bluuebunny/crossref_metadata_2025 huggingface dataset:
Distribution of malignant neoplasms in the eastern Rajasthan region of India.
Authors: Bang Bhavesh Amarnath , Sharma Raj Govind , Kapoor Rahul
Published: March 2020

e12014

Background: Cancer is not a notifiable disease in India. Cancer data in India is derived mainly from Population & Hospital based cancer registries which pursue active data collection. Rajasthan, which is the largest state of India, has no established Cancer registry. Therefore, cancer data from this region is limited. This study was done to put the Cancer data from Eastern Rajasthan region in proper perspective Methods: A retrospective analysis of histopathology records of 5 years was done by studying the proportion & site wise distribution of malignancy cases which were reported at major hospitals & pathology centers in the region. Approximately 200,000 histopathology & cytology reports were analyzed & 34,486 new cancer cases were identified. Cases were classified according to the WHO International Classification of Disease (ICD) coding. Results: Of the 34,486 new cases of cancer that were recorded in five years, 58.58% were (20202) males and 41.42% (14284) females, with the male to female ratio being 1.41:1. Organ wise, Lung (13.25%), Larynx (5.35%), Oropharynx (5.09%), Brain (4.84%), Tongue (4.62%) and Prostate (4 %) were the most common sites involved in males, whereas Breast (25.6%), Cervix (10.26%), Ovary (5.4%), Brain (3.68%), Esophagus (3.4%), Lung (3.01%) & Gall Bladder (2.35%) were common sites of malignancy in females. System wise distribution of cancers revealed that Head & Neck (24.93%), Pulmonary (13.25%), Gastrointestinal (12.01%), Hematological (10.6%) & Genitourinary tract (10.5%) were the most common systems involved in males, where as, in females, Breast cancer was the most common (25.6%) followed by Genitourinary tract (20.27%), Gastrointestinal cancers (11.2%) and Head and Neck cancers (8.11%). Conclusions: A high frequency of tobacco related cancers i.e. Lung cancer and Head & Neck cancer in males, and screening detectable cancers (Breast & Cervix) in females was observed. Frequency of Lung cancer in females was noted to be high in comparison to previous studies from the region. An unusually high frequency of Gall Bladder Cancers especially among the female population in this region is also a cause of concern.
Clinical characteristics of triple-negative breast cancer in the African American population: A retrospective cohort analysis.
Authors: Modi Tejas , Shaaban Hamid , Modi Yashpal , Guron Gunwant K.
Published: March 2020

e12025

Background: Triple-negative breast cancer (TNBC) is defined by a lack of expression of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu. It is a very heterogeneous group of which a subset is clinically associated with an aggressive behavior and poor prognosis. They typically have a high relapse rate despite standard therapy. This study aimed to characterize the clinicopathologic findings and outcomes of these patients in an urban, predominantly African American (AA) population. Methods: Patients diagnosed with TNBC at the Regional Cancer Center at St Michael’s Medical Center in Newark, NJ between 2000 and 2008 were identified from the tumor registry databases. The clinical data was reviewed as a retrospective cohort for demographic information, clinical stage at presentation, recurrence rates and outcomes. Results: 42 pts were identified (median age 56) of which 28 (67%) were AA, 7 (16.7%) Hispanic (H) and 7 (16.7%) Caucasian. 22 patients (52.4%) presented with advanced disease (Stage 3, 4) and 18 of these patients were AA. At mean follow-up of 28 months, 12 (28.5%) pts had progressive disease with pulmonary metastases most common followed by brain metastases. The AA group displayed a trend towards shorter time to progression (TTP) (AA: 10.7 months vs. others: 14.7 months) and the younger patients less than 50 had a shorter TTP (12.3 months vs. 14.1 months). Tumor size was described > than 2 cm in 60%, < than 2 cm in 40%. Lymph nodes were positive in 43% and negative in 57%. Nuclear grade was 1 in 7%, 2 in 8.5% and 3 in 84.5%, respectively. A total of 8 (19%) patients died during the follow-up period. Conclusions: In the cohort we studied, we observed a trend that patients with TNBC in our urban city cancer center were more likely to be AA. These patients were more likely to present with advanced disease. AA and younger patients (less than 50) were more likely to have a more aggressive disease. Whether this could be attributed to non-compliance with mammogram screenings and healthcare disparities in the underserved AA inner city population is not clear but more research is needed to identify germline markers associated with TNBC which could potentiate effective therapies for women with TNBC.
Implementation of a population-based breast screening program for high-risk women in Ontario: The Ontario Breast Screening Program (OBSP) High-Risk Program.
Authors: Eisen Andrea , Carroll June , Chiarelli Anna M. , Heale Esti , Horgan Meaghan , Meschino Wendy , Rabeneck Linda , Shumak Rene , Warner Ellen
Published: March 2020

e12034

Background: Genetic testing for mutations in BRCA1 and BRCA2 has been clinically available in Ontario since 2000. It is estimated that over 15000 individuals have been tested. Evidence from clinical trials have consistently shown that women at high risk of breast cancer such as BRCA1/2 mutation carriers benefit from breast cancer screening that includes both magnetic resonance imaging (MRI) of the breast and mammography, yet access to MRI in Ontario was variable. In 2011, Cancer Care Ontario established an expert panel to develop a protocol for expanding the Ontario Breast Screening Program, initially created for average risk women 50-74, to include MRI and mammography for eligible high risk women. Methods: The panel’s tasks included: 1. determining the criteria for high risk, 2. estimating the prevalence of high risk women, 3. selecting a model to estimate cancer risk, 4. developing a referral and assessment pathway for potentially eligible subjects to receive genetic counseling/risk assessment and screening if eligible, 5. developing educational resources, training plan and communication strategy for relevant stakeholders including primary care providers, oncologists, geneticists and genetic counselors, 6. developing indicators to permit program evaluation, 7. providing guidance for post-implementation issues such as subject eligibility and interpretation of genetic test results. Results: The program was initiated July, 2011 at 19 sites. Women aged 30-69 with and without a history of breast cancer are eligible if they 1. are BRCA1/2 mutation carriers or untested first degree relatives of carriers, 2. have a lifetime risk of breast cancer >=25% based on family history, or 3. received prior radiation therapy to the chest. It is estimated that 34000 high risk women in the target age group live in Ontario. Conclusions: A population based organized screening program for high risk women that includes genetic risk assessment has been implemented in Ontario. To our knowledge, this is the first organized screening program for women at high risk of breast cancer.
Combination therapy for glioblastoma multiforme with primitive neuroectodermal tumor components: Case series.
Authors: Lee Adrian Pak Siu , Brewer Janice , Back Michael , Wheeler Helen
Published: March 2020

e12507

Background: Glioblastoma multiforme (GBM) with sharply demarcated hypercellular nodules of primitive neuroectodermal tumor (PNET) are a rare variant of GBM and present with both diagnostic and management dilemmas. Controversy as to whether these mixed lesions originate from differential clonal expansion stem cells or the PNET element arise from the pre-existing astrocytic component has not been resolved. In a recent series of 53 patients (Perry et al. Brain Pathology. 2009;19:81-90), the median survival for this cohort managed with standard GBM therapy was only 9.1 months. Authors suggested addition of platinum-based chemotherapy appeared to improve survival. Methods: We report 3 cases of GBM and PNET that were treated at our institution with combination adjuvant therapy that included carboplatin. Patients were aged 17, 33 and 42. All patients had gross total resection followed by 60gy radiation. Concurrent chemotherapy included Temozolomide 60mg/m2 daily in combination with carboplatin AUC 1.5 weekly. After a 4 week break, 3 cycles of consolidation Ifosfamide 1600mg d1-3, Carboplatin AUC 5 d1 and Etopside 100mg/m2 d1-3 with G-CSF support every 3 weeks were administered and this was followed up by adjuvant Temozlomide at 150-200mg/m2 d1-5 for 6-36 months. Results: 2 patients remain disease free at 36 and 56 months after diagnosis. 1 patient relapsed with a new lesion in the other hemisphere which on biopsy contained GBM alone with no PNET elements. She succumbed to progression of disease 32 months after diagnosis. There was no grade 3-4 toxicity but low blood counts lead to some treatment delays. Conclusions: Overall this protocol was well tolerated and appears to improve survival compared to the literature. Further studies are warranted but will be limited by the rare occurrence of this disease.
Does the use of complementary and alternative medicine (CAM) influence survival in glioblastoma multiforme?
Authors: Ambady Prakash , Morrison Tara
Published: March 2020

e12509

Background: Glioblastoma multiforme (GBM) is a devastating CNS tumor with an incidence of around 14,000 per year in the USA. Patients often independently adopt complementary and alternative medicines (CAM) in addition to the recommended surgery and chemoradiation due to the poor prognosis of the disease despite maximal therapy. We try to document the most frequently used supplement therapies and identify differences in side effect profiles, and survival rates (PFS and OS) between groups of patients taking standard therapy versus standard therapy with CAM Methods: This is a retrospective single institution study. We reviewed charts of 25 GBM patients seen in Neuro-Oncology Clinic at Fox Chase Cancer Center between September 2010 and September 2011. All patients received standard chemoradiation. Information regarding the age, sex, use of CAM, performance status at diagnosis, side effect profile, PFS and OS was obtained. Results: 9/25 (36%) patients reported using CAM. The most frequently used supplement was the homeopathic medication Ruta-6 followed by curcumin, hydroxychloroquine, melatonin and green tea extract. The mean PFS were 14 vs 17 months in the CAM vs non-CAM groups. OS rates were 17 vs 20.5 months in the CAM vs non-CAM groups. There were no statistically significant differences between the groups. In addition, no differences in side effects were noted. Conclusions: Most neuro-oncologists are eventually confronted with questions about CAM in the treatment of GBM.Considering the limited therapeutic options available for GBM and the multiple options that CAM offers, this retrospective study provides insight into the most frequently used supplements and compares the benefits and their side effect profiles. Information regarding the use of CAM was based on voluntary disclosure at the time of documentation. Information about genetic markers was not always available. Larger prospective studies are required to elucidate any meaningful clinical differences between the groups.
Early-phase trials compared to first- and second-line FDA-approved treatments in patients with advanced gallbladder cancer and cholangiocarcinoma.
Authors: Subbiah Ishwaria Mohan , Tsimberidou Apostolia Maria , Naing Aung , Subbiah Vivek , Kaseb Ahmed Omar , Fu Siqing , Hong David S. , Piha-Paul Sarina Anne , Wheler Jennifer J. , Janku Filip , Hess Kenneth R. , Falchook Gerald Steven , Kurzrock Razelle
Published: March 2020

e13020

Background: Patients with advanced cholangiocarcinoma (CC) and gallbladder carcinoma (GC) have few effective therapeutic options. We compared prognostic factors and clinical outcomes of CC/GC pts treated on phase I trials with that of their first-, second-line and last Food and Drug Administration (FDA)-approved therapy given in setting of metastatic disease. Methods: We retrospectively reviewed electronic medical records of patients with GC and CC evaluated in the phase I program clinic from November 2004 to March 2011. Results: Of the 72 patients with CC or GC, 32 (44%) were not enrolled on a trial mainly due to clinical deterioration (n=25). Of 40 treated patients (GC=6; CC=34; median age 60 years; median prior systemic therapies = 3), 8 (20%) had stable disease (SD) > 6 months; 3 (8%) achieved a partial response (PR); SD > 6 months/PR was observed mainly on protocols with hepatic arterial infusion drug administration and/or angiogenic inhibitors, anti-her2/neu agents or a novel MAPK/ERK kinase (MEK) inhibitor. Median progression-free survival (PFS) on phase I trials was 2.0 months (95% CI 1.7, 2.8) versus 3.0 months (95% CI 2.4, 5.0; p=0.95), 3.0 months (95% CI 2.3, 4.6; p=0.98), and 3.0 months (95% CI 2.4, 3.9; p=0.79) for their first-, second-, and last systemic therapy with FDA-approved agents given in the metastatic setting, respectively. In univariate analysis, factors associated with a shorter Phase I PFS were > 3 metastatic sites, elevated ALT (>56 IU/L), serum creatinine (>1.6mg/dL), and CA19-9 (>35U/mL). Conclusions: In heavily pretreated patients, PFS in the clinical trials setting remained poor but did not differ significantly from that of their first-line, second-line, and last prior therapy with FDA-approved agents. Response rate (SD >6 months/PR) of 28% was seen in trials with locoregional treatment or inhibitors of angiogenesis, her2/neu or MEK.
Pharmacokinetic and pharmacodynamic analysis of fluorouracil in nasopharyngeal cancer patients.
Authors: Zhao Liping , Liu Wanli , Zhao Chong , Guo Xiang , Huang Yan , Xu Fei , Hu Zhihuang , Wang Zhiqiang , Zhao Hongyun , Zhang Li
Published: March 2020

e13021

Background: Pharmacokinetic (PK) variability of 5-FU has been demonstrated for +30 years and a significant link between 5-FU exposure and therapeutic response has been identified. A maximum tolerated exposure (MTE) using area under curve (AUC) has been characterized for various regimens and therapeutic drug management (TDM) has been used to achieve effective dosing in several tumor types. The regimen most used to treat nasopharyngeal cancer (NPC) is cisplatin and 5-FU. The objective of this study was to characterize the PK variability of 5-FU in this population and examine the relationship between AUC and toxicity. The 5-FU MTE in this Chinese population will be compared with the MTE identified for HNC European patients. Methods: Fifty-three treatment naïve Chinese NPC patients were administered cisplatin (80mg/m2, day 1) and 5-FU (4g/m2, 120 h continuous infusion) and had blood samples collected at steady state after the first 18h of 5-FU infusion. Plasma was analyzed by a 5-FU immunoassay and AUC calculated from the steady state concentrations. We examined the relationship between 5-FU AUC and 5-FU-related toxicities (mucositis and myelosuppression). Results: The patient AUC values varied widely, ranging from 20 to 103 mg · h/L. 34% of the patients were within the target range of 25-35 mg· h/L , 15% were below and 51% were above the range. Toxicity was recorded for 53 patients. Severe mucositis in 17 and myelosuppression in 1 of 27 patients occurred with 5-FU exposure above the target range, versus no severe toxicity in any of the 27 patients within or below the target range (p=0.000). ROC analysis for 5-FU AUC and severe mucositis identified a cut-point of 37 mg· h/L (p<0.001). Conclusions: Results of this study demonstrate wide PK-variability of 5-FU exposure and a significant relationship between severe toxicity and AUC in Chinese NPC patients. The study confirms that the MTE in this population is similar to a European HNC population treated with cisplatin/5-FU. TDM using the target range of 25-35 mg· h/L may have benefit in lowering toxicity in NPC patients.
Physicians’ ability to correctly identify values important to cancer patients enrolled in phase I clinical trials.
Authors: Pentz Rebecca D. , Liu Yuan , Wall Louise , Daugherty Christopher , Green Michael J , Hlubocky Fay J. , Peterson Susan K. , Sun Charlotte C. , Dixon Margie , Harvey R Donald , Owonikoko Taofeek Kunle , Khuri Fadlo Raja
Published: March 2020

e13026

Background: ASCO recommends that physicians assess treatment preferences of patients with advanced cancer. To facilitate this process, we developed a tool to assess patients’ treatment-related values, since no standardized tool exists. This study evaluated the need for the tool by testing concordance between patient and physician identification of values important to the patient. Methods: Forty patients enrolled in phase I trials chose the 4 most important values from a list of 16 pretested values. The treating physicians also selected the values they thought their patient would choose based on their independent assessment of the patient. Concordance and discordance between the patient and physician choices were calculated. Subsequently, 18 physicians were given the tool to use during a phase I consent conversation. Satisfaction was tabulated. Results: Physicians (PHY) were unsuccessful in choosing the values selected by patients (P) 56% of the time. The highest concordance was observed for (1) fighting my cancer as much as possible (68%P, 80%PHY); (2) having access to the best cancer treatment (65%P, 58%PHY). The highest discordance was observed for (1) Feeling as good as possible every day given my condition (60%P; 18%PHY p=0.002); (2) Taking part in a research study if it is my only option (8%P; 55%PHY p=0.0001); (3) Having access to new treatments even if they are not yet proven and are a part of research (18%P; 55%PHY p=0.0008). Physicians agreed that the values tool has great utility, influences treatment recommendations and should be used with all patients (4.5/5). Physicians were neutral about whether the tool would save time (3.5/5). Patients were neutral on tool utility (3.8/5). Conclusions: Physicians’ ability to identify their patients’ most important values is poor (44% concordance). This is low compared to levels reported in other concordance studies for treatment choices (53-56%) and for what makes life worth living (57%). While physicians thought patients would value participation in research, patients more frequently identified quality of life as an important value. The tool was considered useful for portraying patients’ values by the majority of physicians, but not by most patients.
Use of inflammation-based scores to optimize the selection of patients with advanced cancer considered for early-phase clinical trials.
Authors: Pinato David James , Stavraka Chara , O'Cathail Sean Micheal , Seckl Michael , Blagden Sarah Patricia
Published: March 2020

e13033

Background: The presence of adequate organ function, favorable performance status (PS) and exhaustion of standard treatments are the main factors guiding accrual onto Phase I trials. As inflammation is inherent to the pathogenesis and prognosis of cancer we investigated the prognostic and predictive performance of inflammation based indices including the neutrophil (NLR) and platelet to lymphocyte ratio (PLR). Methods: Unselected referrals to the Phase I unit (2007-2011) were considered. Demographic, treatment, staging data and routine blood tests were collected. Patients were defined as high risk if NLR>5 or PLR>300 respectively. Changes in the NLR (ΔNLR) were recalculated at disease reassessment. Kaplan Meier and log rank test were used to assess Progression Free (PFS) and Overall Survival (OS) with each variable. Significant factors were further tested in a multivariate Cox model. C-index was used to calculate the discriminative ability of each score and ROC curves to predict 90 days survival (90DS). Results: We included 126 patients with median age 63 years (range: 22-80); median OS 4.4 months (0.2-39), 36% male; 92% with metastases, 23% PS>1. On univariate analysis LDH>450, PS, NLR≥5, hypoalbuminaemia, NLR normalization (ΔNLR) (p<0.001), >2 previous treatment lines (p=0.01) predicted for OS. After multivariate analysis low albumin, high LDH and ΔNLR remained independent predictors (p<0.05). Shorter PFS was predicted by elevated LDH and ΔNLR (p<0.05). PS and NLR ranked as most accurate predictors of both 90DS with area under the ROC curve values of 0.66 (0.55-0.77) and 0.64 (0.54-0.75) and OS with c-index scores of 0.69 (0.56-0.82) and 0.60 (0.50-0.70). When combined to PS, the NLR improved its accuracy to 0.72 (0.59-0.83). NLR≥5 at screening was associated with advanced PS, low albumin (p<0.002), LDH>450 and >2 metastatic sites (p<0.05). Conclusions: The NLR can improve the selection of patients considered for experimental therapies, with its normalization following treatment predicting for a survival benefit of 7 months in our series.
A phase Ib dose escalation study of JX-594 (TK-vaccinia virus expressing GM-CSF) administered by biweekly intravenous infusion in patients with metastatic, refractory colorectal carcinoma.
Authors: Park Young Suk , Lee Jeeyun , Lim Ho Yeong , Lee Jihye , Pelusio Adina , Burke James M. , Breitbach Caroline , Kirn David H.
Published: March 2020

e13044

Background: JX-594 is a recombinant vaccinia virus engineered to selectively replicate in and destroy cancer cells while stimulating a systemic anti-tumor immune response and inducing a reduction in tumor blood perfusion. Preclinical data has demonstrated JX-594 activity is enhanced in cells with up regulation of the EGFR pathway. JX-594 anti-tumor activity in multiple advanced solid tumors has been observed in early stage clinical studies. This study was designed to assess the safety, MTD/MFD, and initial anti-tumor activity of JX-594 administered IV every other week x 4 total treatments in patients with metastatic CRC after failure of standard chemotherapy. Methods: A standard 3+3 dose escalation design was used to enroll patients into three dose levels (106, 107 or 3x107pfu/kg) of JX-594 administered IV every 2 weeks x4. Safety was assessed using CTCAEv3.0. Anti-tumor activity was determined based on serial CT scans and CEA measurements. Patient samples were collected for pharmacokinetics and pharmacodynamics. Results: Enrollment is ongoing with 8 patients treated at total doses ranging from 5x107 to 2x109 pfu. Adverse events have generally been limited to grade 1/2, transient flu-like symptoms (fever, chills, headache). No DLT was reported. Three patients in the top two dose levels demonstrated SD on week 4 CT scan with one maintained at week 8. In these same 3 patients, CEA declined by 50% in a single patient while the other 2 had no significant change in CEA. Conclusions: Preliminary data for this dose escalation trial demonstrates JX-594 is well tolerated after 4 IV treatments administered every other week. CEA and CT scan assessment suggest possible efficacy. Enrollment continues and an expansion cohort at the MTD is planned. Updated data is expected at the time of presentation.
Autologous dendritic cell vaccine (ADCV) in combination with plasmapheresis (PP) and cyclophosphamide (Cy) in patients with disseminated melanoma: A phase II study.
Authors: Moiseyenko Vladimir , Baldueva Irina Alexandrovma , Novik Alexey Viktorovich , Nehaeva Tatyana Leonidovna , Danilova Anna Borisovna , Danilov Alexey Olegovich , Petrova Tatyana , Protsenko Svetlana , Michailichenko Tatyana , Semenova Anna Igorevna , Teletaeva Gulfiya Midhatovna
Published: March 2020

e13059

Background: Low immunogenicity of tumor-associated antigens, cellular and humoral immunosuppressive factors compromise adequate antitumor immune response development. We hypothesized that ADTV, PP and Cy can overcome these immune escape mechanisms by enhancing antigen presentation, suppressing T-regs and removal of various immunosuppressive substances, respectively (Nand S, 1997; Salem M, 2010). Methods: Ten pts (median age 47.3 (24-74)) with stage IV morphologically verified malignant melanoma were included in the study in 2010. All pts signed inform consent form, previously received systemic therapy and have no brain metastases. Pts received 3 procedures of middle-volume PP (removal of 10 ml/kg plasma) on days 1,3,5 of the first 4 cycles, Cy 300 mg IM on day 5 after PP, DCV in 4 intradermal injection of 5-20*106 mature DC on day 8 of 14-day cycle. Pts with no evidence of disease progression after 4 cycles received Cy and DCV without PP once in a month for 1 year and once in 3 month thereafter until disease progression. Primary endpoint was Progression Free Survival (PFS). Secondary endpoints were toxicity (per CTCAE), efficacy (per irRECIST) and immune response using ELISpot and whole cell Elisa tests. Median of patient’s observation was 231 days. Results: Ten pts received 73 (2-21) cycles of therapy. No gr. 4 AE or SAE occurred. One patient (1.4% of cycles) developed gr. 3 fever. Main gr. 1-2 toxicities were fever (34.2%), flu-like syndrome (17,8%) and PP-related reactions, such as citrate intoxication, nausea or hypotension (16,4%). One pt achieved PR (10%, 95% CI 0 - 35%) lasting 956+ days. Four pts (40%, 95% CI 13-70%) had SD for 168, 262, 417 and 454 days (3/4-stage M1c). Median PFS was 168 (95% CI 10-325) days. IFN-γ production increased in all patients irrespective of tumor response (p=0.017). All patients with clinical benefit showed increased production of tumor-specific IgG in whole cell ELYSA. Relative risk of disease progression was 6.0 (95% CI 1.003-35.9, p=0.023) in the absence of tumor-specific IgG production. Conclusions: ADCV with PP and C is well tolerated and shows significant immunological and clinical response in pretreated stage IV pts.
Quantitative contrast peritoneography for intraperitoneal chemotherapy.
Authors: Leinwand Joshua , Guo Xiaotao , Krishnamoorthy Saravanan , Qi Jing , Hare Elethea , Schwartz Lawrence H. , Zhao Binsheng , Taub Robert N.
Published: March 2020

e13064

Background: Catheter-administered intraperitoneal (IP) chemotherapy is used for peritoneal surface-spreading malignancies to maximize local drug concentrations. Computed tomography (CT) peritoneography can be used to assess for catheter failure and infusate maldistribution, which may contribute to treatment failure and systemic toxicities like cisplatin-induced nephrotoxicity. There is no standard system to assess infusate distribution, and no reported outcomes data from patients assessed with CT peritoneography. We hypothesized that volume and surface area of the compartment available to IP chemotherapy is associated with overall survival and post-treatment estimated glomerular filtration rate (eGFR) in malignant peritoneal mesothelioma (MPM) patients. Methods: Chart review identified 38 MPM patients who underwent CT peritoneograms while receiving IP cisplatin between 2000 and 2011. Volume and surface area of the contrast-filled compartments were calculated by semiautomated computer algorithm supervised by a physician. We retrospectively tested whether surface area and volume were associated with overall survival and post-treatment eGFR, controlling for demographic and disease factors. Results: Larger surface areas were associated with decreased likelihood of mortality, controlling for volume, age, sex and histologic subtype (Hazard Ratio=.999 cm-2, p=.035). Larger volumes correlated with higher post-treatment eGFR, controlling for pre-treatment eGFR, body surface area (BSA), surface area and the interaction between BSA and volume (β=.154 cc/min/cm3, p=.017). Conclusions: The association of larger surface areas with improved overall survival is consistent with more direct drug contact with potential areas of tumor spread. The association of larger volumes with higher post-treatment eGFR is consistent with less cisplatin diffusion into the circulation due to lower intra-abdominal pressures, which vary inversely with volume. CT peritoneography is an appropriate modality to assess distribution of catheter-administered intraperitoneal chemotherapy. Quantitative analysis of contrast-filled compartment surface area and volume may be predictive of treatment efficacy and side effects.
Role of gemcitabine along with dendritic cell therapy in advanced-stage pancreatic cancers: Phase I/II trial results in 26 patients from India.
Authors: Khan Jamal Anono
Published: March 2020

e13071^

Background: Pancreatic cancer is the leading cause of cancer deaths worldwide with a very poor survival rate. No adequate therapy allows the patient to have a longer life of even 1 year. Methods: Dendritic cell(DC) based immunotherapy along with gemcitabine chemotherapy is planned to do phase I/II trial in 26 patients of advanced stage adenocarcinoma of pancreas. Inclusion criteria was defined as unresectable disease, ECOG performance status of not more than 2, Blood chemistry and hematocrit within normal range and of all age groups. Peripheral blood mononuclear cells are cultured in GM-CSF/IL-4 in RPMI. At 6th day of culture, the immature dendritic cells are exposed to antigens previously isolated from fresh excised tissue and further matured for 2 days. The cells along with medium are harvested and 1 million mature DC are infused IV by mixing them in 100 ml of dextrose normal saline with ondasnetron 4mg injection. Gemcitabine was given on day 1 and on day 8th and DC on day 15th. The cycle is repeated every month for 3 months followed by DC therapy alone at every 23 days interval till patient survives. The primary end point was overall survival and the secondary end point was improvement in quality quotient. Results: 6 patients survived for 24 months, 10 for 12 months and 3 for 6 months, with radiological improvement in only 4 patients with 25% reduction of disease. The quality quotient of 14 patients improved by second dose of dc therapy with improved appetite and decreased pain in abdomen including cheerfulness in 13 patients. Conclusions: Gemcitabine and DC immunotherapy is a good option for advanced stage pancreas cancer patients.
Ophthalmic acid in plasma: A possible predictor for elevated risk of erlotinib-induced hepatotoxicity.
Authors: Hamada Akinobu , Kai Yuki , Sasaki Jiichiro , Saeki Sho , Kishi Hiroto , Fujii Shinji , Semba Hiroshi , Isobe Takeshi , Hashimoto Yutaka , Kohrogi Hirotsugu , Saito Hideyuki
Published: March 2020

e13072

Background: Erlotinib is metabolized by cytochrome P450 enzymes to form a para-hydroxyaniline metabolite that is further metabolized to quinone-imine. Erlotinib is detoxified when it conjugates with sulfate or glucuronide. We recently demonstrated that patients who experienced severe erlotinib-induced hepatotoxicity had higher metabolic ratios of glucuronides than those who developed moderate toxicity; this finding indicates that glucuronidation could be saturated and high levels of reactive metabolites might be trigger of glutathione (GSH) depletion. Ophthalmic acid (OA), which is an analog of GSH, may be a useful biomarker for hepatotoxicity because it is a sensitive indicator of GSH depletion in animal model. GSH acts as an enzyme-catalyzed antioxidant when cells and organisms experience electrophilic stress that arises from metabolic processes. Here, we examined the association between plasma concentration of OA and hepatotoxicity in patients who were treated with erlotinib in Japanese patients. Methods: We assessed data from 26 patients with NSCLC who each received a 150 mg dose of erlotinib. Plasma concentrations of OA and erlotinib were measured at before treatment using the liquid chromatography-quadrupole mass spectrometer system. Results: All 26 patients experienced one or more erlotinib-induced adverse events. The most frequent erlotinib-induced adverse events were mild to moderate skin rashes and diarrhea. There seemed to be a relationship between the plasma concentration of erlotinib and the grades of skin rashes and diarrhea. Interestingly, OA was detected only in one patient who developed grade 4 hepatotoxicity, indicating that this patient, who had a higher level of OA (36.9 ng/mL) in plasma. In contrast, the other 25 patients, who did not develop hepatotoxicity, had no detectable OA in plasma. Thus, the plasma concentration of OA was not related to the plasma concentration of erlotinib nor to the grade of skin rash. Conclusions: OA might be useful as a predictive biomarker of hepatotoxicity if measured before starting erlotinib treatment. Larger studies are needed to investigate the association between OA levels and the development of severe hepatotoxicity.
Pharmacokinetic study of clofarabine: Oral bioavailability and the effect of cimetidine on renal clearance.
Authors: Foster Matthew Charles , Kumar Parag , Walko Christine Marie , Ivanova Anastasia , Ewesuedo Reginald , Van Deventer Hendrik , Garcia Reynaldo , Park Steven I. , Shea Thomas C.
Published: March 2020

e13074

Background: Clofarabine (CLO) is a purine analog with activity in myeloid neoplasms. Its oral dosing has been based on an estimated bioavailability (F) of 49% from uncontrolled trials. Animal models suggest that CLO renal clearance (CL) may be impaired in the presence of inhibitors of organic cation transporter-2 (OCT2), which mediates transport across the renal tubular basolateral membrane. We conducted a pharmacokinetic (PK) study of CLO to determine F, and examine the effect of the OCT2 inhibitor, cimetidine (CIM) on intravenous (IV) CLO. Methods: Patients had: 1) untreated AML ≥ 60 years of age unsuited for standard induction, 2) relapsed or refractory AML, or 3) MDS after failure of ≥ 1 prior regimen. Treatment was: CLO 15 mg/m2 IV day 1, CLO 30 mg/m2 orally (PO) day 3, CLO 15 mg/m2 IV day 5 preceded by two doses of oral CIM, and CLO 30 mg/m2 PO on days 6 and 7. PK studies were obtained after CLO dosing on days 1, 3 and 5. For each dose, CLO plasma concentration was determined, and concentration-time data was analyzed by non-compartmental methods. F was determined for each patient. The geometric means of area under the curve (AUC), 0-∞, and CL for IV CLO administered after CIM doses were compared with AUC and CL for IV CLO administered without CIM. Results: Interim data for the first ten treated patients, with comparisons of PK parameters are shown in the table below. Conclusions: Using patients as their own controls, F of CLO is higher than previously estimated. AUC of CLO is increased and CL is decreased in the presence of CIM, likely owing to inhibition of OCT2-mediated renal tubular secretion. This study is the first human trial to suggest that CLO CL may be impaired in the presence of OCT2 inhibitors, such as cimetidine, trimethoprim, verapamil and nicotine. [Table: see text]
Tolerability of split-dose oprozomib (ONX 0912) in patients with advanced refractory or recurrent solid tumors.
Authors: Papadopoulos Kyriakos P. , Mendelson David S. , Tolcher Anthony W. , Burris Howard A. , Gordon Michael S. , Bomba Darrin , Gillenwater Heidi H. , Infante Jeffrey R.
Published: March 2020

e13077

Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.
WIDEN: A tool for medical imaging management in oncology clinical trials.
Authors: Chauvie Stephane , Biggi Alberto , Stancu Alexandru , Cerello Piergiorgio , Gallamini Andrea
Published: March 2020

e13093

Background: Recently a novel clinical trial generation based on a therapeutic strategy driven by early treatment response assessment to therapy by functional imaging was conceived and a central review of the images became necessary. We describe hear the application of a new web-based tool for imaging exchange and online review of PET scan (WIDEN) conceived for the prospective multicenter clinical trial HD0607. Methods: In the HD 0607 clinical trial 367 patients affected by advanced-stage Hodgkin Lymphoma (HL), are treated with 2 ABVD courses and a PET scan performed afterwards (PET-2). PET-2 positive patients shift to an aggressive treatment, PET-2 negative patients continue with ABVD. PET-2 along with the baseline scan (PET-0) is uploaded to a dedicated web site thanks to WIDEN and hence distributed to six expert reviewers. The latter report the scans within 72 hours from the upload and determine the choice whether intensify or not the treatment intensity (NCT identifier 00795613). Results: The average (median) time per scan upload and download were 6’39” (1’35”) and 3’26” (1’53”) respectively. The average (median) PET scan size were 133.8 MB (121.5 MB), with a minimum size of 51.2 MB and a maximum size of 469.8 MB. The average (median) time frame between the case files upload by the submitting centre and the case review reporting was 48h 45‘ (40h 31’). 7% of the cases were reviewed among the forth and the fifth days. 3% cases were reviewed after the fifth days. In all cases of a review time spanning over more than three days the delay depended on the presence of a week-end of other holiday time. Concordance rate among reviewers measured with Krippendorff,s alpha was 0.799. Conclusions: WIDEN proved to be an effective tool for medical imaging exchange and review. Data security, simplicity, low cost, feasibility and prompt scan review were demonstrated. Its applicability in any clinical trial in which imaging is decisional for treatment modulation is warranted
A phase I trial to determine the maximum tolerated dose and evaluate the safety and pharmacokinetics (PK) of docetaxel-PNP, polymeric nanoparticle formulation of docetaxel, in subjects with advanced solid malignancies.
Authors: Jung Kyung Hae , Kim Kyu-Pyo , Yoon Dok Hyun , Hong Yong Sang , Choi Chang-Min , Ahn Jin-Hee , Lee Dae Ho , Lee Jae-Lyun , Ryu Min-Hee , Ryoo Baek-Yeol , Chang Heung-Moon , Kim Tae Won , Kim Sung-Bae , Kim Sang-We , Suh Cheolwon , Kang Yoon-Koo , Lee Jungsin , Bae Kyun-Seop , Kim Yong-Man
Published: March 2020

e13104

Background: The aim of this study was to determine the maximum tolerated dose (MTD) and recommended dose of docetaxel-PNP when administered every 3 weeks in patients with advanced solid malignancies. Methods: Three to six patients received docetaxel at dose levels of 20-75 mg/m2 as 60-min infusions every 3 weeks according to the single dose-escalating 3+3 method. Blood samples at the first dose of docetaxel-PNP were collected for PK analysis. Results: Nineteen pts were treated for a median of two cycles (1-14) in the phase I study. Dose escalation was performed up to 75 mg/m2. The most frequently reported adverse events were grade 4 neutropenia (52.6%, 10/19), grade 1 myalgia (42.1%, 8/19) and grade 1 alopecia (42.1%, 8/19). No acute infusion reactions were noted. Two dose-limiting toxicity was observed at 20 and 60 mg/m2, which were grade 3 hypophosphatemia and death of unknown cause, respectively. Although the MTD was not determined, the recommended dose was determined as 60 mg/m2. This was based on neutropenia and PK parameters which are summarized in the table. PK parameters revealed dose linearity. Partial response was seen in one patient and stable disease in seven patients. Conclusions: Administration of docetaxel-PNP was well tolerated up to 60 mg/m2 every 3 weeks by heavily pretreated patients. Further phase II trials are recommended at this dose level. [Table: see text]
Investigating the utilization of pharmacokinetic-guided fluorouracil in colorectal cancer.
Authors: Patel Jai Narendra , O'Neil Bert H. , McLeod Howard L. , Sherrill Gary Bradley , Olijade Oludamilola , Inzerillo John J. , Atluri Prashanti , Chay Christopher H. , Walko Christine Marie
Published: March 2020

e13109

Background: Fluorouracil (FU) has remained the cornerstone of colorectal cancer (CRC) therapy for > 40 years; however, recent evidence suggests inter-individual pharmacokinetic (PK) variability in response. Methods: A total of 58 CRC patients from 6 academic and community sites received mFOLFOX6 (FU 2400 mg/m2 over 46 hours every 2 weeks) +/- bevacizumab. FU doses for cycles 2-4 were adjusted based on an algorithm to target an AUC of 20-25 mg*h/L. Peripheral blood was obtained 2-46 hours post beginning of infusion (BOI) and AUCs were determined using an immune-based assay (OnDose). The primary objective of this study is to describe the feasibility of PK-guided FU in clinical practice using descriptive statistics with a secondary objective of toxicity assessment. Results: Mean AUC post cycle 1 in evaluable patients (n=39) was 19.8 +/- 6.3 mg*h/L (range 7-38) with 31% within, 51% under, and 18% over the AUC target. Based on cycle 1 results, the mean dose estimated to achieve AUC 20-25 mg*h/L would be 2,505 +/- 304 mg/m2 (range 2,040-3,600). For cycle 1, the mean AUC at 2 and 18-24 hours post BOI was 17.5 +/- 6.9 and 21.6 +/- 6.3, respectively. Of 58 patients, 19 were not evaluable due to logistical issues such as sampling errors, dosage deviation from protocol, no stabilizing agent added to sample, or the patient was unable to return to clinic for sampling. Three hospitalizations due to serious adverse events occurred, with 2 at AUCs > 30. See the table for toxicities. Conclusions: Significant heterogeneity is noted in FU AUC with BSA-based dosing, with the majority of patients below the protocol-specified AUC threshold. Although FU should be at steady-state 2 hours post BOI until the end of infusion, a difference in AUC was seen between samples taken at 2 and 18-24 hours. With little study withdrawal observed after initial patient enrollment, appropriate logistical training can allow for individualization of FU in the front-line, community setting for the treatment of CRC; however, larger clinical trials are needed to define the clinical utility of PK-guided FU. [Table: see text]
The effect of tissue factor pathway inhibitor release and interactions with growth factors on the antitumor effects of ultra low molecular weight heparin semuloparin.
Authors: Fareed Jawed , Gray Angel , Kahn Daniel , Cunanan Josephine , Khan Hussein , Viskov Christian , Hoppensteadt Debra
Published: March 2020

e13117

Background: Heparins are known to produce anti-tumor effects beside other pharmacologic actions. More recently an ultra LMWH has been developed for the prevention of thrombosis in cancer patients. Initial studies demonstrated that this agent also exhibits anti-tumor effects in animal models. To understand the mechanism of anti-tumor effects of this agent studies were designed to fractionate this ULMWH in to various AT affinity fractions. Methods: An ULMWH (semuloparin, Sanofi-aventis) and its high (HAF) and low (LAF) affinity fractions were prepare by AT affinity chromatography. These agents were administered at 1 mg/kg to primates via intravenous route. Blood samples were collected for a period of up to 6 hours. TFPI release and anti-Xa activities were measured. The interactions of ULMWH and its fractions with various growth factors such as FGF, VEGF, EGF and beta TGF were measured using a mass spectral method employing SELDI technique. The anti-tumor effects of each of these agents were measured using the mouse model of Lewis lung carcinoma. Results: In comparison to ULMWH the LAF showed minimal anti Xa activity whereas HAF exhibited a higher activity. All agents exhibited a similar release of the TFPI; however, HAF exhibited slightly higher release. All agents also showed varying degrees of binding to growth factors as measured by peak intensities. All agents produce anti-tumor effects in the mouse model resulting in a significant reduction in tumor size. Conclusions: Semuloparin has been clinically proven to prevent venous thromboembolism in patients with cancer (SAVE ONCO). These effects are attributable to the inhibition of factor Xa and the generation of thrombin. The fact that LAF mediates its anti-tumor effects without producing anti Xa effects suggest that these may be related to the release of TFPI. Furthermore the ULMWH, HAF and LAF all interact with growth factors suggest that these interactions may also contribute to anti-tumor effects of semuloparin, therefore, beside antithrombotic effects this agent also exhibits oncostatic effects.