tbuckley/cabot-search huggingface dataset:
Deflexifol (a novel formulation of 5FU): Phase 1 dose escalation study of infusional and bolus schedules after failure of standard treatment.
Authors: Philip R. Clingan, Stephen P. Ackland, Marie Ranson, Daniel Brungs, Morteza Aghmesheh, Ali Tafreshi, Madhu Bala Garg, Suzanne Parker, Anne Henderson, Rebecca Jokela, Paul L. De Souza
Journal: Journal of Clinical Oncology (2017)

2529 Background: 5-Fluorouracil (5FU) is administered in combination with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible as 5FU and LV are chemically incompatible, so the maximum possible interaction for benefit is not achieved Deflexifol, an all in one formulation of 5FU/LV with cyclodextrin (HP-β-CD 100mg/ml, 5-FU 15mg/ml &amp; LV 1mg/ml) at physiological pH, was developed to improve efficacy and tolerance. Methods: A phase I dose-escalation trial to assess the safety, tolerability, MTD and DLT of Deflexifol given in two schedules has been completed. Secondary objectives included the pharmacokinetic (PK) profile and efficacy outcomes. Cohorts of patients with advanced malignancy after failure of standard treatment received Deflexifol as 46-h infusion Q2W or bolus weekly x6 in a standard 3+3 phase I design with no intra-patient dose escalation from dose level 1: 375mg/m² bolus or 1200mg/m² infusional up to dose level 5: 575mg/m² bolus or 3600mg/m² infusional. PK sampling of 5FU and dihydroFU was conducted on all patients to assess PK variability and adequacy of dosing. Results: 40 patients (21 infusional, 19 bolus) with breast (7), colorectal (24), other GI (6) &amp; NSCLC (3) received a total 293 courses of treatment. No &gt; grade 1 toxicity was noted at 375-475 mg/m 2 bolus, or at 1200-2400 mg/m 2 infusion. The DLT in bolus schedule was grade 3 diarrhea and myelosuppression at 575 mg/m 2 , with no DLT in the infusion schedule at the maximum dose 3600 mg/m 2 . The MTD have been established for both treatment arms: bolus 525mg/m²; 46-h infusion 3,600mg/m², with no grade IV toxicity observed. Other grade 3 toxicities were nausea, vomiting, and raised liver function tests. 5FU PK in this mixture is similar to 5FU alone. Encouraging efficacy results were seen with partial response in 1 patient and stable disease in 23 patients. Median PFS was (12.3 wks) and OS was (24.8 wks). Conclusions: Deflexifol has little toxicity and is effective in bolus and infusion schedules at doses equal to or greater than those feasible with 5FU and LV infused separately. A first-line phase II study in combination with oxaliplatin is planned. Clinical trial information: 044867.
Abstract 19241: Evolving Techniques and Outcomes in Left Main Pci With Des
Authors: Jérôme Van Rothem, Nicolas boudou, Julien Rosencher, Jean Fajadet, Didier Carrie
Journal: Circulation (2013)

Objective: To evaluate the impact of technical evolutions on clinical outcomes for patients undergoing percutaneous coronary intervention (PCI) with drug eluting stent (DES) for left main (LM) disease. Background: PCI techniques and materials are improving. Those evolutions could have a positive clinical impact for patients undergoing PCI for LM disease. Methods: We compared baseline characteristics, procedural and clinical outcomes in 601 consecutive patients undergoing PCI for LM stenosis with DES from 2004 to 2009. Patients were analyzed in 3 separate groups according to the PCI timing: 2004/2005 (group 1); 2006/2007 (group 2); 2008/2009 (group 3). The primary outcome was death at 1-year. Results: Comparing to 2004/2005, patients undergoing PCI in 2008/2009 were at higher risk (Logistic Euroscore 8.4±0.7% in group 3 vs. 7.4±0.6% in group 1; p=0.045). The radial approach was increasingly used (28.2% in 2004/2005; 34.2% in 2006/2007 and 61.4% in 2008/2009; p&lt;0.0001), a predilation was more frequently performed (32.1% in 2004/2005; 42.7% in 2006/2007 and 45.8% in 2008/2009; p=0.046) and a second generation DES was more frequently used (38.2% in group 3 vs. 0% in group 1; p&lt;0.0001). The stent diameter significantly increased with time (3.5±0.02mm in group 1; 3.6±0.02mm in group 2; 3.7±0.02mm in group 3; p&lt;0.0001) and a post dilation was more often performed (32.1% in group 1; 37.9% in group 2; 46.4% in group 3; p=0.021). One-year mortality is significantly decreasing with time (9.9% in 2004/2005; 8.9% in 2006/2007; 4.1% in 2008/2009; p=0.028), and this difference is driven by fewer deaths in patients treated for distal LM (13.2% in 2004/2005; 8.6% in 2006/2007; 4.2% in 2008/2009; p=0.033). Conclusion: In this observational study, clinical outcome are improving for patients undergoing LM PCI with DES, because of fewer death at one year for patients with a distal LM lesion.
Cathepsin K Inhibitors for Osteoporosis: Biology, Potential Clinical Utility, and Lessons Learned
Authors: Matthew T Drake, Bart L Clarke, Merry Jo Oursler, Sundeep Khosla
Journal: Endocrine Reviews (2017)

Cathepsin K is a cysteine protease member of the cathepsin lysosomal protease family. Although cathepsin K is highly expressed in osteoclasts, lower levels of cathepsin K are also found in a variety of other tissues. Secretion of cathepsin K from the osteoclast into the sealed osteoclast–bone cell interface results in efficient degradation of type I collagen. The absence of cathepsin K activity in humans results in pycnodysostosis, characterized by increased bone mineral density and fractures. Pharmacologic cathepsin K inhibition leads to continuous increases in bone mineral density for ≤5 years of treatment and improves bone strength at the spine and hip. Compared with other antiresorptive agents, cathepsin K inhibition is nearly equally efficacious for reducing biochemical markers of bone resorption but comparatively less active for reducing bone formation markers. Despite multiple efforts to develop cathepsin K inhibitors, potential concerns related to off-target effects of the inhibitors against other cathepsins and cathepsin K inhibition at nonbone sites, including skin and perhaps cardiovascular and cerebrovascular sites, prolonged the regulatory approval process. A large multinational randomized, double-blind phase III study of odanacatib in postmenopausal women with osteoporosis was recently completed. Although that study demonstrated clinically relevant reductions in fractures at multiple sites, odanacatib was ultimately withdrawn from the regulatory approval process after it was found to be associated with an increased risk of cerebrovascular accidents. Nonetheless, the underlying biology and clinical effects of cathepsin K inhibition remain of considerable interest and could guide future therapeutic approaches for osteoporosis.
Triple negative breast cancer: An Indian problem— Experience from a tertiary care oncology centre.
Authors: Sameer Gupta, Jeetendra Paryani, Arun Chaturvedi, Vijay Kumar, Naseem Akhtar
Journal: Journal of Clinical Oncology (2017)

e12583 Background: Breast cancer is a heterogeneous disease with distinct biological subtypes as determined by gene expression profiling studies. Breast cancer is most common cancer in Indian females and is believed to be biologically different from west, notably in terms of high prevalence of Triple negative subtype (TNBC). Reliable data on clinical and epidemiological profile of TNBC in Indian population is scarce. Aim of this study was to analyze the epidemiological and clinical profile of TNBCs Methods: Data of 355 patients of breast cancer registered in our department between 2013 and 2015 and followed up until December 2016 was collected and reviewed for epidemiological and clinical features Results: Of total 355 patients analysed, TNBC group was most common (n = 152) (43%) followed by Luminal A (25%). Median age at disease presentation in TNBC was 42.4 years compared to overall age of 45.3 years (24–73 years). In TNBC subgroup, 48% patients presented in locally advanced and 15% in metastatic stage, more commonly in pre-menopausal patients. Overall 268 (76%) patients underwent surgery with Modified radical mastectomy being preferred surgical option (86%), followed by adjuvant chemotherapy. TNBC subgroup demonstrated low response rate to neoadjuvant chemotherapy with only 9% of patients having complete response and 25% patients having progressive disease. Median followup was 34 months (6 50 months). Of the total recurrences (n = 19), nearly 2/3rd (n = 13) were documented in TNBC subgroup. Disease free survival (DFS) of TNBC subgroup was lower than of other luminal subtypes (p = .043) Conclusions: TNBC was the most common breast cancer subtype (43%) in Indian population which is nearly twice the rate reported in Western countries. This finding has significant clinical relevance as it may contribute to poor outcomes in Indian patients. Our study also corraborated this fact with higher prevalence of premenopausal breast cancer, poor response to neoadjuvant chemotherapy, high recurrence rates and decreased disease free survival. Additional research is needed to understand the determinants of TNBC in India as it is a prognostic group with aggressive behaviour that commonly lack the benefit of any specific targeted therapy
Prevalence of clonal hematopoiesis in patients with advanced cancer.
Authors: Ahmet Zehir, Catherine Callaghan Coombs, Sean Devlin, Ashwin Kishtagari, David Michael Hyman, David B. Solit, Mark E. Robson, Jose Baselga, Maria E. Arcila, Martin S. Tallman, Ross L. Levine, Michael F. Berger
Journal: Journal of Clinical Oncology (2016)

1511 Background: Recent analysis of blood-derived genome profiling data has demonstrated clonal hematopoiesis (CH) with associated somatic alterations is frequent in otherwise normal populations . However, the prevalence of CH and how it might affect clinical outcomes for primary tumors or development of secondary myeloid malignancies have not been investigated in a cohort of patients (pts) with advanced tumors. Here, we describe patients who have undergone paired tumor/blood genomic sequencing with MSK-IMPACT, a 410-gene targeted clinical assay, at MSKCC. Methods: Mutations identified in the normal blood of pts enrolled in an IRB approved protocol were genotyped in the matched tumor sample. To identify pts with CH, we required at least one mutation with > 2% mutant allele frequency (MAF) in a leukemia related gene or > 5% MAF in a non-leukemia gene; blood MAF was required to be at least twice the MAF seen in tumor. Additional mutations in these patients were called down to 1% and 3% in leukemia and non-leukemia genes, respectively. Any mutation with MAF greater than 35% was censored as a likely germline event. Results: Out of 5695 pts, we identified 1485 pts with CH (26.1%) harboring a total of 4112 mutations. Out of 349 mutated genes, the most common alterations were observed in DNMT3A (n = 528), TET2 (n = 219), PPM1D (n = 131). Unlike myeloid leukemias where DNMT3A R882 missense mutations are present as the predominant allele, our CH cohort displayed a variety of mutated codons, half of which were truncating events. 64% of patients harbored only one mutation. The mean age was 65.4 for pts with CH and 55.9 for pts without (p < 0.0001). The likelihood of presenting with CH increased by 8.8% per 10 years of age for pts older than 40. Detailed chart review of a subset of pts (n = 2146) showed an increased portion of pts with CH had prior radiation therapy (51% vs 45%, p = 0.057). Age and sex adjusted survival analysis showed trend towards adverse OS for CH with > 1 mutation compared to no CH (HR: 1.46, p = 0.060) Conclusions: CH seems to be present in cancer patients at higher incidence than the normal population; increased monitoring and clinical follow up is warranted to develop a detailed understanding of CH, disease response and progression to myeloid neoplasia.
Evaluation of the usefulness of the indocyanine green fluorescence imaging method in patients with high body mass index and early-stage breast cancer.
Authors: Tsuyoshi Mori, Mina Kitamura, Kaori Tomida, Tomoyuki Ueki, Tohru Miyake, Sachiko Sakai, Sachiko Kaida, Koichiro Murakami, Yuki Kawai, Hiroya Akabori, Hiroyuki Ohta, Tsuyoshi Yamaguchi, Hiromichi Sonoda, Tomoharu Shimizu, Tomoko Umeda, Masaji Tani
Journal: Journal of Clinical Oncology (2016)

e12530 Background: Sentinel lymph node (SLN) biopsy has been established as a method of predicting axillary nodal status in early-stage breast cancer. High body mass index (BMI) has been shown to correlate with a high incidence of failure in identifying SLNs. The indocyanine green (ICG) fluorescence imaging method has been reported to be useful for SLN detection in early-stage breast cancer. In this study, we investigated the usefulness of the ICG fluorescence imaging method in patients with high body mass index and early-stage breast cancer. Methods: We evaluated 484 patients with clinically node-negative breast cancer by using the ICG fluorescence imaging method from January 2006 to December 2014. A 0.3-mL 0.5% ICG solution was intradermally injected in the areola closest to a tumor. Fluorescence images were obtained by using the fluorescence imaging system PDE-Neo (Hamamatsu Photonics Co., Japan). SLNs were then dissected by fluorescence navigation. SLN biopsy was performed by referring to the axillary compression technique using a plastic device. Results: The patients’ mean age was 57.8 years (range, 26–86 years). The high BMI group ( > 25 kg/m2) included 107 patients, and the normal BMI group ( < 25 kg/m2) included 377 patients. The Japan Society for the Study of Obesity defined obesity as a BMI of > 25 kg/m2 for Japanese. Subcutaneous lymphatic channels were successfully visualized in all the patients. The detection rate of SLN was 99.1% (106/107) in the high BMI group and 99.7% (376/377) in the normal BMI group. The number of detected SLNs ranged from 0 to 7 (mean, 2.4) in the high BMI group and from 0 to 8 (mean, 2.4) in the normal BMI group. On pathological examination, 6 patients (5.6%) in the high BMI group and 25 patients (6.6%) in the normal BMI group were found to have lymph node metastases. However, this difference between the 2 groups was not significant. Conclusions: The ICG fluorescence imaging method allowed highly sensitive and real-time imaging and enabled the detection of SLNs regardless of BMI in all the patients with early-stage breast cancer in this study.
Incidence of Early Thrombosis in Myeloproliferative Neoplasms (MPN): A Prospective Analysis from the Gruppo Laziale of Ph-Negative MPN
Authors: Ambra Di Veroli, Marianna De Muro, Alessandro Andriani, Malgorzata Trawinska, Elena Rossi, Cristina Santoro, Sabrina Crescenzi Leonetti, Cinzia De Gregoris, Atelda Romano, Luca Petriccione, Ada D'Addosio, Antonia Centra, Annamaria Rauco, Nicoletta Villivà, Barbara Anaclerico, Elisabetta Abruzzese, Massimo Breccia, Luca Maurillo, Giuliana Alimena, Roberto Ricci, Valerio De Stefano, Marco Montanaro, Roberto Latagliata
Journal: Blood (2016)
Primary Cutaneous Angiosarcoma Mimicking Metastasis on 18F-FDG PET/CT in Woman With Cervix Cancer
Authors: Jae Pil Hwang
Journal: Clinical Nuclear Medicine (2017)

Primary cutaneous angiosarcoma is a rare vascular tumor usually affecting the whole body, and its hypermetabolic features on F-FDG PET/CT may be confused with those of infection, metastasis, or primary malignancy. This is a case report of a cutaneous angiosarcoma of the lower anterior abdomen showing increased FDG uptake on F-FDG PET/CT mimicking a cutaneous metastasis in an 84-year-old woman with cervical cancer.
Prevalence of EGFR mutations in the Peruvian population: Study in a large cohort of patients with NSCLC.
Authors: Luis Mas, Christian Piscocha, Jose Landa, Carlos Roe, Eduardo Roe, Claudia Barletta, Raul E. Velarde, Luis Larrabure, Sandra Jauregui, Christina Flores, Juan C Gomez de la Torre
Journal: Journal of Clinical Oncology (2017)

e13076 Background: The evaluation of EGFR mutational status of the EGFR in non-small cell lung cancer (NSCLC) is crucial to select the adequate targeted therapy and to know the outcome of patients. Previous studies in relative small sample sizes have described a higher prevalence of EGFR mutations in Peruvian population than other Latin American countries. Our aim in this study was to determine the prevalence of activating and resistance mutations of EGFR in a large cohort of Peruvian patients. Methods: We profiled metastatic tumor samples from 847 NSCLC patients for known EGFR mutations associated to sensitivity or resistance EGFR inhibitors, including exon 18 (G719X), exon 19 (deletions), exon 20 (T790M, S768I and insertions) and exon 21 (L858R). All samples were centrally tested in reference laboratory (Roe laboratory, Lima-Peru). Results: A total of 847 samples were profiled for EGFR mutational status. EGFR mutations were present in 32.9% of cases (n = 279). In regard to distribution of mutations in cases EGFR mutated, G719X (in exon 18) was present in 2.5% (n = 7); deletions in exon 19 had a frequency of 58.4% (n = 163). Mutations in exon 20 were present in 9.7% (n = 27). In patients with exon 20 mutated, 14 cases had insertions, 9 cases had the mutation T790M and 4 cases had the mutation S768I. Mutation L858R (exon 21) was present in 34.1% (n = 95) of cases. Coexistence of two mutations were present in exon 18/exon 20 (n = 1), exon 19/exon 20 (n = 7) and exon 20/ exon 21 (n = 5). In tumors with EGFR mutated. The sensible profile for EGFR tyrosine kinase inhibitors (TKI´s) was present in 96.8% of cases (n = 138). Conclusions: We have a high prevalence of EGFR mutations compared than Caucasian or other Hispanic cohorts. It has relevance in the Peruvian public health because more efforts should be done to screen NSCLC patients for EGFR mutations.
Phase I/II study of carfilzomib plus melphalan-prednisone (CMP) in elderly patients with de novo multiple myeloma.
Authors: Brigitte Kolb, Cyrille Hulin, Denis Caillot, Lotfi Benboubker, Mourad Tiab, Nicolas Blin, Xavier Leleu, Murielle Roussel, Michel Attal, Thierry Facon, Philippe Moreau
Journal: Journal of Clinical Oncology (2012)

8009 Background: Melphalan-prednisone + thalidomide (MPT) or bortezomib (MPV) are approved in frontline MM patients (pts) &gt;65 years. Both regimens demonstrated significant benefit over MP alone in terms of PFS and OS but this benefit could be hampered by the risk of peripheral neuropathy (PN). Carfilzomib (Cfz) is a novel proteasome inhibitor that has demonstrated promising activity and favorable toxicity profile, with low rates of PN. This phase I/II study was designed to determine the maximum tolerated dose (MTD) of CMP, to assess safety and evaluate efficacy of this combination in newly diagnosed MM &gt;65. Methods: In Phase I, Cfz was the only escalating agent starting at 20 mg/m2 (level 1) with maximal planned dose 36 mg/m2 (level 3), given IV on days 1, 2, 8, 9, 22, 23, 29, 30 for nine 42-day cycles. Oral melphalan 9 mg/m² and prednisone 60mg/m² were given on days 1 to 4, for all dose levels. Based on toxicity assessment, the study was amended to add dose level 4 (Cfz 45 mg/m2). MTD determination was based on occurrence of Dose limiting toxicities (DLTs) during the first cycle only. DLTs were defined as any grade 4 hematologic toxicity or preventing administration of 2 or more of the 8 Cfz doses of the first treatment cycle except grade 4 thrombocytopenia without bleeding or grade 4 neutropenia lasting ≤ 7 days; or grade ≥ 3 febrile neutropenia; or any other grade ≥ 3 nonhematologic toxicity. Results: As of January 20th 2012, 24 pts have been enrolled in the phase I: 6 pts at level 1 (Cfz 20), 6 at level 2 (Cfz 27), 6 at level 3 (Cfz 36), and 6 at level 4 (Cfz 45). There were 2 DLTs at level 4 (fever and hypotension not related to sepsis) and the MTD was considered to be 36 mg/m². Then, 16 additional pts were included in the phase II at level 3. Overall, 40 pts have been enrolled into the phase I/II study and 26 pts are evaluable for response. The ORR was 92% including 42% at least VGPR. These results compare favorably to those achieved with MPV, MPT, MPR or lenalidomide-dex (ORR 71, 76, 80 and 85%, respectively) in the same population. Conclusions: Frontline carfilzomib (36 mg/m2) + MP is a tolerable and very effective combination in elderly MM pts. Treatment is ongoing, with updated toxicity and efficacy data to be presented at the meeting.
Long-term bisphosphonate therapy in bone metastatic breast cancer patients.
Authors: Berna Oksuzoglu, Oznur Bal, Ummugul Uyeturk, Ayse Demirci, Ayse Durnali, Ibrahim Turker, Necati Alkis
Journal: Journal of Clinical Oncology (2014)

e11561 Background: Bisphosphonates are the standard therapies used in the prevention of skeletal-related complications in bone-metastatic breast cancer patients. However the optimal duration of bisphosphonate treatment is controversial. Methods: Ninety-nine female bone metastatic breast cancer patients treated with bisphosphonates (zoledronic acid 4mg or ibandronic acid IV 6 mg every 4 weeks or ibandronic acid oral 50 mg / day or clodronic acid 1600 mg / day) for more than two years were evaluated, retrospectively. Results: The median age was 47 (23-71) and (57%) were postmenapousal. Hormone receptor and HER2 were positive in 88 (89%) and 24 (24.2%) patients, respectively. Sixty nine (68.7%) patients used zoledronic acid, 21 (21.2%) ibandronic acid, and 9 (9.1%) clodronic acid as the bisphosphonate therapy. The median duration of bisphosphonate therapy was 3.9 (2.1-16.5) years. Eight (8.0%) patients had complications including osteonecrosis of the jaw in seven and renal failure in one. There was no significant difference in the frequency of complications according to the type or duration of bisphosphonates (p = 0.30 , p = 0.05, respectively).The median follow-up was 6.7 ± 4.3 (2.4-25.8) years. overall survival (OS) was evaluated according to the duration of bisphosphonate. Significant increase in the survival of users for 3.9 (n= 51 ) and 5 years (n= 22 ) (p=0.001 , p<0.001, respectively). None significant difference was found in terms of OS and the time to progression according to the type of bisphosphonate (p = 0.50,p = 0.06, respectively). Bisphosphonate treatment of 36 patients was switched to another kind of bisphosphonate due to the progression of bone metastasis. OS was observed to be better in the subgroups who had bone metastasis progression only and of whom bisphosphanate therapy was switched (p=0.036). Conclusions: In this study we have found that the patients using bisphosphonates for more than 3.9 (the median of the cohort) and 5 years displayed significantly higher survival advantage with the cost of increased rates of osteonecrosis of the jaw. After the progression of bone metastasis, switching the current bisphosphonate therapy to another provided an advantage in survival.