black, Hispanic, and blind/disabled patients had greater delays, while older patients were less likely to experience delays. Conclusions: Low reimbursements were associated with less timely surgery for Medicaid enrollees with breast cancer. In addition, within the Medicaid population, disparities in timeliness of surgery based on patient race, age, and eligibility category were observed. With substantial expansion of Medicaid expected as part of the Affordable Care Act, state legislators and health policy makers need to consider how reimbursements affect receipt of high quality care and develop programs to address disparities within this vulnerable population.
Intraoral JP4-039 to ameliorate irradiation-induced mucositis in tumor-bearing Fanconi anemia (FA) mouse model.
Authors: Ashwin Shinde, Byung Han Rhieu, Hebist Berhane, Michael W. Epperly, Eva Guinan, Kalindi Parmar, Hong Wang, Darcy Franicola, Xichen Zhang, Tracy Dixon, Joel S. Greenberger
Journal: Journal of Clinical Oncology (2014)

2571 Background: The DNA repair defect in Fanconi anemia (FA) patients makes radiotherapy of head and neck cancers a challenge due to mucositis as a dose limiting toxicity. We tested intraoral delivery of mitochondrial-targeted antioxidant, JP4-039, in a novel F15 emulsion, to reduce mucositis in fractionated irradiated FA mice with orthotopic tumors. Methods: Fancd2+/+, Fancd2+/-, and Fancd2-/-mice from C57BL/6J background with palpable tumors, measureable by calipers, were irradiated to single 28 Gy or 8 Gy x 4 daily fractions to the oral cavity. Subgroups of mice (N=4/group) received intraoral JP4-039/F15 (100 ul containing 4 mg/ml of drug) 10 minutes prior to irradiation, F15 alone or irradiation alone. Tumor size was measured daily. Five days after the last radiation dose, mice were sacrificed, and tumors and tongue tissue removed for histopathology. Statistical analysis was performed using Students t-test, with a p-value < 0.05 considered significant. Results: Intraoral JP4-039/F15 prior to irradiation significantly decreased oral cavity ulceration (p < 0.001). Following 8 Gy x 4, F15-JP4-039 treated Fancd2-/- knockout mice had 47.8 ± 11.1% of the tongue ulcerated compared to 81.7 ± 11.6% ulceration in untreated mice (p < 0.001). Results in JP4-039/F15 treated irradiated heterozygotes and wild-type Fancd2+/+ mice (34.1 ± 21.2 or 16.9 ± 12.6% ulceration, respectively) were also improved compared to untreated irradiated mice (88.3 ± 8.0 or 76.3 ± 17.2% ulceration, respectively) (p < 0.001 for all groups). F15 alone did not reduce ulceration. JP4-039/F15 treated FA mice had increased ulceration compared to Fancd2+/+ mice (47.8 ± 11.1% and 16.9 ± 12.6% respectively, p < 0.0001). Both single fraction and fractionated radiation treatment controlled tumors at 5 days in Fancd2+/+, Fancd2+/-, and Fancd2-/- mice (0.4 ± 0.3, 0.05 ± 0.05, or 0.1 ± 0.1 mm3, respectively) compared to nonirradiated controls (2.1 ± 0.4, 1.9 ± 0.5, or 3.1 ± 0.1 mm3, respectively, p < 0.027). Tumor size was comparably reduced in all irradiated groups. Conclusions: Intra oral JP4-039 protects normal tissue in irradiated FA mice without associated tumor protection.