bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of goshajinkigan on peripheral neuropathy in breast cancer patients treated with docetaxel.
Authors: Abe Hajime , Mori Tsuyoshi , Kawai Yuki , Cho Hirotomi , Kubota Yoshihiro , Umeda Tomoko , Mekata Eiji , Tani Tohru
Published: March 2020

e11564

Background: Although taxanes have become a key chemotherapeutic drug in breast cancer treatment, one of the side effects is peripheral neuropathy. Goshajinkigan (GJG) is a traditional Japanese medicine that is used for the treatment of several neurological symptoms including pain and numbness. Recently, GJG has been reported to prevent anticancer drug-induced peripheral neuropathy in colorectal cancer in the gynecology field. We investigated the efficacy of GJG and mecobalamin (B12) on peripheral neurotoxicity associated with docetaxel (DOC) in breast cancer patients. Methods: Between 2007 and 2011, 60 breast cancer patients were treated with DOC. Thirty-three patients (GJG group) received oral administration of 7.5 g/day GJG every day during DOC therapy and 27 patients (B12 group) received oral administration of 1500 μg/day B12. Peripheral neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm), Common Terminology Criteria for Adverse Events (CTCAE) ver. 3.0, and a visual analogue scale (VAS). Results: The median age of the GJG group was 58 years old (35 to 70 years old), the B12 group was 55 years old (33 to 69 years old), and they were all females. For the regimens, in the GJG group, TC (DOC and cyclophosphamide), DOC only, and XT (capecitabine and DOC) were administered in 19 cases, 13 cases and 1 case, respectively. In the B12 group, they were 15 cases, 11 cases and 12 cases, respectively. The cumulative dose of DOC was 338.5 mg/m2 in the GJG group, and 340 mg/m2 in the B12 group. The completion rate was 100% in both groups. The incidence of peripheral neuropathy was 39.3% in the GJG group, and 88.9% in the B12 group (p < 0.01). In the GJG group, grade 1 DEB-NTC was observed in 2 cases, grade 2 in 5 cases and grade 3 in 5 cases. Grade 1 CTCAE was observed in 7 cases, grade 2 in 6 cases, and VAS was 2.7 ± 2.2. In the B12 group, grades 1, 2 and 3 DEB-NTC were observed in one case, 12 cases and 12 cases, respectively; and grades 1 and 2 CTCAE were observed in 12 cases each, and VAS was 4.9 ± 2.4. Peripheral neuropathy was significantly controlled in the GJG group. Conclusions: Concomitant administration of GJG is useful in preventing peripheral neuropathy in breast cancer patients treated with DOC regimen.
Resection of breast cancer brain metastases: A single institution experience.
Authors: Brady Claire , Bambury Richard Martin , Battley Jodie E , Murray Susan , O'Reilly Seamus , Power Derek G , Moylan Eugene J. , Bermingham Niamh , Keohane Catherine , Karr George , Marks Charles , O' Sullivan Michael GJ
Published: March 2020

e11569

Background: Resection of a single brain metastasis (SBM) in metastatic cancer has been shown to improve overall survival (OS). A previously reported series from MD Anderson of breast cancer patients undergoing SBM resection reported a median overall survival of 19 months. We report our experience of SBM resection for breast cancer. Methods: Retrospective observational study of patients who underwent resection of SBM from breast cancer brain in a tertiary referral centre from 2000-2011. Results: 20 patients underwent SBM resection from 2000-2011. All patients received WBRT after surgery. 2 patients had progressive metastatic disease presenting as brain metastases. Median time from original breast cancer diagnosis to development of SBM was 53 months (range:1-286months). 9 patients had solitary brain metastases (no metastases elsewhere) and 11 patients had synchronous metastases elsewhere. Regarding the primary breast tumour: 41% of patients were ER+, 57% were HER2+ and 25% were triple negative. 1 patient had discordance of ER status between the primary tumour and brain metastasis (changed from ER- to ER+). Median overall survival was 9 months (95% CI: 5-18 months) with 1 year OS of 50%, 2 year OS of 15% and 3 year OS of 5%. Patients treated between 2006-2011 had better median OS than those treated 2000-2005(18 months vs 6 months – p-value not significant). Patients with a solitary brain metastasis had better median OS than those with synchronous extracranial disease (13 months vs 6 months – p-value not significant). An additional 2 patients underwent craniotomy for presumed breast cancer metastasis but histology revealed glioblastoma multiforme. Conclusions: We report on a cohort of patients undergoing metastatectomy for single brain metastasis from breast cancer. Median OS was 9 months but there was a trend towards better survival in patients treated in recent years when compared with those treated from 2000-2005. Improved systemic therapies may account for this difference. Also of note 2 patients undergoing resection for presumed brain metastases were found to have GBM, highlighting the role of tissue diagnosis in patients presenting with a solitary brain lesion.
Oral health-related quality of life among children undergoing cancer therapy.
Authors: Wong Hai Ming , Chu Chun Hung , Chan Godfrey Chi Fung
Published: March 2020

e12006

Background: Despite much interest in oral complications in cancer patients and studies reporting their prevalence, aetiology and management, there has been little understanding of how they affect the patients and the family. The aim of this study was, therefore, to assess the impact of oral complications on life quality for children undergoing cancer therapy. Methods: Seventy 6 - 14 years old paediatric patients undergoing cancer therapy in the Department of Paediatrics and Adolescent Medicine, Queen Mary Hospital, Hong Kong participated in this study. A clinical examination of the dentition and oral soft tissues was performed using criteria suggested by the World Health Organization. Clinical examination evaluated the status of: i) dental caries (DMFT/dmft Index), ii) periodontal health (CPI Index), iii) infection, such as herpes and candidiasis, iv) thrombocytopathy in the form of oral petechiae and spontaneous gingival bleeding, v) xerostomia, and vi) mucositis (WHO Mucositis Scale). Two questionnaires were filled by the children and their parents: i) the Child Perceptions Questionnaire (CPQ), and ii) a questionnaire contained simple closed questions to collect the information of oral health habits of children and demographic data from the parents. Results: Higher CPQ scores were found in children with mucositis (p < 0.001), dental caries (p < 0.001), children who were born in mainland China (p < 0.05), or parents of lower education or income level (p < 0.05). In multiple regression analyses, mucositis and dental caries were the significant predictors (p < 0.001) of the higher CPQ scores among the various parents and children characteristics collected in this survey. Conclusions: The findings of this study showed that paediatric cancer patients with mucositis and dental caries had poorer oral health-related quality of life.
Five vitamin D receptor polymorphisms (FokI, BsmI, Apa1, Taq1, and Cdx2) and lung cancer risk.
Authors: Li Rong , Tian Ming , Ma Meili , Pei Jun , Song Yiyi , Han Baohui
Published: March 2020

e12013

Background: Vitamin D and its receptor (VDR) have been implicated in lung cancer incidence and mortality. Here we assess the relationships between VDR single nucleotide polymorphisms (SNPs) (FokI, BsmI, ApaI, Taq, Cdx2) and lung cancer incidence in Chinese patients. Methods: Genomic DNA was extracted from peripheral blood samples. Five VDR SNPs (FokI, BsmI, ApaI, Taq, Cdx2) were detected by polymerase chain reaction. Genotype analysis was conducted using mass spectrograph. Results: A total of 67 lung cancer patients and 72 healthy controls participated in the study. There were more males and current smokers among the lung cancer patients than among healthy controls. Lung cancer patients were much older than controls. Age and smoking status were included in the equation for predicting disease status. The CC-AA (Apa1-Cdx2) and the CC-AA-CC (ApaI-Cdx2- FokI) haplotypes were associated with higher lung cancer incidence. The rs1544410 (BsmI) and rs731236 (TaqI) were not associated with higher lung cancer incidence, but they were associated with rs797523 (ApaI). Conclusions: There is a significant correlation between certain VDR SNPs (FokI, ApaI, Cdx2) and lung cancer incidence in Chinese people.
Malignancies and lung transplantation.
Authors: Perez Callejo David , Almagro Elena , Doger de Speville Bernard Gaston , Huelves Miriam , Ibeas Patricia , Lopez-Gonzalez Ana , Palka Magda , Ruiz-Valdepeñas Andrea , Mohr Raphael , Carreño MariCruz , Laporta Rosalia , Provencio Mariano
Published: March 2020

e12015

Background: Malignacies rank fourth on the leading causes of death in recipients of solid organ transplantation. High-dose immunosuppression, infections with oncogenic viruses and the pre-transplant risk, mainly due to tobacco, make these patients more susceptible for developing cancer. In the present study we reviewed a collective of 50 patients with lung transplantation (LT) and cancer. Methods: Retrospective study of 503 lung transplant patients, performed at the Hospital Universitario Puerta de Hierro during 1993 and 2012. We included the following variables: date of birth, reason and date of transplantation, date of diagnosis of malignancy, histology and response to treatment, date and cause of exitus. The contrasts between proportions were performed using Chi-square test and survival curves using the product-limit method of Kaplan-Meier. Results: The 503 included transplant patients developed a total of 55 post-transplant malignancies in 50 patients. Four patients presented tumors already previous to the transplantation. The main underlying pathologies of the patient collective are idiopathic pulmonary fibrosis (50%), emphysema (30%) and cystic fibrosis (14%). Histology of the 55 post-transplant tumors: 18 skin cancer, 12 lung cancer, 8 gastrointestinal cancer, 6 Non-Hodgkin Lymphomas, 2 bladder cancer, 2 myelodysplastic syndromes, 2 sarcomas and 5 others. The mean age of diagnosis of malignancies is at 59 years (18-68). The mean time from transplantation to tumor diagnosis amounts 4 years (1-15). Of the 21 patients (42%) that have died until data collection, cancer was death cause in 15 (30%) Conclusions: Relying on our data, the majority of malignancies are skin and lung cancer and lymphoproliferative syndromes, attributing complications that should be considered in lung transplantation.
Identification and functional characterization of a novel MUTYH gene mutation.
Authors: McDonnell Kevin , Chemler Joseph A. , Marvin Monica L. , Stern Ralph H. , Raskin Leon , Sherman David H. , Gruber Stephen B.
Published: March 2020

e12026

Background: Biallelic germline mutations in MUTYH result in the autosomal recessive syndrome of MUTYH associated polyposis (MAP).Three well-known, common mutations account for the vast majority of identifiable germline mutations, and serve as the basis for current genetic testing strategies. Comprehensive sequencing of MUTYH often identifies variants of uncertain pathologic significance, and studies to determine the pathogenicity of newly identified variants may offer valuable clinical information and mechanistic insights. In the present study we seek to describe the base-excision repair function of a novel MUTYH (p.C306W) mutation identified in a patient with multiple colon polyps and a family history of colon cancers. Methods: A 50 year old patient with >50 adenomas underwent clinical and laboratory evaluation to assess for germline genetic mutations. We performed Sanger sequencing of tumor and germline DNA together with targeted restriction enzyme digest of germline DNA and fragment DNA sequencing of the alleles. We prepared MUTYH proteins with protein liquid chromatography and assessed their mismatched adenine excision repair capacity employing a glycosylase assay. Results: Analysis of the patient's germline DNA revealed an absence of APC mutations, and the presence of the previously well characterized p.G396D MUTYH mutation as well as a novel p.C306W mutation. Targeted restriction enzyme digest demonstrated trans configuration of the p.G396D and p.C306W MUTYH mutations. Mismatched adenine excision functionality of wildtype MUTYH, known mutant controls p.G396D and p.Y179C, and putative mutant p.C306W were assessed in the glycosylase assay. Consistent with previous experimental observations, relative to wildtype MUTYH, the p.G396D and p.Y179C MUTYH mutants demonstrated attenuated adenine excision activities of 43% and 0%, respectively. Comparable to the activity of the pY179C mutant, the novel p.C306D mutant demonstrated 0% adenine excision activity. Subsequent tumor analysis demonstrated G:C to T:A transversion in the APC gene in somatic DNA derived from an adenoma. Conclusions: Experimental and clinical data demonstrate that p.C306D MUTYH is a pathogenic mutation contributing to the phenotype of MAP.
Spanish national hereditary pancreatic cancer registry (PanFAM).
Authors: Guillen-Ponce Carmen , Mocci Evelina , Earl Julie , Guerrero Carmen T , Calcedo Maria Celia , Salazar Maria Teresa , Molina-Garrido MJ , Marquez Mirari , Gonzalez Gordaliza Cristina , Vazquez Sequeiros Enrique , Custodio Ana , Real Francisco X , Malats Nuria , Carrato Alfredo
Published: March 2020

e12033

Background: Inherited predisposition to Pancreatic Cancer (PC) corresponds 10% of all cases and includes members of families affected with hereditary cancer syndromes as Familial Pancreatic Cancer (FPC), Peutz-Jeghers, familial melanoma, hereditary breast and ovarian cancer, hereditary pancreatitis. An inherited predisposition in early onset PC (≤ 50 years) has also been suggested. We report preliminary data on PanFAM patients and screening of high risk individuals. Methods: PamFAM is a part of the European PANGEN PC case/control study of hereditary PC, co-ordinated by the Ramón y Cajal (RC) hospital and the Spanish National Cancer Research Center, with 16 participating hospitals. All families with clinical evidence of an inherited PC syndrome were recruited and multi-generational pedigrees were constructed. Cancer diagnoses were confirmed, when possible, by review of medical records. Blood samples and epidemiological data were collected for all participating family members. A screening program for early detection of PC, based on endoscopic ultrasound (EUS), CT and circulating tumour cells (CTCs) was offered to high risk individuals. Results: Of 505 Spanish PCs collected by PANGEN, 31 (~6%) were FPC cases; 18 (58%) revealed only PC and the remaining showed clustering with other tumor types, gastric cancer was the most common (13%). Among FPC families, 3 had 3 cases of PC and the remaining had 2 cases. The mean age of diagnosis was 67 years (range 47-85), 20 male and 11 female. Four FPCs were previously diagnosed with cancer (Hodgkin lymphoma, breast and prostate cancer) and 3 with acute pancreatitis. 37 PCs with no family history of cancer were diagnosed at the age of 50 years or earlier (mean 45, range 30-50), 18 male and 19 female. Other 27 eligible families were recruited by RyC hospital, 8 (30%) with FPC and 3 (11%) with PC ≤ 50 years. A cohort of 61 high risk individuals participes in the screening study: 3 had abnormal EUS, 1 a benign pancreatic node and 1 a renal angiolipoma; one young man had 2 CTCs. Conclusions: PanFAM is the first registry in Spain collecting hereditary PC cases and it represents an important resource to identify underlying gene defects and to the development of screening methods precursor lesions detection in high risk individuals.
Breast cancer detection among Irish BRCA1 and BRCA2 mutation carriers.
Authors: Walsh Elaine , Farrell Michael P. , Gallagher Fergal , Clarke Roisin , Nolan Carmel , Kennedy M. John , Daly Peter , McCaffrey John , Connolly Elizabeth M. , Boyle Terence , Kell Malcolm R. , O'Keefe Sylvia , Gallagher David J
Published: March 2020

e12038

Background: High-risk breast cancer screening for BRCA1/2 mutations carriers with clinical breast exam, mammography and MRI have sensitivities approaching 100%. Even with intensive screening BRCA mutation carriers can present with self-detected interval cancers. We investigate screening practices and presentation among a cohort of Irish BRCA1/2 mutation carriers. Methods: Females with breast cancer belonging to kindreds now known to harbour BRCA1/2 mutations were retrospectively identified. Records were reviewed for BRCA mutation, demographics, breast cancer diagnosis, stage, histology and screening. We assessed screening modalities and whether breast cancers were diagnosed at screening or as interval cancers. Results: 53 cases of breast cancer were diagnosed from 1968-2010 among 53 Irish hereditary breast ovarian cancer kindreds. BRCA mutation status was unknown at time of diagnosis but subsequently confirmed. Detection method was identified in 50% of patients: 84% by clinical breast exam (CBE), 4% mammography, 4% MRI and 8% by a combination of CBE and mammography. Fifteen women (28%) developed second breast cancer; 9(60%) were undergoing screening, 2 were not and 27% were unknown. 22% were detected by CBE alone; 34% mammography; 22% a combination of mammography and CBE and 22% by MRI. In 41%, histology changed between first and second diagnosis. Two women developed a third breast cancer. In one, her second was an interval cancer despite being in a screening programme. Her third was radiologically detected. Conclusions: In this cohort of Irish BRCA1/2 mutation carriers almost 25% of second breast cancers were not detected by screening. 4% of cases were phenocopies and in 41% histology changed between first and second diagnosis. [Table: see text]
Rate of depressive episode in Peruvian oncologic outpatients.
Authors: Furuya Luis , Infanzon Erick , Venegas Diego
Published: March 2020

e12043

Background: Depression in Lima, Peru has a prevalence rate of 6.7% and lifetime prevalence of 19%. The relationship between depression and cancer has been widely studied, affects approximately 15% to 25% of cancer patients. However, there is little research in latin population. We report the results of evaluate the frequency of depressive disorder in Peruvian oncologic outpatients and describe clinical and epidemiological features Methods: A descriptive transversal study was performed to 70 patients that attended to oncology clinic at the Hospital Nacional Cayetano Heredia. Data was collected through a survey that included a clinical demographic record and the spanish version – ICD 10 of the Mini International Neuropsychiatric Interview for the diagnosis of depressive episode. Results: The 52% of the participants were females. The mean age was 57 years (18- 83 y) Breast cancer (21%) and lymphoma non Hodgkin (21%) were the most common types of cancer. The mean period from diagnosis was 5 month. The frequency of depressive episode was 21.4%. The 33.3% of women with breast cancer had depression, while patients with NHL had only 13.3% of frequency. We founded two factors with statistically significant association: poor financial status (p =0.041) and advance clinical stages (III and IV) (p = 0.026; OR: 6.8) Conclusions: The frequency of depressive episode was similar to other reports in the literature, the poor financial status and advanced stage are most associated with depression in our population
Association of gliomas and BRCA 1 germline mutation: A possible linkage.
Authors: Frenay Marc , Met Domestici Marie Amelie , Berthet Pascaline , Burel-Vandenbos Fanny , Vennin Philippe , Sobol Hagay , Lebrun Christine , Mari Véronique
Published: March 2020

e12502

Background: Gliomas are known to occur in association with several well-defined hereditary tumor syndromes such as NF1 and NF2, tuberous sclerosis, Li Fraumeni syndrom and Turcot syndrome. In addition, familial clustering of glioma in absence of these tumor syndrome have also been described. Methods: We have already reported the case of a 35 years old man who was diagnosed with an oligodendroglioma. Familial history reported 3 ovarian cancers at the first degree. Genetic testing had shown the BRCA1 exonic deletion c.3819del GTAAA, p. 1241 ter. (Patient 1 ) We collected 2 more cases of patients diagnosed with glioma and carrying BRCA1 mutation, whom have been seen by other physicians in an other hospital. Results: The second patient is a 59-year-old woman diagnosed with a glioblastoma with important oligodendroglioma differenciation (Patient 2). She was 43 at the time of diagnosis. At the age of 54, she developed a bilateral breast cancer. Moreover, the pedigree revealed a familial history of 4 breast cancers at the first degree. Genetic testing had shown the BRCA1 exonic substitution c.181T>G, p.Cys61Gly. The third patient is a 40-year -old woman diagnosed with an intra medullar pilocytic astrocytoma (Patient 3). This tumour is not usual which allows to keep in mind the genetic procedure. Beforehand, she had been diagnosed with a breast cancer at the age of 36. The pedigree revealed 6 breast cancers among the family and thus, BRCA analysis had been performed and showed the BRCA 1 exonic substitution c.3403 C>T, p.Gln 1135 X. Consequently, the patient had a prophylactic ovarian surgery at the age of 37 and contralateral prophylactic mastectomy at the age of 40. Interestingly, P1 had a BRCA1 deletion whereas P2 and P3 had BRCA1 substitution. On the other hand, P1 and P3 had Exon 11 mutation that both resulted in a truncated protein. Whereas, P2 had an exon 5 missens mutation. Conclusions: No specific association has been reported between BRCA1 mutation and glial tumor occurrence. These cases point out a possible relationship between BRCA1 germline mutation and glioma occurrence such as the relevance of familial history screening in glioma patients. Further investigations are needed to identify a disease-causing locus by genetic linkage analysis.
Meningeal hemangiopericitoma (HPC): Treatment outcome in a retrospective series in a single institution.
Authors: Muggeri Alejandro Daniel , CALABRESE BERNADETTE , Cerrato Sebastian , Cervio Andres , Diez Blanca D.
Published: March 2020

e12511

Background: HPC is a rare malignant tumor with a high proclivity toward recurrence and metastasis. Methods: The purpose of this study was to analyse retrospectively a series of eighteen patients with HPC treated between January 1992 and Oct 2011 with respect to clinical presentation, treatment results and long-term follow-up outcomes.Survival rate and PFS were analyzed by Kaplan-Meier method, with the use of two-sided log-rank test statistics Results: Twelve were females with a median age of 44.5 years (21-62). In 17 the tumor was intracranial, in one in the spinal cord. Median follow-up was 75,5 months (4 -314). Eight underwent gross total resection (GTR) and 2 of them received adjuvant radiotherapy. Ten had subtotal resection (STR) and 2 of them received RT. Three of 6 with GTR without RT relapsed. All patients with STR suffered local progression (2 after RT). Five developed systemic metastases after reiterate surgical resection (more than 3); three of them are alive with disease after further treatment at 11, 18 and 28 month. The median progression free survival (PFS) was 42,5 months (4-264), with 2 and 5-year PFS rates of 88% and 27% respectively. The 2, 5 and 10-year survival rates was 100, 93 and 81% respectively. All patients with GTR are alive (median follow-up: 60,5 months, range 30-125) and 3 of 10 patients with STR died (median follow-up: 81,5 months, range 4-314). Conclusions: When safe and feasible, GTR should be pursued as an initial surgical strategy to maximize overall survival. Adjuvant RT may show promise in preventing tumor progression in GTR patients. In metastatic disease long term survival could be achieved. The lack of a standard of care for HPC patients makes it especially important to do a complete workup, especially among patients presenting with recurrent HPC.
Once-daily oral afatinib (A) combined with pemetrexed (P) in patients (pts) with advanced solid tumors: A phase I dose escalation trial.
Authors: Chu Quincy , Sangha Randeep , Hotte Sebastien J. , Deng Qiqi , Gyorffy Steve , Chand Vikram K. , Hirte Hal W.
Published: March 2020

e13011

Background: A is an oral, irreversible, ErbB Family Blocker with single-agent activity in a variety of solid tumors. Preclinical studies have demonstrated additive antitumor effects when combining A or erlotinib with P in non-small cell lung cancer cell lines with sensitizing or resistant EGFR mutations. We hypothesized that once-daily A given with P would be safe and feasible in pts with advanced solid tumors. Methods: This Phase I trial was a standard 3+3 dose escalation design where A was administered orally at a starting dose of 30 mg/day on days 2–21 and combined with IV P (500 mg/m2) on Day 1 of a 21-day cycle. A was increased by 10 mg for each successive cohort until determination of the MTD, defined as the dose of A below which ≥2 of six pts experienced dose-limiting toxicity (DLT) in Cycle 1. MTD cohort was expanded to 18 pts and incidence and severity of AEs were graded according to CTCAE v3.0. Pts were treated to a maximum of 6 cycles with the option for A monotherapy thereafter. Results: 23 pts with advanced tumors were treated: 10 males, 13 females, ECOG 0/1/2 (30%/65%/4%), median age 58 yrs, and 57% received ≥3 prior chemotherapies. In Cycle 1, treatment-related DLTs were observed in six pts; two pts of three treated at 40 mg/day A dose and four pts of 20 treated at the MTD of 30 mg/day A dose. A and P were well tolerated, with the most frequent treatment-related AEs being diarrhea (91%; of which 86% were grade 1–2), stomatitis (65%) and rash (61%). Pts received a median of 2 cycles of treatment; five pts received >4 cycles, including one patient with serous ovarian cancer who continues on trial treatment beyond 14 months. Best response of 21 available pts included two partial responses, 14 with stable disease, and three with progressive disease. Detailed response and PK data will be further analyzed. Conclusions: In pts with relapsed or refractory advanced solid tumors, oral A at 30 mg/day combined with standard dose P (500 mg/m2) administered on Day 1 of a 21-day cycle, had an acceptable safety and tolerability profile. The study is currently evaluating an intercalated schedule of A on Days 2–6 with P based on preclinical synergy thought to arise from cell-cycle pharmacodynamic separation of A and P.
Proposal for a credentials-based clinical trials system.
Authors: Burke Lillian P.
Published: March 2020

e13012

Background: Molecular subtyping has identified drugable targets in many cancers; yet, often only a small proportion of cancers are affected by any specific alteration. This results in small patient subgroups, even for common cancers such as lung cancer. Agents such as imatinib and crizotinib have shown dramatic clinical efficacy but others with promise, e.g., PARP inhibitors, have difficulty in obtaining trial resources despite scientific rationale and support from both patients and physicians. Rare malignancies are not studied. The current clinical trials system makes it expensive to open a trial for rare cancers as reimbursement occurs only when patients are entered, leading to high costs per patient. Methods: Critical requirements for clinical trials in patient subgroups were identified and a system proposed to address these needs. Results: Requirements are: patient safety, oversight, data and biospecimen management, accurate imaging and dosing of drugs and radiation, pharmacy accountability, and efficiency. Regulations emphasize errors of commission while ignoring ethical issues related to failure to study rare cancers (i.e., errors of omission). A trials system that can address these concerns is proposed and is based on the well-established privileging system at hospitals. Physicians and others (e.g., nurses, data managers, pathology and radiology departments) would be credentialed to participate in trials depending on the skills required, e.g., PIs might be credentialed by study type/procedure (e.g., first in Man; phase I; phase I/II trials, or only phase IV; pharmacokinetic studies; Whipple procedures; sentinel node biopsies, biospecimen collection). Protocols could access this network only after rigorous review by a panel of experts. When a patient with a rare cancer/subtype is diagnosed, the PI would download the protocol from the internet and put the patient on study if the PI/institution met required credentials. Local IRBs would sign off on privileges, investigate complaints and monitor adherence to guidelines. Conclusions: A credential-based system might allow safe trials for rare patient groups although substantial regulatory issues would need to be addressed.
Selecting peptides for breast cancer treatment.
Authors: Suarez Eloah Rabello , Nader Helena Bonciani , Pinhal Maria Aparecida Silva , Del Giglio Auro
Published: March 2020

e13016

Background: HER2 is a member of epidermal growth factor family of receptors that is an essential mediator of cell proliferation and differentiation. In breast cancer patients, HER2 overexpression is associated with aggressive disease, chemo and hormone therapy resistance and poor prognosis. Currently, a HER2 specific monoclonal antibody, trastuzumab, is in use as a treatment for these breast cancer cases; however, there are many reports of resistance to this treatment. As an alternative we have selected specific peptides to HER2 using a phage display technology. Methods: A cyclic 7 aminoacids random peptide library had been panned using an external domain of recombinant HER2. After each round of binding assays, peptides were sequenced and two were selected. Cellular viability, migration and apoptosis/necrosis induced by these peptides were evaluated using SKBR3 cells. Confocal microscopy was used to determine the peptides co-localization with acidic vesicles and heparan sulfate. Western blotting was performed to evaluated some cell signalling pathways induced by these peptides. Results: The peptides were able to reduce the cell viability and migration around 50% alone and 85% in association. Tavelorb was able to induce apoptosis/ necrosis in 70% of SKBR3 cells and when associated with Hercid, the effect has increased to 90%. These peptides co-localize with acidic vesicles around 40-50%. The peptides and trastuzumab co-localized with heparan sulfate around 70%. The association between Hercid and Tavelorb inhibits Akt (pSer473) and the proteins enrolled in this pathway, as GSK3 and the transcription factor c-myc, however Akt inhibition is not dependent of PTEN. In addition, this peptides decreases BCL-XL, and MCL-1, while enhance Bax. The most important effect of this peptides is the reduction in β-catenin expression. Interestingly, p53 is downregulated in the presence of trastuzumab showing a mechanism by some tumors could be resistant to this therapy. Conclusions: The association of peptides has a very effective antitumoral effect in vitro, and their action seems to be HS dependent. The data propose a potential use of these peptides as a future alternative for breast cancer treatment. Supported by FAPESP, CNPq, CAPES.
Liver enzymes elevation due to concurrent dexamethasone and lapatinib: Clinical and in vitro evidence.
Authors: Teo Yi Ling , Saetaew Manit , Chanthawong Suthan , Yap Yoon Sim , Chan Eric Chun Yong , Ho Han Kiat , Chan Alexandre
Published: March 2020

e13023

Background: Concomitant usage of lapatinib (L) and dexamethasone (D), which are cytochrome P450 (CYP) 3A4 substrate and inducer respectively, may increase the formation of potentially hepatotoxic reactive L metabolites. This study aims to evaluate the effect of D on the occurrence of liver enzyme elevation and to ascertain its role using a parallel in vitro experiment. Methods: Clinical effects of D on L-induced liver enzyme elevation were evaluated in a nested case-control study. Liver enzyme elevation is defined as the first clinically significant change (from baseline) of either total bilirubin (TB), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) by at least 1 grade, based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.02. In the in vitro study, metabolically-competent transforming growth factor α mouse hepatocytes (TAMH) cells were treated with L and viabilities were compared in the presence or absence of D. Results: Among 97 patients, liver enzyme elevation episodes (87.5% vs. 60.3%, p=0.01) and ALT elevation (41.7% vs. 19.2%, p=0.03) occurred more frequently among patients receiving concomitant L+D comparing to L only. After adjusting for confounders (age, liver and brain metastasis, baseline liver function test (TB, AST, ALT, alkaline phosphatase), underlying liver disease, concurrent use of hepatotoxic medications), patients receiving concomitant L+D were 3.48 times (95% CI 1.24-9.80, p=0.02) and 4.57 times (95% CI 1.23-16.88, p=0.02) more likely to develop a change in ALT and among all liver enzymes respectively. Parallel to our clinical findings, treatment of TAMH cells with L reduced viability in a concentration-dependent manner. The introduction of D further reduced the viability. At 5 µM of L, the introduction of 10 µM and 20 µM of D resulted in a 19% and 59% decrease in viability respectively. Conclusions: The concomitant usage of L+D was associated with an increased occurrence of liver enzyme elevation. The in vitro findings have provided commensurating evidence on the role of D that increases the formation of L-derived hepatotoxic metabolites.
Impact of weight and creatinine measurements in carboplatin dosing.
Authors: Boumedien Feriel , Arsenault Youri , LeTarte Nathalie
Published: March 2020

e13027

Background: Controversy surrounding weight in Carboplatin dosing is still current. Also, new methods of measuring serum creatinine have raised more questions regarding the precision of Carboplatin dose calculations. The two objectives of this study were to evaluate the impact of alternative weight indicators (actual and adjusted body weight) in the Cockcroft–Gault equation and the use of different creatinine measurements (standard and IDMS) in order to accurately predict Carboplatin dose. Methods: We performed a retrospective chart review on all patients who received at least one dose of Carboplatin between March 7th and May 8th 2010. The patients were divided into two groups according to their body mass index (BMI): 20 < BMI < 27 and BMI ≥ 27. The differential creatinine clearance and Carboplatin dose were assessed in each group using the actual body weight and the adjusted body weight with IDMS creatinine. Moreover, for patients who had their creatinine measurement at the CHUM hospital, we calculate the difference in Carboplatin dose by using the standard creatinine (SC) measurement and IDMS creatinine with the same weight. Results: A total of 95 patients, representing 119 Carboplatin doses, were included in the analysis. 82% were women and median age was 63. The average BMI was 26,6. The Carboplatin expected AUC was 5 for 89% of patients and Carboplatin was associated to Paclitaxel in 78% of patients. In patients with a 20<BMI< 27 (44%), the average difference between the calculated dose using their actual body weight and adjusted body weight was +6.03% (95% CI, 5.2 to 6.9%). For patients with a BMI ≥ 27 (43%), the mean dose difference was +20.6% (95% CI, 18.8 to 22.5%). The use of SC or IDMS creatinine led to a discrepancy in doses of 5.2% (95% CI, 4.7 to 5.7%) for patients with BMI <27 (35 patients) and 5.5% (95% CI, 4.9 to 6.2%) for those with BMI ≥ 27 (23 patients). Conclusions: Based on these findings, we decide in our clinic, to use the actual body weight for patients with a BMI between 20 and 27, and the adjusted body weight for those with a BMI ≥ 27. We also chose not to modify our doses based on the type of the serum creatinine measurement.
Safety and efficacy of dendritic cell immunotherapy with ad-GMCAIX in an immunocompetent preclinical tumor model of renal cell carcinoma.
Authors: Birkhäuser Frédéric D. , Koya Richard C. , Neufeld Caleb , Lu Xuyang , Micewicz Ewa D. , Chodon Thinle , Atefi Mohammad , Kroeger Nils , Rampersaud Edward N. , Chandramouli Gadisetti V.R. , Li Gang , Said Jonathan W. , Ribas Antoni , McBride William H. , Kabbinavar Fairooz F. , Pantuck Allan J. , Belldegrun Arie S. , Riss Joseph
Published: March 2020

e13045

Background: We have previously reported the successful ex vivo generation of hCAIX-specific cytotoxic T lymphocytes (CTLs) by adenoviral (Ad) transduction of the GMCAIX fusion protein in dendritic cells (DC). We then produced GMP-grade material (NIH-RAID program, NSC 740833). Now we test, for the first time, the in vivo anti-tumor activity of DC-Ad-GMCAIX against renal cell carcinoma (RCC) in a unique immunocompetent mouse tumor model. Methods: Tumor growth inhibition and specificity were studied in BALB/c mice s.c. transplanted with either syngeneic RENCA cells transduced with hCAIX (URCAIX) or with non-hCAIX-expressing RENCA cells (RENCA). In a tumor prevention model, cohorts of mice were first immunized s.c. twice with DC-Ad-GMCAIX, DC-Ad-null, or no DCs, followed by tumor challenge with s.c. transplantation of URCAIX or RENCA cells. In an intervention model, tumors were first established and then immunotherapy was employed. Tumor volume and body weight were regularly assessed. Partial necropsy, immunohistochemistry of harvested tumors, and complete blood count were performed at termination of each study. Results: In the prevention model, URCAIX tumor growth was specifically and significantly inhibited for 15 days (p<0.0001). At termination, median growth inhibition reached 79% (113 vs. 531 mm3) and half of the mice remained tumor-free. In the intervention model, DC-Ad-GMCAIX-treated mice showed specific and significant growth inhibition of URCAIX tumors for 8 days (p<0.0018) with a median growth inhibition reaching 60% (487 vs. 1,205 mm3). The threshold of 15% weight loss was delayed in the therapeutic groups of both models (p<0.0167). No treatment-related weight loss or organ toxicity was observed. hCAIX staining was absent or minimally present in URCAIX-tumors that evaded DC-Ad-GMCAIX therapy. Conclusions: DC-Ad-GMCAIX therapy in a novel immunocompetent mouse model demonstrated, for the first time, both tumor prevention and growth inhibition of established RCC tumors without evidence of systemic toxicity. These studies form the basis for first-in-human clinical trial in patients with advanced RCC.
Phase I trial of everolimus, gemcitabine and cisplatin for patients with solid tumors refractory to standard therapy.
Authors: Costello Brian Addis , Qi Yingwei , Borad Mitesh J. , Kim George P. , Northfelt Donald W. , Erlichman Charles , Alberts Steven R.
Published: March 2020

e13052

Background: The combination of GEM and CDDP has shown activity in a variety of cancers, including biliary tract/gallbladder. Preclinical testing shows a potential benefit to the addition of EV. Methods: Using a standard 3+3 design, the MTDs of GEM + EV (Cohort I) and GEM + CDDP + EV (Cohort II) were determined as shown in the table. The MTD was defined as the dose level below the lowest dose that induces a DLT in at least one-third of pts. At the MTD of Cohort II, 10 patients were enrolled with biliary tract/gallbladder cancer (Cohort III). A weekly CBC was obtained. Assessments occurred every 3 weeks and imaging for response at every other cycle. Results: In Cohort I (N=12), no DLT occurred at dose level 0, and in dose level 1, grade 3 thrombocytopenia was found in 2 of 6 pts. The MTD for Cohort I was determined to be dose level 0. Responses were seen in 3 pts: 2 CRs (primary peritoneal, pancreatic) and 1 PR (breast). In Cohort II (N=15) DLTs at dose level 0 were neutropenia and thrombocytopenia in 2 of 3 pts and at dose level -1, thrombocytopenia in 2 of 6 pts. At dose level -2, 1 of 6 pts experienced a DLT (grade 3 thrombocytopenia), establishing this dose level as the MTD. Responses were seen in 2 pts, both PRs (ampullary, pheochromocytoma). All 10 pts have been enrolled in Cohort III with 2 DLTs (neutropenia and thrombocytopenia). Stable disease seen in 5 of 7 evaluable pts. Conclusions: Gem + EV was well tolerated at dose level 0, though dose escalation was limited by thrombocytopenia. GEM + CDDP + EV had DLTs of neutropenia and thrombocytopenia leading to the MTD of dose level of -2. Cohort III is fully accrued and the 2 DLTs are hematologic. [Table: see text]
International guidelines for antithrombotics in cancer patients.
Authors: Farge Dominique , Debourdeau Philippe , Beckers Marielle , Buller Harry ,   Working Group on International Recommandation for Thrombosis and Cancer
Published: March 2020

e13062

Background: Venous thromboembolism (VTE), defined as deep-vein thrombosis (DVT) or pulmonary embolism (PE), including those related to indwelling central venous catheter (CVCT), is reported in 15 to 20% of patients with cancer. To date, VTE impact on oncology patients remains elusive and the increased incidence of cancers and of CVC for chemotherapy leads to an increased number of VTE. Methods: Heterogeneity in clinical practices worldwide, and lack of international recommendations led us to establish international guidelines for the management of VTE in cancer patients according to the GRADE methodology. These international guidelines were elaborated under the auspices of the International Society of Thrombosis and Haemostasis (ISTH) following an initiative from the “Groupe Francophone Thrombose et Cancer” (GFTC,www.thrombose-cancer.com) with the collaboration of the Academic Medical Centre (AMC), Amsterdam, The Netherlands, and the methodological support and quality control of the French national cancer institute (INCa). A literature review of the studies published on this topic between 1996 and 2011 was performed. A first version of the guidelines was established based on the corresponding levels of evidence derived from analysis of the selected studies. The recommendations were classified as Strong or Weak according to GRADE and Best Clinical Practices based on international expert’ agreement in the absence of literature data. In the absence of data we provided guidance based on experts opinion. The document was then peer-reviewed by a group of 200 international independent experts. Results: The main topics of the guidelines are the treatment and the prophylaxis of VTE with heparins and vitamin K antagonists in medical and surgical cancer patients, including CVC related thrombosis. Recommendations on the use of vena cava filters, thrombolysis and VTE treatment in patients with intracranial malignancies as well as for prophylaxis in the ambulatory setting are also proposed. Conclusions: These first international guidelines, the methodological steps, the data analysis and critical appraisal, the conclusions with their levels of evidence and the argued judgement of the experts will be available on the GTC, INCa and ISTH web sites
Retrospective analysis of intravenous iron-sucrose therapy in patients undergoing chemotherapy at a tertiary-care center in India.
Authors: Bajpai Jyoti , Gupta Sudeep , Shah Kajal , Ghosh Jaya , Noronha Vanita , Prabhash Kumar , Kanujia Arti
Published: March 2020

e13068

Background: Cancer patients frequently have anemia as a result of nutritional deficiencies, malignancy or its treatment. Administration of intravenous (IV)-iron is a therapeutic option in cancer patients with iron-deficiency-related-anemia. Methods: This is a single-institution retrospective-study of 399 patients who were undergoing chemotherapy for non-myeloid malignancies from January 2006 to December 2009 and had hemoglobin ≤11 gm/dl. They received two doses of iron-sucrose, 200-300 mg each as short IV- infusion, 3 weeks apart. The data was recorded at baseline and 3-6 weeks after IV-iron administration in all patients. Results: Of 399 patients, 326(81.7%) had non-hematological malignancies. Transferrin-saturation (TSA) was available in 149 patients. The mean (range) baseline hemoglobin, mean-corpuscular-volume (MCV) and TSA were 9.75(8.0-11.3) gm/dl, 82.4(52.5-100.3) fl and 18.38 (5.2-34.0)%, respectively. After 2 doses of IV-iron hemoglobin increased in 340 (85.2%), reduced in 32 (8.0%) and did not change in 27 (6.7%) patients. The mean (range) increase in hemoglobin was 0.7 (-3.2 to +3.2) g/dl in all patients and 0.95 (0.1-3.2) g/dl in 340 patients in whom it increased after IV-iron. The data were analyzed by low (≤ 83 fl) versus normal (>83 fl) MCV and low (≤20%) versus normal (>20%) TSA. Hemoglobin increased more than the mean increment (0.7 g/dl) in 63.8% patients with low MCV compared to 39.2% of patients with normal MCV (p=0.002). Hemoglobin increased more than the mean increment (0.7 g/dl) in 60.4% of patients with low TSA compared to 58.6% with normal TSA (p=0.479). These results suggest that IV iron was more efficacious in patients with low MCV. Two patients (0.005%) developed anaphylactic shock during or shortly after IV-iron administration and 35 (11.7%) had minor side effects. Thirty (7.5%) patients received RBC transfusions during their continued chemotherapy. Conclusions: Intravenous-iron improved hemoglobin during continued chemotherapy in the large majority of cancer patients with anemia and was safe and tolerable. Low MCV might serve as a surrogate for iron-deficiency-microcytic-anemia in developing-world.
Autologous cytokine-induced killer and dentritic cells in treatment of advanced and unresectable lung cancer.
Authors: Zhang Lei , Li Baoping
Published: March 2020

e13069

Background: Both experimental and clinical studies showed cytokine-induced killer (CIK) cells have been shown capable of efficiently lysing target tumor cells, which activity can be enhanced by dendritic cell (DC) stimulation. This study demonstrated that co-cultured autologous CIK and tumor antigen-pulsed DC are effective in in treatment of advanced and unresectable lung cancer Methods: Sixteen patients having stage III-IV lung cancer with a malignant pleural effusion, 9 females and 7 males with an average age of 54.3 years old, were included in this study. Autologous CIK and DC were prepared from isolated peripheral blood mononuclear cells and were induced by multiple cytokines. Generated DCs were pulsed by the antigen generated from tumor tissues and co-cultured with CIK. Those patients received 4-6 times of CIK-DC intravenous infusion, 2-3 ×109 cells each time. Results: Eleven (68.8%) patients achieved a partial remission. The pleural effusion decreased in all those patients, and in 9 of them the effusion decreased over 50%. The clinical symptoms were relieved in all the patients. There were no significant adverse effects were found. Those patients are still followed for long-term survival outcome. Conclusions: CIK-DCs immunotherapy provides a new and effective treatment for the late stage lung cancer.
In vitro chemosensitivity assay for patients with gynecologic sarcoma.
Authors: Santin Alessandro , Varughese Joyce , Chan John K. , McClure Candace , Lea Jayanthi
Published: March 2020

e13078

Background: This study describes the in vitro drug response of gynecologic sarcomas and clinical implications of in vitro testing. Methods: Ovarian or uterine sarcomas were analyzed for response to any of 7 drugs (carboplatin [Carb], cisplatin [Cis], paclitaxel [Ptx], docetaxel [Dtx], doxorubicin [Dox], gemcitabine [Gem], Ifosfamide [Ifo]) with a chemosensitivity assay (ChemoFx, Precision Therapeutics, Inc, Pittsburgh PA). In combination therapy, tumors were considered sensitive if responsive to at least 1 drug. Results: 68 tumors were analyzed (21 ovarian and 47 uterine; 54 primary and 14 recurrent; carcinosarcoma [n=53], leiomyosarcoma [n=13], other [n=2]). 24% of tumors were responsive to Carb, 30% to Cis, 33% to Ptx, 9% to Dtx, 18% to Dox, 26% to Gem, 27% to Ifo, 40% to Carb+Ptx, 39% to Cis+Ifo, 48% to Ptx+Ifo, 24% to Gem+Dtx, and 27% to Gem+Dox (Table). Ovarian sarcomas were more responsive than uterine sarcomas and primary more than recurrent tumors. Carcinosarcomas were more responsive than leiomyosarcomas to Ifo (P=0.02). Conclusions: In vitro tumor response testing may enable physicians to individualize chemotherapy regimens for their patients. [Table: see text]