bluuebunny/crossref_metadata_2025 huggingface dataset:
Results of the MARS study on the management of antiangiogenics’ renovascular safety in breast cancer.
Authors: Gligorov Joseph , Janus Nicolas , Daniel Catherine , Beuzeboc Philippe , Ray-Coquard Isabelle , Rey Jean-Baptiste , Jouannaud Christelle , Spano Jean-Philippe , Thery Jean Christophe , Morere Jean F. , Goldwasser Francois , Mir Olivier , Scotte Florian , Oudard Stephane , Azizi Michel , Dorent Richard , Deray Gilbert , Launay-Vacher Vincent
Published: March 2020

e12504

Background: Anti-VEGF drugs (AVD) are widely used in cancer patients (pts). Hypertension (HTN) and proteinuria (Pu) are class-side-effects of AVD, related to the inhibition of the VEGF pathway. The MARS study has been conducted to assess the renovascular tolerance of these drugs in the clinical setting. Methods: This multicentric, prospective, observational study evaluated the renovascular safety of AVD in pts naive from any AVD, conducted in 7 centres in France, from 2009 to 2012, with a follow-up (f/u) of 1 year. Data collected included: gender, age, serum creatinine (SCr), diabetes, HTN, hematuria (Hu) and dipstick Pu, at baseline and at each visit. Results: 1,124 pts were included; 402 breast cancer (BC) pts received bevacizumab. Median age at inclusion was 55 years. Visceral, bone and cerebral metastasis frequencies were 74.7, 5.1 and 2.5%, respectively. HTN prevalences: 12.4%. Baseline renal assessment retrieved: Pu 23.9%, Hu 16.2%, mean aMDRD 96.4 ml/min/1.73m2 and 14 pts with aMDRD<60. The incidence of de novo Pu and HTN during f/u was 61.7 and 16.8% (Table). 69.7 % of pts with Pu at inclusion improved or remained stable. Among pts with de novo Pu, 75.7% afterwards improved/normalized. No grade 4 Pu has been reported. Renal function remained stable with a mean aMDRD of 96.2 at the end of f/u. 7.4% had grade 2-3 SCr increase (no grade 3-4). No thrombotic micro-angiopathy (TMA) was reported. Conclusions: These results on the renovascular safety of bevacizumab in BC patients showed that 1) TMA is rare, 2) Grade 3 Pu developed in 4.6% of pts, with no grade 4, 3) less than 17% developed HTN, and 4) aMDRD was stable. Furthermore, in case of a renovascular effect, investigators followed the recommendations from the French Society of Nephrology (Halimi JM. Nephrol Ther 2008) and no treatment withdrawal for unmanageable renovascular toxicity occurred. [Table: see text]
Familial breast cancer in Spain: A retrospective study of family history and clinical/pathologic characteristics from the GEICAM “El Álamo III” project.
Authors: Marquez-Rodas Ivan , Pollán Marina , Lluch Ana , Ramon y Cajal Teresa , Guerrero-Zotano Angel , Servitja Sonia , Martin Miguel , Blanco Ignacio , Martinez del Prado Purificacion , Gonzalez-Santiago Santiago , Santaballa Ana , Llort Gemma , Andres Raquel , Ortega Granados Ana Laura , Jara-Sanchez Carlos , Juan Fita Maria Jose , Caballero Rosalia , Escudero Maria Jose , Carrasco Eva Maria , Lopez-Tarruella Sara ,   Spanish Breast Cancer Research Group (GEICAM)
Published: March 2020

e12513

Background: Family history (FH) of breast cancer (BC), ovarian cancer (OC), and individual features (IF), like early age of onset, bilateral BC, coexistence of BC and OC, and triple negative BC (TNBC) younger than 50 years, are suspicion criteria of hereditary BC. Although it is assumed in the literature that 15-30% of BC cases can be familial BC (FBC), only 5-10% of BC are hereditary, explained by a germline mutation in BRCA1 or 2. Moreover, there is no international consensus to define FBC (e.g. number of relatives affected, age of onset), in contrast with, e.g. Lynch syndrome and Amsterdam/Bethesda criteria, in order to offer genetic counseling. In Spain, there are not population-based studies analyzing the real percentage of BC with familial and/or individual high risk features. Methods: A retrospective study based on 10,641 Spanish BC patients diagnosed from 1998-2001, collected in the “El Álamo III project”, was conducted. Specific data regarding FBC were analyzed: IF (age of onset, bilateral breast cancer, ovarian cancer and TNBC; and FH features (first and second degree relatives with BC and /or OC). Results: The Table summarizes the results. Conclusions: 21% of BC patients in Spain diagnosed from 1998 to 2001 have at least one relative with BC and/or OC. In addition, 2.8 % of patients with no FH of BC/OC fulfill high risk criteria. However, several study characteristics, such as 18% patients with no FH recorded, and lack of data regarding age of affected relatives, limit the interpretation of these results, being necessary to improve the family data collection in further “El Álamo” project studies. [Table: see text]
SMRP in screening of mesothelioma in asbestos-exposed workers: A study of 1,704 subjects.
Authors: Mencoboni Manlio , Cioe Alex , Michelazzi Luigi , Bruzzone Andrea , DelCorso Lisette , Simonassi Claudio , Mortara Virginia , Filiberti Rosangela , Marroni Paola , Spigno Fabio
Published: March 2020

e12518

Background: The soluble mesothelin-related peptide (SMRP) is a marker in the diagnosis for mesothelioma. The role of SMRP as a potential screening tool in subjects with a past asbestos exposure is being debated. Objective: to evaluate SMRP and incidence of malignant mesothelioma in an asbestos exposed cohort. Methods: 1,704 subjects (Median Age 62) occupationally exposed to asbestos were enrolled in the study. A questionnaire on individual characteristics, disease history, and occupational or non-occupational exposure to asbestos was administered. All subjectsunderwent clinical examination and collection of serum sample for SMRP measurement that were repeated after 1 and 2 years. The samples were stored at -80 °C until assayed. Results: Median baseline SMRP was 0.45 nmol/l (range 0.1-4.45). SMRP was higher than 1.5 nmol/l (defined as cut-off) in 40 participants. 9 subjects had recognized lung cancer at the time of screening (median baseline SMRP 0.65 nmo/l, range 0.1-1.7) and 109 had recognized tumors at other sites (median 0.52 nmol/l, range 0.1-3.0). Overall, median follow-up of all subjects was 31.5 months During follow-up, recurrent or metastatic tumors were observed in 23 out of 118 tumors. Sixty-one subjects developed a new tumor. An epithelioid pleural mesothelioma occurred in two subjects, 13 and 17 months after the last SMRP evaluation, respectively. Baseline SMRP was 0.52 nmol/l and 0.17 nmol/l, respectively. In subjects with tumor, SMRP increased of 20-50% in 13 subjects (15%), two of them with abnormal SMRP (1 bladder and 1 prostate cancer). An increase greater than 50% was found in 19 subjects (22%). SMRP was higher than the threshold value in 3 tumors (1 lung, 1 colon and 1 prostate, diagnosed 2 months from last SMRP measure). Overall, mesothelin was above the cut-off in 58 subjects without any evidence of neoplastic disease. Conclusions: we cannot confirm the predictive role of SMRP for mesothelioma because we found two cases with low mesothelin levels 13 and 17 months before the diagnosis. The low number of mesotheliomas could be due to the low median age of our population. It will be intriguing to follow up in the future the subjects that showed an increase of SMRP.
Epidemiology of oral cancers referred for NACT, the demographics, clinical profile, and organ functions.
Authors: Rath Sushmita , Patil Vijay Maruti , Noronha Vanita , Joshi Amit , Bhosale Bharatsinha Baburao , Punatar Snehal , Poladia Bhavesh , Sahu Arvind , Juvekar S , Chaturvedi Pankaj , D'cruz Anil K , Prabhash Kumar
Published: March 2020

e12520

Background: The use of neoadjuvant chemotherapy(NACT) in head & neck cancers is not well defined. Very few publications on this topic deal with the epidemiology ,clinical & biochemical profile. These factors have an important say in deciding the choice of regimen. Methods: An prospective analysis of oral cavity cancer patients ,who were referred for NACT at our center, was done. The analysis focussed on the demographics, clinical & biochemical parameters of these patients at presentation . Results: From 2010-2012 , 528 patients of oral cavity cancers were referred for NACT from the multidisciplinary clinic. The median age of patients was 45 years (22-78 years) ; 10.4% were above the age of 60 years and 83.7% were males. Only 16.5% of patients were from the city in which the hospital was located. 69.1% were tobacco users, 53.8% were smokers , 37.5% were alcoholic & 81.5% had in addition other local tobacco containing chewable preparations. Only 2.65% denied any addictions. Amongst the symptoms pain, facical swelling,oral ulcer , oral bleeding, foul smell, trismus & weight loss were present in 41.9%, 72.5%, 57.6% , 72.5% , 77.1%, 41.4% & 49.4% respectively. The ECOG performance status were 0,1,2 in 8.3%, 84.7%, 2.7% patients respectively. The subsite of the disease were buccal mucosa,tongue, floor of mouth, alveolus, hard palate in 67.8%, 24.4% ,4.7% , 0.9% ,1.1% respectively. 65.3% & 16.7% patients were in T4a and T4b stage. N2b(42%) and N2c (31.4% )were the most common N stage seen. All patients had stage IV disease. Comorbidites like diabetes mellitus, hypertension and cardiac disease were seen in 22.3%, 18.9% & 13.3%. The median BMI was 21.45 Kg/m2 & 24.3% had BMI below 18.5 Kg/m2 (severly malnourished). The need for NACT was mainly due to extensive disease ,edema reaching upto zygoma and edema upto hyoid bone .The regimens administered were TPF in 6.6% and Taxane with Platinum in rest others. The major reasons for not selecting TPF were logistics (75%) & malnourished status (25%). Conclusions: Patients referred for NACT at our center had locally advanced disease,nearly all were addicts, one fourth had severe malnourishment & current standard TPF could be administered in only a few of them.
Evaluation of chemotherapy benefit in patients who continue to smoke: Preliminary experience.
Authors: Jirillo Antonio , Rescigno Paola , Mazurek Magdalena , Trojniak Marta Paulina , di Maggio Antonio , Imbevaro Silvia
Published: March 2020

e12534

Background: The smoking continuation during chemotherapy treatments affects positive results. As reported for instance by Mazza et al. in the review "Taking care of smoker cancer patients: a review and some recommendations" (Ann Oncol. 21(7):1404-9, 2010), nicotin seems to inhibit the potential of cisplatin in determining tumor cell death (Int J Oral Maxillofac Surg 2007; 36: 739–744), while some new anti-cancer drugs can give an excellent response only in people who have never smoked (Proc Natl Acad Sci U S A 2004; 101(36): 13306–13311). Methods: It is an observational monoistitutional analysis. The analysis covered 886 patients undergoing chemotherapy at the Veneto Oncology Institute of Padua during an observation period of six years (from 2006 to 2011). We have been taken into account all patients included in the Onco-AIFA national register for the monitoring of innovative anticancer drugs, focusing on the three big killer diseases: colon and rectum cancer (40% of the sample analyzed), lung cancer (36%) and breast cancer (24%). The Kaplen-Meier method was used to analyze the overall survival data. Results: Among the information collected, the aspect of smoking was taken into account: it was possible to extract the data for about half of the patients (n = 473), 48% of whom were non-smokers, 31% were smokers and the remaining 21% ex-smokers. Although there are three types of cancer that have three different natural histories, the study revealed that being a smoker or ex-smoker is a determinant of the OS of patients: in particular non-smokers showed a median survival of 27 months, ex-smokers of 18 and smokers of 13 (p <0.001). Conclusions: It should be noted then, that in the entirety of the sample smoking continuation reduces survival. Therefore, in addition to an increased risk, there is a reduced benefit in terms of clinical conditions and response since tobacco reduces the effects of anticancer chemotherapy. That being so, although the data are still preliminary, every effort must be made to ensure that a patient stops smoking during chemotherapy treatments as it has been demonstrated that the ex-smokers live an average 6 months longer.
Mammographic findings in locally advanced breast carcinoma treated with neoadjuvant chemotherapy.
Authors: Castañeda Carlos , Flores Raymundo , Rojas Katerin Ingrid , Flores Claudio J , Morante Zaida , Pacheco Christian , Ruiz Rossana Esther , Calderon Gabriela , Gomez Henry Leonidas , Vidaurre Tatiana
Published: March 2020

e12538

Background: Breast Cancer (BC) is a heterogeneous disease. Mammograpy images of BC has been associated with tumor features. We evaluated relationship between radiologic features of pre-neoadjuvant chemotherapy (NAC) lesions and clinico pathological tumor features. Methods: We evaluated mammography films and clinicopathological information of BC patient who received NAC followed by tumor resection at Instituto Nacional de Enfermedades Neoplásicas from 2000 to 2011. Results: 495 BC cases were selected. Most cases were staged in clinical Tumor size stage 4 (48.2%) and node stage 1 (58.7%); and had a GIII histological grade (51.2%). Breast density (BD) was classified as BIRADS grade 1 in 17%, grade 2 in 22%, grade 3 in 35% and grade 4 in 25.3%. High BD has been associated to younger age (p<0.001) and obesity (p=0.012). An association between mammographic rounded shape and triple-negative (TN) phenotype was found (p=0.002). An association between the dusty microcalcification and HER2 group as well as between the casting and the TN BC group (p=0.001) is found. NAC included anthracyclines and taxanes in 422 (85.4%) cases. Four and 5 Miller Payne pathologic response (pR) in the primary lesion and absence of axilary lymph nodes involvement were found in14.8% of the whole population, and in 10.5% of luminal cases, 17.7% of HER2- enriched and 23% of TN BC. pCR was associated to patient age (p<0.001), tumor grade (p<0.001) and high breast density (p=0.001), as well as better DFS (p=0.05). Conclusions: Radiographic images are related to tumor features in pre-NAC BC cases. pCR is associated to high density breast as well as previously described clinicopathological features.
Risk of colorectal cancer and endoscopic screening in families of patients with hereditary nonpolyposis syndrome of colorectal cancer.
Authors: Belev Nicodim F. , Mindruta-Stratan Rodica , Iarovoi Diana , Kazubskaya Tatiana , Brega Diana
Published: March 2020

e12543

Background: Relatives of patients with hereditary nonpolyposis colorectal cancer (HNPCC) have an elevated risk of colorectal cancer (CRC) and adenomas. To determine the efficacy of endoscopic screening among relatives of patients with HNPCC syndrome. Methods: 50 relatives of the first and 17 relatives of the second-degree relatives of 127 families of patients with HNPCC syndrome was subjected to endoscopic screening (colonoscopy). Results: The analysis of cancer register database of families, which includes clinical and genealogical information about 1,505 patients with colorectal cancer (CRC) and 407 with the primary multiple malignant neoplasms (PMMN), found 127 (6.6%) families, which are consistent with Amsterdam criteria of HNPCC. Among the 1057 first-degree relatives malignancies were detected in 238 (22.5±2.7%). The CRC among of the first degree relatives of patients with HNPCC syndrome was identified in 118 (11.2±2.9%), which is 20 times the population frequencies (0.56±0.004%) (p<0.001). The frequency of aggregation of PMMN and adenomas of the colon was 1.8±3.1% (19) è 0.6% (6), respectively. Prevalence of PMMN in the general population is 0.009±0.0005%, and adenomas - 4.7±1.4%. From 809 of first degree relatives 50 were available for the survey, and from the 924 second degree relatives - 20. The endoscopic screening of first degree relatives found the presence of different pathology in 35(60.0%±8.3%) surveyed persons, including CRC – at 19(38.0±11.4%) (p<0.01), primary multiple colorectal cancer – at 6(12.0±14.5%), adenomas - at 5(10.0%). Among the surveyed second degree relatives the pathology was identified at 8(40±18.5%), primary multiple colorectal cancer at 3(15.0%), and adenomas of the colon – at 5(25%). Conclusions: Colonoscopy is an effective method for identifying malignant and benign tumors of the colon at relatives in the families of patients with HNPCC syndrome. A high percentage of cancer detected in these families need to refine the survey mode in order to identify early forms of cancer and its secondary prevention.
Molecular profiles of screen-detected breast cancers from a Turkish breast cancer screening program.
Authors: Cabioglu Neslihan , Ozkan Gurdal Sibel , Kayhan Arda , Ozaydin Nilufer , Aribal Erkin , Ozmen Vahit
Published: March 2020

e12545

Background: TurkishBahcesehir Breast Cancer Screening Project is a 10-year organized population based screening program carried out in one of the largest counties in Istanbul, Turkey. The aim of this study is to determine the biological features of screen detected breast cancers detected during the initial 4-year study period as an interim analysis. Methods: Between January 2009 and December 2012, a total of 5938 women with ages 40–69 years were recruited in this prospective study. Two-view mammographies were obtained by 2-year intervals, and classified according to Breast Imaging Reporting and Data System of the American College of Radiology (ACR). Patient and tumor characteristics were analysed for those diagnosed with breast cancer. Tumors were stained for estrogen (ER) and progesterone receptors (PR), HER2-neu and Ki-67 by immunohistochemistry. Results: A total of 49 breast cancers (% 0.83) were detected during the study period. The median age was 50 (40-70). The majority of patients (78%) were stage 0 or 1, whereas 23 patients (47%) were <50 age. Of 49 tumors, 38 (78%) were invasive cancers and 11 (22%) were ductal carcinoma in situ. Forty-four patients (90%) underwent breast conservation, whereas 35 patients (75%) had sentinel lymph node biopsy. Of 38 invasive cancers, 24 (63%) were ductal carcinoma and 8 (21%) were lobular cacinoma. Among 31 invasive cancers stained for ER, PR, HER2-neu and Ki67, the majority of them (92%) were hormone receptor positive, whereas 13% were HER2-neu positive and 58% had low Ki67 levels (<14). As molecular subtypes, the majority of them were found to be either luminal A (48%) or luminal B type (42%), whereas other nonluminal HER2 (7%) and triple negative cancers (3%) were less frequently detected. Conclusions: Our findings suggest that the majority of screen-detected breast cancers exhibit either luminal A or B subtype. However, more aggressive subtypes such as nonluminal HER2-neu or triple negative cancers are less likely to be detected by mammographic screening programs, requiring other preventive strategies.
Evaluating the hidden biology of cancer of unknown primary (CUP) in comparison to known metastatic disease.
Authors: Hannouf Malek Bassam , Mahmud Salah , Winquist Eric , Brackstone Muriel , Zaric Gregory S
Published: March 2020

e12549

Background: No consensus exists yet on whether CUP is a group of metastatic tumours with undetected primary sites or a unique clinicopathological entity with distinct genetic and phenotypic characteristics. We aimed to characterize the clinical and pathologic features of a cohort of CUP patients who had their latent primary site subsequently detected during their life or at autopsy in comparison to a cohort of patient presented with metastatic known primary cancers at initial diagnosis. Methods: We used historical snapshot files available in the Manitoba Cancer Registry (MCR) to identify all patients diagnosed with histologically or cytologically confirmed metastatic tumours in Manitoba during the period from January 1, 2002 to December 31, 2012. We linked all identified patients with their updated tumour-specific files available in the MCR for the purpose of identifying our two study cohorts. The first cohort included all patients who were initially diagnosed with CUP and who had their latent primary cancer identified and confirmed using either histology, cytology or autopsy at least 2 months after their initial CUP diagnosis. The second cohort included all patients initially diagnosed with a metastatic known primary cancer and whose cancer diagnosis did not change during lifetime or at autopsy. Information on patient and tumour characteristics was obtained from the MCR. Results: Out of 16,085 patients diagnosed with metastatic tumours, 2654 (%16.5) patients were initially diagnosed with CUP and 13,431 (84.5%) patients diagnosed with metastases of a known primary cancer. Out of the CUP group, 1033 (39%) patients had their latent primary site subsequently detected. Distribution of primary sites did not differ significantly between CUP patients who had their latent primary detected and patients diagnosed with metastases of a known primary cancer (p=0.44, Wilcoxon rank sum test). With the exception of tumour size, all other patient and tumour characteristics did not differ significantly between the two study cohorts across primary tumour sites. Conclusions: The clinical and pathologic features of CUP patient do not appear to be fundamentally different from those with metastatic known primary cancers.
An epidemiologic study of lifestyle of cancer patients presenting at National Hospital and Cancer Research Centre Pvt. Ltd., Jawalakhel, Nepal.
Authors: Pun Rashmey , Acharya Sandhya Chapagain , Piya Madan Kumar
Published: March 2020

e12572

Background: Nepal being one of the economically challenged developing countries has been lagging behind in all healthcare facilities. Cancer is now emerging as a major Non-communicable (NCD) disease accounting for 9% of all NCDs. Lack of preventive measures, screening and awareness programme is hindrance in the early diagnosis. Hence, we aimed to study the epidemiological variables of various cancers so that risk factors can be identified. Methods: A Prospective, observational, cross sectional study was conducted from July 2012 to December 2012 for a period of six months. All patients with histological diagnosis of cancer attending the National Hospital and Cancer Research Centre were enrolled. A Questionnaire was formed in English and patients were asked to answer the questionnaire. Results: Out of 142 patients diagnosed with cancer, 22 different types of cancer were noticed and the most common was lung cancer in both sex with 28% incidence followed by breast 18%, gynecological cancer 15%, colorectal 9%, hepatobillary 9%, gastrointestinal 8%, lymphoma 6%, Head and neck 4%. Out of them, 61% were females and 39% were males and 96% of patient were married. The most common age group at diagnosis was 41-60 years and comprised of 42% of total. About 37% of the patient earned their living by agriculture. About 44% of the patient has annual income of over USD 2500. The most common ethnic group with cancer was identified as Newar with 48% prevalence of cancer. About 36% of the patients were illiterate, 20% are literate. Total of 51% of the patient were smoker, 19% are taking alcohol till recently and 27% consume alcohol occasionally. Only 9% of the patient are vegetarian and the 91% non-vegetarian group mostly eat red meat. Significant number (64%) of the patient is consuming the commercial, canned food. Very few patients are aware of exercise (22%) and meditation (11%). Conclusions: This is a single institution study and with lots of limitation. However, this can be used to find risk factors associated with our ethnic and cultural variation and thus a multicentric study is advisable to formulate National level preventive and screening programme.
Glioblastoma and increased survival with longer chemotherapy duration.
Authors: Abou-Jaoude Dory , Moore Joseph A , Moore Matthew B , Twumasi-Ankrah Philip , Ablah Elizabeth , Moore Dennis F. , Moore Dennis F
Published: March 2020

e13006

Background: The 5-year survival for patients (pts) with glioblastoma (GBM) is low at approximately 3%. Radiotherapy plus concomitant and adjuvant temozolomide (TMZ) remain the standard of care. The optimal duration of therapy with TMZ is unknown, though treatment periods of 6 months (mo), 12 mo and longer have been utilized. Whether or not there is a benefit with longer treatment duration is controversial. Methods: A retrospective chart review of all pts diagnosed with GBM who were treated at a regional referral center was conducted with data obtained from their electronic medical records. These pts were treated with TMZ for up to 2 years between January 1, 2002 and December 31, 2011. Survival was calculated as the time from initial surgical diagnosis until death. The Kaplan-Meier method with log-rank test was used to estimate the progression-free survival (PFS) as well as the overall survival (OS) distribution of pts after treatment. The results were compared to historical controls and data from previous clinical trials of pts treated up to 1 year. Results: Data from 56 pts were evaluated, the majority of whom had gross total resection and had external pathology review confirming the diagnosis of GBM. The OS probability was 55.4% (SE = 0.068) at 1 year, 26.9% (SE = 0.067) at 2 years and 20.1% (SE = 0.065) at 3 years. The median PFS time in this study group was 8 mo (95% CI = 4.0 – 9.0 mo). The probability of no progression at 2 years was 8.6% (SE = 0.05). Seven pts (12.5%) were treated with TMZ for 2 years. The probability of disease progression at 2 years among these pts was 33.3% with a median time-to-progression of 20 mo (95% CI = 5.0-28.0). These patients showed an increased survival probability at 3 years compared to pts who did not receive the 2 year treatment of TMZ (log-rank test Chi-square = 12.4, p = 0.0004). Conclusions: This analysis suggests that there may be an advantage for a longer duration of TMZ therapy in pts with GBM. In this review, treatment with TMZ for 2 years was associated with an increased survival benefit. While we consider the sample size to be too small for generalization, a prospective/multicenter study with a larger sample size might better evaluate the question of duration of TMZ therapy, particularly if both clinical and basic science data are paired.
Potential biomarkers for pseudoprogression in malignant glioma.
Authors: Momota Hiroyuki , Fujii Masazumi , Motomura Kazuya , Natsume Atsushi , Wakabayashi Toshihiko
Published: March 2020

e13012

Background: Pseudoprogression (psPD) is defined as an increase of enhancing lesions on MRI without a real advancement of the disease, and it occurs in up to 20% of glioma patients who have been treated with temozolomide chemoradiotherapy. However, there are no reliable methods to distinguish psPD from true progression. Methods: To elucidate the utility of immunophenotypic markers in predicting psPD, we retrospectively investigated 21 consecutive patients with malignant glioma operated between August 2007 and December 2010 and treated with temozolomide therapy. Immunostaining for CD44, CD68, EGFR, and p53 was used to determine the immunophenotypic profile of these gliomas. Immunohistochemical scoring was made as follows: weak CD44 staining (1 point), weak CD68 staining (1 point), no strong EGFR staining (1 point), and strong p53 staining (1 point). Results: Fourteen glioblastomas (GBMs), 2 glioblastomas with oligodendroglioma component (GBMOs), and 5 anaplastic oligodendrogliomas (AOs) were included in this study. psPD occurred in 6 patients (3 GBMs, 1 GBMO, and 2AOs). In our scoring system, 2 tumors obtained 4 points and these tumors showed psPD (100%), 5 tumors obtained 3 points and 2 psPDs occured (40%), 5 tumors obtained 2 points and 2 psPDs occured (40%), and 9 tumors obtained 1 or 0 point and no tumors had psPD (0%). Median overall survial time was 36.3 mo in patients with psPD and 18.1 mo in patients without psPD, but there was no significant difference between the groups. Conclusions: Our study demonstrates that psPD can be predicted by simple immunohistochemical scoring method. In this scoring system, the sensitivity for psPD is 100% in patients with high score (4 points), 40% in patients with medium score (2–3 points), and 0% in patients with low score (0–1 point). Careful follow-up is needed after chemoradiation therapy in glioma patients with high to medium score.
Association of the development of bone metastases with the development of brain metastases in patients with non-small cell lung cancer.
Authors: Salem Mohamed , Elson Paul , Pennell Nathan A. , Sukari Ammar , El-Refai Sherif , Ali Khaled B. , Gadgeel Shirish M. , Szerlip Nicholas , Wozniak Antoinette J.
Published: March 2020

e13030

Background: In patients (pts) with non-small cell lung cancer (NSCLC), it is unknown whether pts with bone metastases are predisposed to the development of brain metastases. The impact of bevacizumab (Bev) on the development of bone and brain metastases is not fully characterized. Methods: Retrospective review of pts with stage IV NSCLC without brain metastasis at diagnosis was undertaken. The primary endpoint was to determine whether the development of bone metastases is predictive of the development of brain metastases. Secondary endpoints involved the proportion of pts who developed brain and/or bone metastases while being treated with Bev. Data were analyzed using competing risks methods. Results: A total of 175 pts (52% males, median (range) age: 60 y (35-80)) were studied. Of whom 79% received Bev and 21% did not receive Bev as part of their treatment. Overall 34% of pts had bone metastases at the start of therapy. Pts with pre-existing bone metastases tended to develop new bone disease more frequently than pts who did not initially have bone metastases (39% vs. 19%, p =. 01). The incidence of the development of brain metastases among pts who had pre-existing bone metastases was 17% vs.16 % in pts without pre-existing bone metastases. However, the incidence of brain metastases among pts with pre-existing bone disease who developed new bone metastases was 33% vs. 6% in pts who did not develop new bone disease but had pre-existing bone metastases. Adjusting for initial bone disease, development of new bone metastases was associated with a shorter brain metastases-free interval HR 5.06 (2.03-12.65; p = 0.005). In a subgroup analysis based on Bev exposure, the likelihood of developing brain and bone metastases within 2 years of starting Bev was estimated to be 25% and 27%, respectively, while the likelihood of developing brain and bone metastases without Bev treatment was 33% and 43 %, respectively. Conclusions: In pts with NSCLC, the development of new bone metastases may be indicative of the subsequent development of brain metastases. Additionally, Bev therapy may have an effect on the development of both bone and brain metastases. A prospective investigation may be warranted.
Postoperative radiotherapy (RT) with or without chemotherapy (CT) in anaplastic astrocitoma (AA) patients.
Authors: Brugnara Sonia , Russo Lucianna , DiPasquale MariaChiara , Nagliati Michele , Basso Gianpaolo , Trevisan Diego , Chioffi Franco , Pulcrano Giuseppe , Colarusso Enzo , Barbareschi Mattia , Rozzanigo Umberto , Pellegrin Andrea , Amelio Dante , Donner Davide , Buganza Manuela , Magri Elena , Dallabona Monica , Decarli Nicola L , Galligioni Enzo
Published: March 2020

e13046

Background: Although the evidence for the benefit of adding temozolamide (TMZ) to RT is limited to glioblastoma patients (pts), there is currently an increased tendency toward a combined RT + TMZ approach also in AA patients. Methods: We report in this study the survival outcome of 2 groups of pts, treated at in 2 different periods at our institution with RT after surgery ± CT. GROUP A (years 1984-2001): pts treated with surgery followed by RT; GROUP B (YEARS 2004-2009): pts treated with surgery followed by radical RT and CT according to the STUPP’s protocol; Results: Data were retrospectively collected on a consecutive series: GROUP A: 17 pts: 10 Males (M), 7 Females (F); median age 50 years (range: 31-65). Ten out of 17 pts received radical surgery and 7 subtotal surgery. All were treated with postoperative RT, median dose 5082 cGy (range: 2160-6300). The mean time between surgery and beginning of RT was 44.7 days (range 20-87). GROUP B: 17 pts: 10 M, 7 F; median age 44 years (25-72). Eleven out 17 pts received radical surgery and 6 subtotal surgery. All were treated with postoperative RT, median dose 5800 cGy (range: 4000-600). The mean time between surgery and beginning of RT was 56.3 days (range 26-111). All patients received TMZ 75 mg/mq for a median of 6 weeks (range 3-7), followed by adjuvant treatment with TMZ (200 mg/mq) for a median of 5 cycles (range 0-13). At a median follow-up of 45 mos , the median OS was 29.1 mos for the group A and 49,1 mos for the group B. Among pts treated with RT + CT after surgery, median OS was significantly longer (p= 0.03), compared to those treated with only RT after surgery. Conclusions: The limited sample sizes of 2 groups and differences such as the median RT dose and the median time between surgery and RT, does not allow any conclusion. However, our data suggest that the combined RT-CT treatment is feasible in AA pts after surgery and may possibly contribute to a prolonged control of disease. These suggestions should be explored in a prospective randomized trial.
Treatment of advanced glioma with an energy restricted ketogenic diet: Case report and literature summary.
Authors: Schwartz Kenneth A. , Noel Mary , Nikolai Michele , Chang Howard T. , Olson Lawrence Karl , Kurniali Peter C. , Pernicone Joseph , Hord Norman , Sweeley Charles
Published: March 2020

e13047

Background: We initiated a pilot study to evaluate an energy restricted ketogenic diet (ERKD) as treatment for patients with glioblastoma multiforme (GBM) whose brain tumor had progressed with standard therapy. Methods: This reports documents our experience using an ERKD with an IRB approved, clinical trials #NCTO1535911 registered treatment protocol and briefly summarizes the 5 published case reports that document favorable responses with ERKD. Results: Our patient, a 55-year-old white male, presented with a left sided visual field cut, decreased analytical mental skills, a slow methodical wide based gait and a right posterior brain mass with a histological diagnosis of GBM. After documented progression following surgery, radiation therapy and TMZ the patient was treated with ERKD. He was hospitalized to induce a decrease in glucose and an increase in ketones using Ketocal 20-25 Cal/Kg. Adherence and efficacy to the diet was monitored using AM and PM measurements of blood glucose and ketones. Initial treatment with Ketocal decreased his blood glucose so that his PM glucose was <80mg/dl and increased his PM ketones to >3mm(our protocol’s target concentrations). However, his AM glucose was still >80mg/dl and his AM ketones decreased to >2mM. Because of the low palatability of the Ketocal, the patient was switched to a ketogenic regular food diet with a 3:1 ratio of fat to proteins and carbohydrates. Out of the hospital and on this diet his PM ketones remained > 3mM and his AM > 2mM, but his AM and PM blood glucose increased to > 80mg/dl. After 4 weeks of treatment with the ERKD, the patient’s disease advanced; his vision, mobility and cognition decreased and MRI demonstrated tumor growth and he withdrew from the study. Five patients with advanced brain tumors and favorable responses to ERKD have been reported. The best response was a C.R. 5 years after diagnosis. In 4 of the 5 patients ERKD was combined with one of the standard modalities of treatment. At last report 3 of the 5 patients were C.R. and 2 had documented disease progression after stopping the ERKD. Conclusions: Investigation of ERKD in patients with malignant brain tumors using an approved, registered protocol under the guidance of a dietician is feasible.
3'-deoxy-3'-[18F]fluorothymidine position emission tomography for target delineation in resected malignant gliomas before radiotherapy.
Authors: Zhao Fen , Li Minghuan , Fu Zheng , Yu Jinming
Published: March 2020

e13052

Background: To analyze the FLT PET image feature of malignant gliomas and evaluate the usefulness in the visualization of residual tumor volume compared with MRI. Methods: Patients with postoperative residual malignant gliomas were enrolled on this prospective trial. MRI and PET were performed in the same week, 1 to 4 weeks after surgical resection.,we compared the SUVmax of tumor and the T/N ratio between the grade III and IV gliomas and the residual tumor volume and the geometric position defined by FLT uptake and the abnormalities signals on MRI were compared using FLT PET/MRI fusion images. Results: 19 patients were analyzed. The SUVmax were 0.86±28 for grade 3 gliomas , and 2.68±2.22 or 2.05±0.44(with or without one gliosarcoma whose SUVmax was as high as 9.6) for grade IV gliomas (P <0.001). The mean (±SD) value of T/N ratio in grade IV gliomas were 15.43±10.47 or 12.48±2.20(including or not of the gliosarcoma ) and 4.84±1.77 in gade III gliomas(P <0.001). The mean Vol-T1, Vol-T2 and Vol-PET was 13.08cm3,33.46cm3 , and 15.04cm3 , respectively. The Vol-PET were not significant larger than the Vol-T1( P>0.05). The areas between the increased FLT PET activity and abnormality in MRI were imperfectly correlated .In 13 (68.4%) and 11 patients(57.90%) , the FLT uptake regions exceeded the area of contrast enhancement and the area of hyperintensity areas on the MRI. In 5 (26.3%) and 4(21.05%) of 19 patients, FLT uptake extended 25 mm from the margin of Gd enhancement and hyperintensity areas. And the FLT uptake was measured up to 43mm and 39mm outside of the Gd enhancement and hyperintensity areas on MRI. Conclusions: FLT PET was found to be useful in assessment of grade in malignant gliomas. FLT PET can provide complement information to the MRI for defining the remaining tumor volume accurately in patients with malignant gliomas postoperative residual .
Relationship between intravenous (IV) busulfan pharmacokinetics (PK) and patient characteristics in allogeneic stem cell transplant patients.
Authors: Simmons Ashley Erickson , Keisler Meredith Deal , Ivanova Anastasia , Rao Kamakshi V. , Shea Thomas C. , Walko Christine Marie
Published: March 2020

e13507

Background: Busulfan is an alkylating agent commonly used for myeloablation in hematopoietic stem cell transplantation (SCT). Narrow therapeutic index and 2-3 fold interpatient PK variability underscores the need to further explore predictors of busulfan clearance. This analysis aimed to determine patient (pt) characteristics that may impact the clearance of busulfan. Methods: This retrospective analysis assessed allogeneic SCT pts who received a test dose of 0.8 mg/kg IV busulfan, dosed by adjusted body weight, over 2 hours on days -15 to -10 prior to conditioning therapy containing therapeutically dosed busulfan. All pts were treated between June 2004 and July 2012 at the University of North Carolina at Chapel Hill. Noncompartmental PK parameters were calculated from this test dose using Phoenix WinNonlin Pharsight software. A linear model with log of busulfan test dose clearance as an outcome and pt characteristics that included disease state, bone marrow donor type, gender, race, ethnicity, body surface area (BSA), body mass index, type of anticonvulsant prophylaxis used (levetiracetam or phenytoin), total bilirubin and serum creatinine was fit. Results: The study reviewed a total of 88 pts with a mean age of 41.1 (range 18-63). The analysis included 54 males, 76 Caucasians, and 5 African Americans (AA). Seizure prophylaxis with levetiracetam was given to 27 pts, and 51 received phenytoin. After adjusting for pt characteristics, a unit increase in BSA was associated with 0.69 (p = < 0.001) increase in log(clearance). Regression coefficients for phenytoin use with no seizure prophylaxis as reference and for African American race with Caucasian race as reference were significant (0.22, p = 0.033, and -0.31, p=0.13, respectively). No correlation was seen for age (p = 0.357), gender (p = 0.337), levetiracetam use (p = 0.3525), or for any other variable. Conclusions: Our data suggests that higher BSA and phenytoin use are associated with a higher busulfan clearance, while AAs have a lower clearance. These findings may help inform future dosing strategies in order to decrease interpatient PK variability and accurately predict plasma concentrations of busulfan.
Phase I/IIa, randomized, open-label, drug-drug interaction study of trabectedin and rifampin in patients with advanced cancer.
Authors: Staddon Arthur P. , Parekh Trilok V. , Knoblauch Roland Elmar , Keung Chi , Bernard Apexa , Aymes Ana L. , Phelps Charles , Sharma Sunil
Published: March 2020

e13512

Background: Trabectedin (Yondelis; T) is a tetrahydroisoquinoline compound initially isolated from the marine tunicate, Ecteinascidia turbinata, and currently produced synthetically. It is primarily metabolized by the cytochrome P450 (CYP)3A4 enzyme. Thus, potent inducers or inhibitors of this enzyme may alter the plasma concentrations of T. This study assessed the effects of rifampin (R), a strong CYP3A4 inducer, on the pharmacokinetics (PK) and safety of T. Methods: In this 2-way crossover study, patients (≥18 years of age) with locally advanced or metastatic disease were randomized (1:1) to receive one of the 2 treatment sequences: sequence 1: R plus T followed 28 days later by T; sequence 2: T followed 28 days later by R plus T. During each sequence, R (600 mg/day) was administered for 6 consecutive days and T (1.3 mg/m2, IV) was administered over a 3 hour infusion. Dexamethasone (20 mg, IV) was administered before T administration. PK and safety of T were evaluated with and without coadministration of R. Results: Of the 11 enrolled patients, 8 were PK evaluable. Coadministration of R with T decreased mean maximum plasma concentration (Cmax) by approximately 22% and mean area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) by approximately 31% (Table 1). Coadministration of R with T also resulted in 23% shorter elimination half-life. Overall, the safety profile of T was comparable when administered alone or with R. Conclusions: In comparison with T alone, coadministration of R resulted in reduced systemic exposure of T in these 8 patients, as measured by Cmax and AUClast. The coadministration of potent inducers of CYP3A4 with T may increase the metabolic clearance of T. Clinical trial information: NCT01273480. [Table: see text]
Prediction of individual tamoxifen activation in breast cancer patients.
Authors: Gusella Milena , Bertolaso Laura , Fraccon Anna Paola , Barile Carmen , Rizzi Anna , Carturan Sabrina , Modonesi Caterina , Ghiotto Cristina , Crepaldi Giorgio , Mion Marta , Segati Romana , Padrini Robeto , Toso Silvia , Zaninelli Marta , Ramello Monica , Tomassi Ottaviano , Magazu' Marcello , Minicuci Nadia , Bassan Franco , Pasini Felice ,   Italian TAM Group
Published: March 2020

e13514

Background: Endoxifen (EN), the main active metabolite of tamoxifen (T), reaches steady state (SS) plasma levels after about 4 months of administration. It derives principally by cytochrome CYP2D6 activity, which is highly variable among patients. In order to predict individual SS EN exposure, three different approaches were investigated. Methods: Before starting T administration, 73 breast cancer patients (median age: 59 yrs, range: 30-89) were characterized by means of: 1) a phenotyping test of CYP2D6 activity, based on the urinary metabolic ratio of dextromethorphan/dextrorphan (log transformed, LMR). 2) CYP2D6 genotyping (alleles *1, *3, *4, *5, *6, *9, *10, *41), to classify patients in 3 functional groups: Extensive (EM), Intermediate (IM) and Poor (PM) Metabolizers. After starting T treatment (20mg/day), EN plasma levels were measured after 1 month (1M EN, pre- steady state) and 4 months of therapy (SS EN). ANOVA, paired and unpaired T test and linear regressions were performed to analyze associations between LMR, CYP2D6 genotype, 1M EN and SS EN. Multivariate linear regression was used to create a predictive equation; its mean prediction and absolute errors (MPE% and MAE%) and the positive and negative predictive values (PPV% and NPV%, according to median SS EN) were calculated. Results: SS EN plasma levels varied between 2.4 and 39.2 (median: 8.7) ng/ml. LMR (median: -1.6; range: -3.1- +1.2) showed a significant linear correlation with SS EN (r=-0.59; p<0.0001). CYP2D6 genotypes (EM=35.6%; IM=50.7%; PM=13.7%) were significantly associated with SS EN (ANOVA, p<0.0001). First month EN plasma levels (median: 5.9 ng/mL; range:1.2-27 ng/ml) were significantly lower than (p<0.0001), and correlated (r=0.87; p<0.0001) with, SS EN. Multiple regression analysis including age, LMR, CYP2D6 genotypes and 1M EN gave the following predictive equation: SS EN= 0.055-1.53 x LMR + 1.11 x 1M EN; (r=0.88; p<0.0001). MPE was 4.1% and MAE was 30%; PPV was 88.5% and NPV was 84.6%. Conclusions: Individual EN exposition at steady state can be reliably predicted by measuring baseline CYP2D6 activity, through the log (dextromethorphan/dextrorphan) metabolic ratio, and EN plasma concentration after 1 month of tamoxifen treatment. Funded by Regione Veneto. Clinical trial information: 532.
SMAD5 expression and inhibition of the mitotic kinase aurora-A on sensitivity of breast cancer cells to chemotherapy.
Authors: Opyrchal Mateusz , Iankov Ianko , Ingle James N. , Salisbury Jeffrey L. , Galanis Evanthia , D'Assoro Antonino
Published: March 2020

e13516

Background: Breast cancer affects thousands of women each year. Epithelial to Mesenchymal transition (EMT) has been associated with increased metastatic potential of cancer cells as well as resistance to chemotherapy. Predicatively, presence of EMT leads to worse prognosis. We have recently showed that Aurora-A plays a key role in development of EMT and increased ability of breast cancer cells for self renewal. Therefore we hypothesized that inhibition of Aurora-A will lead to increased sensitivity to chemotherapy. Methods: The hypothesis was tested in vitro. Cellular proliferation was tested using MTT assay and protein levels were determined on Western blots. Results: In ER+ cell line, MCF7, constitutive activation of Raf-1/MAPK signaling pathway leads to aberrant activation of Aurora-A kinase activity. These cells have decreased sensitivity to treatment with paclitaxel when compared to parental MCF7 cells. This effect is even more pronounced with over-expression of Aurora-A. The sensitivity to paclitaxel was restored with inhibition of Aurora-A by novel inhibitor, Alisertib. This was further explored in triple negative cells (MDA-MB-231) and cells expressing Her-2/neu (BT474) which express higher levels of Aurora-A. Combination of Alisertib and paclitaxel was superior when compared to either therapy alone. Similar effect was seen with use of anthracyclines. Inhibition of Aurora-A resulted in decreased SMAD5 expression as well as decreased Akt phosphorylation. Current studies are investigating a role of Aurora-A in developing chemoresistance through activating SMAD5. In vivo experiments evaluating combination therapies in breast cancer animal model are ongoing. Conclusions: Inhibition of Aurora-A by Alisertib resulted in decreased SMAD5 nuclear phosphorylation and increased effectiveness of chemotherapeutic agents in breast cancer cells. These results contribute to better understanding of signaling pathways involved in resistance of breast cancer cells to chemotherapy. This knowledge could be extremely useful in developing more effective treatments for breast cancer patients both in neo-adjuvant, adjuvant and metastatic settings.