bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic factors influencing the selection of bevacizumab combined with chemotherapy in patients with HER2-negative metastatic breast cancer in routine clinical practice: Oncosur-Avalox—Observational cross-sectional study.
Authors: Manso Luis , Garcia-Palomo Andres , Perez-Carrion Ramon , Chacon Jose Ignacio , Mielgo Rubio Xabier , Gallegos Sancho Isabel , Cassinello Javier , Llorente Rosa , Calvo Elena Galve , Llorca Cristina , Alvarez Inaki , Fernandez Antonio , Catalan Gustavo , Garcia Lopez Maria Jose , Torregrosa Maria Dolores , Blanco Esperanza , Bueno Coralia , Perello Antonia , Méndez Miguel , Cortes-Funes Hernan ,   on behalf of ONCOSUR Study Group
Published: March 2020

e12020

Background: Combining bevacizumab (BEV) with chemotherapy (CT) improves survival in HER2-negative metastatic breast cancer (MBC). We investigated the influence of age, ECOG, hormonal status, number of sites, location of metastases and patient decision on the selection of BEV combined with CT in MBC. Methods: Observational cross-sectional multicenter study in patients with HER2- negative MBC who have received first-line CT with BEV. Results: 219 patients were included: median age 51(44-63) yr; ECOG: 0=53%; 60.4% pre-menopausic; 23.9% triple-negative (TN);76.2 % hormone receptor positive (HR+).Metastatic disease: ≥3 sites=39.2% (TN: 22%; HR+: 43.9%); location: 45.2% bone, 37.4% liver, 30.1% lung. Most frequent BEV combinations were paclitaxel/BEV(60.7%) and docetaxel/BEV(12.8%); median no. of CT cycles: 6 (5- 8). A disease-free survival (DFS) ≥12 months was achieved by 82.8%; TN: 78.9%; HR+: 83.3%. Overall response rate (ORR) was 62.7%: 53.6% partial response (PR), 9.1% complete response (CR); 25.4% stable disease (SD) and 7.2% disease progression (4.8% non evaluated). TN:ORR 54.2% (47.9% PR), clinical benefit 80% (27.1% SD); HR+:ORR 65.8% (55.7% PR), clinical benefit 89.9% (24.1% SD). 66.2% presented at least one toxicity, mainly grade 1-2; 32% BEV-related: only 3 grade 3 toxicities; no grade 4. Receiving adjuvant hormonal therapy was associated to DFS ≥12 months (p<0.05). ER+ tumors (OR:0.326;95%CI:0.16-0.65;p=0.002) and patient decision after consider doctor opinion (OR:0.026;95%CI:0.01-0.74; p=0.085) were independent factors associated with the selection of paclitaxel-BEV in the overall population (TN or HR+). Liver metastases were significantly related to paclitaxel-BEV administration (p<0.01). Conclusions: First-line CT with BEV is an effective and safe scheme for patients with TN and HR+ MBC. ER+ tumors and patient decision after consider doctor opinion were identified as independent factors for the selection of paclitaxel-BEV therapy. The presence of liver metastases was significantly associated to the administration of a paclitaxel-BEV regimen.
Long-term outcomes of post-mastectomy radiation therapy in the setting of neoadjuvant chemotherapy for locally advanced breast cancer.
Authors: Wong Winnifred M. , Korde Larissa A. , Roberts Toni K. , Arnett Andrea L. , Mart Dylan A. , Barnes Brie S. , Neradilek Moni B. , Polissar Nayak L. , Amlag Joanne O. , Kim Janice N.
Published: March 2020

e12030

Background: The role of post-mastectomy radiation therapy (PMRT) after neo-adjuvant chemotherapy (NCT) in those with T3N0 disease, younger age, and different tumor subtypes is unclear. Methods: We conducted a single institution, retrospective analysis of patients treated with NCT and mastectomy from 1985-2010. The primary objectives were to (1) assess the association between PMRT and long-term outcomes, and (2) describe outcomes and practice patterns based on tumor subtype, pathologic response, and age at diagnosis. Secondary objectives were to analyze the benefit of PMRT in those with favorable tumor subtypes, cT3N0 disease, and patients younger than 40. Log-rank test and Cox regression was used to test the association of predictors with outcomes. IRB approval was obtained. Results: Of 131 evaluable patients, 115 (88%) received PMRT. Mean±SD age was 48±10 years (range 29-79). Of patients <40 years of age (n=33) 88% received PMRT. At diagnosis, 69.5% were cT3; 53.5% were cN1; 12.3% were cT3N0. Seventy-eight percent of patients received anthracycline-based NCT and 52% received both anthracycline and taxane NCT. Twenty-eight percent of all patients achieved pCR. With a median f/u of 39 months (range 8-177), 30.5% of patients had a recurrence event (6.9% local, 5.3% nodal, 16.8% distant). Ten year OS and DFS for all patients were 56.7% (95% CI, 43.5-73.8) and 66.1% (95% CI, 52.3-83.5), respectively. Those with pCR had a non-significant trend toward better outcome, with 10 year OS=68.0% vs. 54.0% (p=0.7); DFS=70.2% vs. 65.2% (p=1.0). In the Cox regression analysis, pathologic T-stage, triple negative disease, and tumor grade were significantly associated with OS; triple negative disease was also predictive of DFS. Benefit of PMRT was not analyzable in cT3N0 due to small numbers. Conclusions: Most patients had PMRT, with outcomes on par with historical data. Most patients <40 years received PMRT, with no events for the non-PMRT cohort most likely due to selection bias. Unfavorable subgroups were not more likely to receive PMRT, but of those who did, only triple negative was predictive of outcome. A future non-PMRT matched cohort study is necessary to further elucidate the role of PMRT.
Microdochectomy for pathologic nipple discharge.
Authors: Baldota Sanjay Zumberlal , Lai Lee Min , Raymond S P , Thomson Simon David
Published: March 2020

e12032

Background: Nipple discharge has a known association with breast cancer, determing which cases to identify as being at high risk is a complex task for the clinician. The current policy at West Herfordshire hospital NHS Trust is to offer microdochectomy to all women who present with unilateral single duct nipple discharge, dominant duct discharge, or peristent duct discharge. The aim of this study was to determine if on basis of the pattern ofnipple discharge, patients could be subselected for microdochectomies, and to create a base line to allow future subselection of patients for survillience only. Methods: All patient with single duct unilateral spontaenous nipple discharge, who underwent microdochectomy, were assessed. Demongraphics, clincial presentation, radilogical assessment, cytology, core biopsy. This group of patients was anlysed and correlated with their final histological assessment. Results: 122 patients were analysed in this study. 7 ( 5.74%) were diagnosed with carcinomas. 4patients had ductal carcinoma in situ, three patients had dutcal carcinoma in situ and invasive ductal carcinoma, of these two patients had blood stained nipple discharge. two other patients had papillary carcinomas, one patient of these two had blood stained nipple discharge. 47 out of 122 patient presened with history of blood statined discharge,30 were negative for cytology, two patients had (ductal carcinoma in situ with Invasive ductal carcinoma and papillary ca) at final histololgy. 17 of the 47 showed cellular cytology.and one patient had intermediate grade DCIS confirmed on final histology, whereas in the remaining sixteen patients histological feaatures of papillomas, duct ectasia, and benign breast disease was noted. Of the 122 patient 42 patients had mammary duct ectasia (34%), 52 patients had papillomas (42%) at final hisotology. Conclusions: The negative predictive value (2/30), appears in this series appreas to be more valuable than, the positive predictive value (1/17) in cellular smears to predict ductal carcinoma or invasive ductal carcinoma. Cytological assessment of nipple discharge is equivocal at its best. Microdochectomy perford for nipple discharge results in a low rate of malignacy on excision and is comparable with other series.
Off-label capecitabine, eribulin, or ixabepilone use in metastatic breast cancer (MBC).
Authors: Bobolts Laura Rose , Kumar Akhil , Fishman Marc L. , Shimp William S. , Krook James Edward , Fishman Val , Davis Sharon , Anthony Carol , Walton Robert , Huff Dinah , Hrushesky William John Michael
Published: March 2020

e12034

Background: Anthracyclines and taxanes have proven to be the most effective treatments for MBC. The FDA indications for capecitabine, eribulin, and ixabepilone recommend prior anthracycline and taxane therapy, unless contraindicated. The proportion of patients who receive these drugs after having received an anthracycline and/or taxane is unknown. We retrospectively reviewed capecitabine, eribulin, and ixabepilone treatment requests to examine the utilization patterns, specifically in relation to prior anthracycline and/or taxane therapy. Methods: All capecitabine, eribulin, or ixabepilone requests for MBC from 2009 through January 2013 were reviewed. The proportion of requests for these agents with and without FDA stipulated prior therapies were contrasted, using Chi squared analyses. Results: 36 MBC requests were identified for capecitabine, eribulin, or ixabepilone. The majority (67%) of these occurred among patients who had no documentation of prior anthracycline therapy. 36% of all requests were not preceded by any documented taxane therapy. Anthracyclines were avoided more frequently than taxanes (p=0.011). All requests without documentation of prior taxane use (36%; 13/36) were also made without prior anthracycline use. Oncologists were more likely to initiate capecitabine without prior anthracycline and taxane, as compared to eribulin or ixabepilone (64% v 18% v 18%, respectively; p=0.042). Conclusions: In our sample, more than two thirds of MBC treatment requests for eribulin, capecitabine, or ixabepilone occurred prior to a request for an anthracycline, and more than a third prior to receiving a taxane. Since, in general, it is considered standard of care to use the most active drugs early in the course of disease, this trend could have negative effects upon the optimal control of MBC. [Table: see text]
Disease and treatment characteristics of breast cancer in an urban, low-income hospital following a major hurricane: A temporal and racial analysis.
Authors: Gadinsky Naomi , Keeport Melissa Lina , Shin Adeline Jae Hyun , Srivastav Sudesh , Kruse-Jarres Rebecca
Published: March 2020

e12503

Background: The Medical Center of Louisiana, New Orleans (MCLNO) serves a metropolitan area and is the only hospital delivering care to the indigent population in the area. Hurricane Katrina devastated New Orleans on 8/29/05. No oncology services were available for two years. We examined characteristics/care for patients with breast cancer 2 years after re-opening clinics compared with the subsequent 2.5 years. Differences between Whites (W) and African Americans (AA) were examined and compared to state and national averages. Methods: After IRB approval, we reviewed charts of patients establishing care for breast cancer at MCLNO between 09/07-05/12: Group 1 (09/07-08/09) vs. Group 2 (09/09 – 05/12). Racial analysis was done between W and AA independent of temporal factors. Results: Our cohort included 153 patients (25 W, 105 AA , and 23 other race): Group 1- 68 patients, Group 2- 85. There were no significant temporal or racial differences in age, race, insurance, menopausal status, family history, cancer type, stage, or treatment regimen. More AA were triple negative (25.5% AA, 0% W; p= 0.002). Compared to state and national averages, our patients underwent more mastectomies: 58% mastectomy (M) and 42% lumpectomy (L) - compared to Louisiana (M - 50.7%, L - 48.7%) and the National (M - 42.0%, L - 57.8%) data. Our cohort presented with more advanced disease: 10.5% presented with stage IV breast cancer, which is higher than the state average (6.0%) and the national average (5.5%). Conclusions: Despite the suspicion that tumor presentation would be worse after a delay in access to care due to Katrina and that AA might have even worse characteristics, our data showed this not to be the case. Interesting was the finding that triple negative cancers seemed to be an AA phenomenon. It is important to continue following these patients to see how these presenting and prognostic factors will affect long term patient outcomes. [Table: see text]
An analysis of the temporal, age, and gender trends in human papillomavirus virus (HPV)-related versus non-HPV-related head and neck cancers (HNC) in Alberta, Canada.
Authors: Hao Desiree , Lau Harold Y. , Huang Longlong , Doll Corinne M. , Dort Joseph C. , Shack Lorraine
Published: March 2020

e12505

Background: Recent epidemiologic studies have suggested that the incidence of HPV-associated HNC is increasing. This study assessed temporal, age-specific and gender specific changes in cancer incidence for HPV- versus non-HPV associated HNC compared with other HPV versus non-HPV associated malignancies in a population-based setting. Methods: We used the Alberta Cancer Registry, a population-based registry of all cancers diagnosed in the province of Alberta, Canada (population est. 3.6 million), to identify patients diagnosed with cancers of the oropharynx, cervix, vulva, vagina, anus, and penis (HPV-associated group) and compared this with non-oropharyngeal cancers of the head and neck and lung cancer (non-HPV associated, modifiable risk group) between January 1, 1975 and December 31, 2009. The age-standardized incidence rates (ASIR) for each cancer by gender and age-specific incidence was estimated with the annual percentage change (APC) assessed using Joinpoint regression. Results: The ASIR for oropharyngeal cancers (OPC) increased over time for both men (APC 3.5) and women (APC 1.5) with rapid increases seen in men under 35 (APC 27.3). Non-oropharyngeal squamous cell carcinomas of the head and neck had a higher ASIR overall with moderate temporal increases (APC 2.5) and age-specific increases highest in those aged 55 to 74. ASIR for anal canal cancers also increased over time, with greater increases amongst younger females, in contrast to OPC. By comparison, the ASIR of cervix cancer declined with more significant decreases in younger females; while the rates of other HPV-associated cancers (vulva, vagina, penile) showed little change. The ASIR for lung cancer decreased after 1987 (APC -1.5) for men and continued to moderately increase for women. Conclusions: Our findings suggest the greatest increases in OPC are occurring in younger men. Programs of HPV prevention such as vaccination should be explored to reduce the incidence of OPC in males.
Are there disparities in adjuvant treatment of HER2 positive breast cancer patients by age, race/ethnicity, and socioeconomic status?
Authors: Parise Carol , Caggiano Vincent
Published: March 2020

e12512

Background: Standard adjuvant therapy for HER2-positive female breast cancer patients who are estrogen receptor (ER) positive is chemotherapy, trastuzumab, and endocrine therapy. Some studies report disparities in receipt of adjuvant treatment based on race/ethnicity, age, and socioeconomic status (SES). This study assessed the likelihood of receipt of adjuvant chemotherapy and endocrine therapy (C+E) versus endocrine therapy (E) alone by race/ethnicity, age, and SES in the ER+/PR+/HER- and ER+/PR+/HER+ subtypes. These subtypes differ only by HER2 status. Methods: We identified 86,666 cases of stages 1-3 ER+/PR+/HER- (n=74,422) and ER+/PR+/HER+ (n=12,244) breast cancer diagnosed between January, 2000 and December, 2010 from the California Cancer Registry. Logistic regression evaluating the odds of receipt of C+E versus E alone adjusting for age, race/ethnicity, SES, grade, and year of diagnosis was conducted separately for each stage and subtype. Odds Ratios (OR) and 95% confidence intervals were reported. Results: For both subtypes in all stages, patients over age 70 were less likely to receive C+E. Stage 1 ER+/PR+/HER-: Blacks were less likely to receive C+E (OR=0.77;0.59,0.99). The opposite was true for Hispanics (OR=1.31;1.15, 1.50) and Asians (API) (OR=1.25; 1.10;1.43). Stage 1 ER+/PR+/HER+:Hispanics were more likely (OR=1.67;1.24,2.24) to receive C+E while patients in the lowest SES category were less likely to receive C+E. Stage 2: ER+/PR+/HER-:Hispanics were more likely to receive C+E (OR=1.40;1.22,1.59) Stage 2: ER+/PR+/HER+:There were no treatment differences among race or SES. Stage 3: ER+/PR+/HER-:APIs were more likely (OR=1.87;1.19,2.94) to receive C+E. Stage 3: ER+/PR+/HER+:Patients in the lowest SES category were more likely to receive C+E (OR=2.97;1.29,6.87). Conclusions: Based on this investigation of a racially diverse population, there is no striking disparity in receipt of adjuvant treatment by race/ethnicity or SES. However there are some differences among the stages and subtypes. Patients over 70 are less likely to receive chemo and endocrine therapy for the subtypes studied.
U.S. Preventive Services Task Force (USPSTF) recommendations on PSA screening (PSAS) for prostate cancer (PC): Are they justified?
Authors: Strauss Gary M.
Published: March 2020

e12535

Background: PSAS has been debated since the Amer Can Soc recommended it in 1992 without data from randomized trials (RTs). Recent RT reports indicate that PSAS does not clearly reduce PC mortality (PCM). In Oct 2011, the USPSTF recommended against PSAS. Does the evidence support this position? Methods: Quebec Trial (QT) randomized 46,193 men 45-80 yrs 2:1 in 1988. Experimental group (EG) was invited for annual PSAS while control group (CG) was not invited. PLCO (Prostate-Lung-Colon-Ovary) randomized 76,693 men 55-74 yrs to annual PSAS or usual care starting in 1993. ERSPC (European study) randomized 162,243 men 55-69 yrs to EG invited to PSAS q4 yrs or CG not invited starting in 1994. Results: QT investigators reported in 1998 that PSAS reduced PCM. The problem was poor compliance with PSAS invitation in QT. Of 30,956 EG, 7,155 (23%) accepted. Of 15,237 CG, 982 (6%) underwent PSAS. Of 8,137 screened (SC), there were 5 PC deaths compared to 137 among 38,056 unSC (RR=0.17; 95% CI: 0.07-0.42). However, this analysis ignores the randomization. Intent to treat (ITT) analysis reveals no PCM reduction (RR=1.11; CI: 0.78-1.59). Selection bias did not account for lower PCM in SC vs unSC. In PLCO, there was no PCM advantage (RR=1.09; CI: 0.87-1.36). However, contamination was high; 72% of CG had PSAS. In ERSPC, there was a reduction in PCM (RR=0.79; CI: 0.69-0.92). Staging of SC detected PC was favorable. In PLCO & ERSPC, increased low/intermediate risk PCs in EGs reflect some overdiagnosis. However, there were significant reductions in high risk or metastatic PC, a hallmark of effective screening. In QT, no pt had distant metastases on repeat PSAS. In PLCO, 10-yr PC survival was ≈94% in both EG & CG. Conclusions: USPSTF recommendations against PSAS are not justified. While PCM comparisons by ITT do not show that PSAS clearly saves lives, ITT analyses are biased due to compliance or contamination. Conversely, RTs demonstrate that PSAS reduces high-risk and metastatic PC. From a population perspective, there has been a dramatic 42% reduction in PCM in US between 1991-2005, largely the result of our "national experiment" in which PSAS was widely introduced. If USPSTF guidelines are implemented, PCM will likely rise in US.
What would the experts do? Genetic testing, surveillance, and risk-reduction preferences for BRCA and Lynch syndrome.
Authors: Bonadies Danielle C. , Matloff Ellen T. , Brierley Karina L. , Moyer Anne
Published: March 2020

e12542

Background: Extensive data and national guidelines are now available regarding surveillance and risk reduction options for BRCA and Lynch syndrome mutation carriers. However, most of these options are presented as choices to patients who will often ask their providers, “What would you do?” We surveyed providers from multiple specialties to learn what they would do if at 50% risk to carry a BRCA or Lynch syndrome mutation. Methods: In July of 2012 we surveyed providers from multiple specialties via internet- based surveys. Participants were obtained through the American Medical Association and the National Society of Genetic Counselors. All responses were anonymized. Results: 1,313 specialists completed the online questionnaire. Those providers who commonly treat breast, ovarian, colon and uterine cancers were grouped and compared to providers who are less likely to be the treating specialist. We found statistically significant differences in the percentage of cancer genetics specialists who would pursue BRCA and Lynch syndrome testing compared with providers in other specialties (p=0.000, 0.007, respectively). We found statistically significant differences in the percentage of providers who treat breast or ovarian cancer that would opt for prophylactic bilateral mastectomy or prophylactic oophorectomy if BRCA+ (p=0.000, p=0.004, respectively) compared to other providers. We found statistically significant differences in the percentage of providers who treat colon or uterine cancer that would have their colon or uterus removed if found to carry a Lynch syndrome mutation (p=0.000, p=0.04, respectively) compared to other specialists. Conclusions: Providers’ specialties and, possibly, disease-specific exposure to surveillance and treatment regimens impacted their personal choices with respect to cancer genetic testing, surveillance and prophylactic surgeries for BRCA and Lynch syndrome.
Florida's breast cancer deaths in the holidays.
Authors: Ana Sandoval , Hurley Judith , Koru-Sengul Tulay , Miao Feng , Tannenbaum Stacey , Lee David J , Byrne Margaret M
Published: March 2020

e12547

Background: Several studies have been done to determine if there is an increase in the death rate associated with the holiday season or important events. Data has shown that there is an increase in death due to cardiovascular causes but the evidence for cancer related death is non-conclusive. Anecdotal information suggests that women with breast cancer expire more frequently during the Thanksgiving to Christmas holiday season compared with the rest of the year. It is unclear if this constitutes a real finding or if the circumstances connected with the patient’s death makes the dates more memorable. We evaluate if death occurs more frequently during the holiday season (11/15-01/07) for female breast cancer patients. Methods: Data on deaths from female breast cancer patients (n= 34,664) were obtained from linkage of the 1996-2009 Florida Cancer Data System, a population-based cancer registry, to the Florida Agency for Health Care Administration database providing procedure and diagnoses codes. Holiday season was defined as from 11/15-01/07 to create a dichotomous outcome measurement. Clustered logistic regression models were used to predict death during holidays; demographic, clinical, treatment factors and comorbidities were included in adjusted models with race, ethnicity, SES, marital status and presence of depression as the main factors. Results: Deaths (16%) occurred significantly more during the weekends, January-March and November-December. We found a temporal cluster of deaths during the holiday season defined from 11/15-01/07. Overall deaths were significantly more than expected during Thanksgiving and New Year. In the adjusted model, uninsured (OR: 1.24: 95% CI: 1.04-1.47) and been married (OR:1.13; 95%CI:1.03-1.23) were significant predictors of dying during the holiday season. Conclusions: Our results show that there is a seasonal effect on the time of death for Florida breast cancer patients. Marital status and non-insurance were significant predictors of dying during the holiday season.
Outcomes of HER2-positive nonmetastatic breast cancer patients with or without deleterious BRCA mutations after trastuzumab treatment.
Authors: Afrough Aimaz , Lin Heather , Gutierrez-Barrera Angelica M. , Litton Jennifer Keating , Valero Vicente , Arun Banu
Published: March 2020

e12550

Background: Human epidermal growth factor receptor (HER2) overexpression or amplification occurs in 20–25% of all breast cancers and is associated with an aggressive form of the disease with reduced disease-free survival (DFS) and overall survival (OS). However, the outcome of patients with HER2+ tumor and BRCA mutation is poorly described. The purpose of this analysis was to analyze the clinical and pathological features and outcomes of patients with HER2+ breast cancer regards to their BRCA status. Methods: Patients who were referred for genetic counseling between 2004-2012 and who had a HER2+ breast cancer treated with trastuzumab were included in our analysis. Patients were considered Her2+ if immunohistochemistry was 3+ or had a ratio of ≥2 by FISH. Patients with metastatic breast cancer at diagnosis were excluded. Clinical and pathological and outcome data was extracted from a prospectively maintained research data base after IRB approval was obtained. Results: Ninety-four patients were identified. The median age at diagnosis was 39 years (range 21 – 58). The majority of the patients were White (76%). Tumors were invasive ductal carcinoma in 89% and had nuclear grading of 3 in 76% of patients. Hormone receptors were positive in 66% and BRCA 1 or 2 mutations were positive in 16% (N=15). The majority of the patients were treated with a combination of Anthracyclines plus Taxanes (76%). All patients received trastuzumab in the neoadjuvant or adjuvant setting. After a median follow-up of 4.4 years, OS and DFS in all patients were 97% and 88%, respectively. Three HER2-positive breast cancer patients had died (3.2 %). Recurrence had occurred in 11 patients; all of these patients were BRCA negative. OS and DFS of patients with BRCA mutations were then compared with OS and DFS of patients without BRCA mutation (both 100% vs. 96% and 81.9%, respectively). There was no statistically significant survival difference in BRCA mutation carriers compared with non-carriers (p=0.362). Conclusions: The presence of a BRCA mutation does not seem to offer prognostic information in this population. Further investigation with larger cohort are needed for confirmation.
Prevalence and outcomes of cancers in Ekiti State, southwest Nigeria.
Authors: Babatunde Oluwole Adeyemi , Elegbede Olusegun Elijah , Ayodele Majekodunmi Lawrence , Abidoye Sunday David
Published: March 2020

e12553

Background: There is an increase in the prevalence of cancer in Nigeria with a change in disease pattern from predominantly infectious to one with both communicable and non-communicable diseases. This study was carried out to determine the prevalence and outcomes of cancers in Ekiti State, Nigeria. Methods: This was a review of the data on patients diagnosed with cancers in Ekiti State as recorded in the database of the Cancer Registry of the Federal Medical Centre, Ido Ekiti between 2007 and 2012. The data was obtained from the cancer registry of the hospital and analysed with SPSS version 15 using descriptive statistics. Results: There were 612 diagnosed cancer patients on record in the cancer registry within the five-year period under review. Most (67.6%) were females, 97.1% belonged to the Yoruba ethnic group, 93.5% were Christians, and 86.6% were married while 13.2% were single and 0.2% were separated. The site most commonly affected was the breast (14.6%) followed by the prostate gland (14.1%), cervix (6.9%), ovary (6.8%), uterus (3.1%) and the stomach (1%). Also, the commonest morphological type of cancer seen was adenocarcinoma (8.5%). The highest levels of education were tertiary, secondary and primary education for 47.4%, 30.2% and 15.2% of the patients respectively while 7.2% had no formal education. Of all the patients seen, 85.3% were symptomatic and 14.7% were not while 79.7% were alive, 2.1% dead and the outcome for 7.6% of the patients was unknown at the time of this survey. Conclusions: The prevalence of cancer is increasing with many of the patients not being able to afford the drugs for treatment. More needs to be done by all stakeholders to encourage early screening and diagnostic measures, reduce exposure to risk factors for cancers and subsidize or waive treatment costs for patients.
Using ANG4043, a brain-penetrant anti-HER2 mab, to increase survival in a murine intracranial breast tumor model.
Authors: Lachowicz Jean E , Demeule Michel , Regina Anthony , Tripathy Sasmita , Che Christian , Currie Jean-Christophe , Lord-Dufour Simon , Houle Emilie , Castaigne Jean-Paul
Published: March 2020

e13013

Background: Treatments for metastatic brain tumors originating from HER2-positive breast disease are limited due to the inability of most anti-tumor agents to enter the brain. While the selectively permeable blood-brain barrier (BBB) restricts access of therapeutics such as mAbs to the brain, transcytosis of hormones, nutrients, and other homeostatic modulators is mediated by endogenous receptors such as LRP1, low density lipoprotein receptor-related protein 1. We have created a family of peptides (Angiopeps) that are recognized by LRP1 and enter the brain via transcytosis. Using these proprietary Angiopeps, we have created novel, brain-penetrant Peptide-Drug Conjugates. An iterative process of linker selection and reaction condition optimization led to the discovery of ANG4043, consisting of the Angiopep An2 attached to a trastuzimab biosimilar. This brain-penetrant peptide-mAb conjugate, which displays HER2 binding affinity and in vitro anti-proliferative properties similar to that of the native mAb, was tested in a murine model of breast tumor brain metastases. Methods: Athymic nude mice were stereotactically implanted 1.5 mm anterior and 2.5 mm lateral to bregma with 1X106 BT-474 cells twelve days prior to initiation of drug treatment. Body weight and morbidity/mortality were monitored daily. Results: Median survival in the control group was 45 days, compared with 68 days and 80 days for the 5 mg/kg (p = 0.0005) and 15 mg/kg (p = 0.0003) groups, respectively, demonstrating a 52% and 78% improvement over the control group. Conclusions: These data demonstrate that ANG4043 increases survival in a mouse HER2-positive intracranial tumor model. These results extend the validation of An2 conjugation beyond small molecules and peptides to include larger molecules such as therapeutic mAbs for development of new brain-penetrant anti-tumor therapeutics.
A 10-year review of primary CNS lymphoma treatments and outcome: The Irish experience.
Authors: Alken Scheryll Paula , Teo MinYuen , Bambury Richard Martin , Mohd Sharial Mohd Syahizul Nuhairy , Jayaram Anuradha , Brett Francesca , Keohane Catherine , Farrell Michael Anthony , Keane Maccon M. , Power Derek Gerard , Moylan Eugene J. , Grogan William , O'Reilly Seamus , Breathnach Oscar S.
Published: March 2020

e13020

Background: PCNSL is a rare variant of diffuse large B cell lymphoma. Optimum treatment strategies are yet to be defined. We report the Irish experience. Methods: We examined the Irish National Cancer Registry to assess the incidence of PCNSL. Patients diagnosed between 2001 and 2011 were cross referenced and identified from medical oncology, neuropathology and pharmacy database in the 3 cancer centres. Progression-free survival (PFS) and overall survival (OS) were estimated via Kaplan-Meier methods, and Cox proportional hazard model was used to identify risk factors. Results: 74 patients were treated in the 3 centres over the time period, representing 57% of all cases diagnosed in Ireland (ranging from 12.5% in 2001 to over 90% from 2008 onwards). 39 (52.7%) were male, with a median age of 60 years (range 17 – 78). 64% had an ECOG PS of 0 – 1 at presentation. Involvement of the deep structures occurred in 37.5% (n=24), with 29.7% (n = 19) having multifocal disease. 20.3% presented with hemiparesis with 18.6% presenting with symptoms suggestive of raised intracranial pressure. 80% were treated with the DeAngelis regimen and 14% with the Ferreri regimen. 35.7% received whole brain radiotherapy. The median PFS was 22.4 months, (95% CI, 14.2 – 32.1), and median OS was 33.3 months, (95% CI, 22.3 – 68.8). ECOG PS and presence of hemiparesis at diagnosis were independent poor prognostic factors for PFS but not for OS. Age, tumour site, multi-focality, chemotherapy regimen and delivery of radiotherapy did not significantly affect PFS or OS. Conclusions: Our data compares favourably with published series. Increased understanding of the molecular biology of PCNSL is urgently needed in order to define optimum therapies. PCNSL should be treated in specialist centres to facilitate increased casemix, enrolment in clinical trials and banking of tumor tissue.
Relationship of the p75 neurotrophin receptor (p75NTR) and hypoxic response and treatment resistance in malignant gliomas.
Authors: Kenchappa Rajappa , Forsyth Peter A. J.
Published: March 2020

e13026

Background: Malignant gliomas (MGs) are resistant to Radiotherapy (RT). The molecular pathways that produce resistance to therapy and ability to tolerate hypoxia are poorly understood. We previously found that the p75NTR causes invasion & proliferation of MGs/Brain Tumor Initiating Cells (BTICs). We think MGs use the neurotrophin-rich brain environment as a survival advantage to resist treatment by expressing the p75NTR. We hypothesize that hypoxia cause p75NTR proteolysis which produces HIF-1α stabilization and activation of hypoxic responses. This repertoire of hypoxic responses leads to resistance to both hypoxia & radiotherapy (RT) and account for MG recurrence. Methods: We used glioma cells and BTICs they express very low or and high levels of p75NTR and manipulated the expression of p75NTR by shRNAs and activation by mutant receptors and pharmacological inhibitors. We exposed these cells to hypoxia and radiation treatment and performed biochemical and functional assays. We have also used paired pre and post-RT frozen patient specimens. Gene expression profiles were analyzed for patients using microarray expression data for 516 primary GBM patients from the TCGA and 239 patients from Moffitt’s Total Cancer Care (TCC) project. Results: We found that inhibiting p75NTR pharmacologically significantly reduced invasion/proliferation of MGs/BTICs in vitro & in vivo. We have also found that p75NTR is required for HIF-1α stabilization and VEGF expression in MGs/BTICs in vitro & in vivo, that p75NTR expressing MGs/BTICs are very resistant to hypoxia & RT in vitro, and these effects are reversed with inhibition of p75NTR signaling. In addition, p75NTR expression and its cleavage are associated with treatment resistance in patient specimens. We also found using TCGA and Moffitt patient specimen data that the p75NTR/Siah2/PHD axis is expressed in MG patients and associated with RT resistance/poor prognosis. Conclusions: These results suggest that p75NTR expression/cleavage are required for HIF-1α pathway activation and hence the phenotype of MGs/BTICs and their treatment resistance. Targeting the p75NTR signaling axis therefore will provide novel therapeutic approaches.
Quantifying the impact of antiangiogenic therapy on hypoxia and implications for radiation therapy in glioblastoma multiforme with a biomathematical model.
Authors: Hawkins-Daarud Andrea , Rockne Russell , Kinahan Paul , Muzi Mark , Alessio Adam , Krohn Kenneth A. , Swanson Kristin
Published: March 2020

e13028

Background: Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor. As angiogenesis is a major hallmark of GBM, it can be inferred that hypoxia plays a prominent role in the progression of the disease. However, due to difficulty in assessing hypoxia, the development and evolution of hypoxia has not been well studied for GBM. 18F-Fluoromisonidazole (FMISO) PET indirectly measures hypoxia. It is known that hypoxia reduces the efficacy of radiation therapy, and one current strategy being explored is to combine anti-angiogenic therapy and radiation therapy. However, it is unclear whether anti-angiogenic therapy is ultimately reducing or increasing hypoxia nor is it clear how long the effects last. Methods: We have developed a spatio-temporal biomathematical model for glioma proliferation and invasion that incorporates the angiogenic cascade. In this context, we can simulate the action of anti-angiogenic treatment, such as bevacizumab, by modifying the availability of angiogenic factors. By applying a pharmacokinetic model for the uptake of FMISO to the simulation results, we can generate the corresponding FMISO-PET images during and after anti-angiogenic therapy to compare with what would be seen in the clinic. Results: Simulation results for a wide range of tumor kinetics demonstrated that hypoxia in general decreased during anti-angiogenic therapy. However, the rates at which it decreased and the time for the hypoxia to return to pre-treatment levels were not uniform. Conclusions: Dynamic understanding of anti-angiogenic therapy effects on vascular normalization and hypoxia suggest that optimal timing of radiation therapy and anti-angiogenic therapies would vary by patient. This biomathematical model can be tuned to individual patients’ tumors and provide similar information as a FMISO-PET image and also give insight into the dynamics of the hypoxia over time. Such insight could be invaluable to patient-specific treatment planning for combining radiation with antiangiogenics.
Comparative dosimetric study of three-dimensional conformal (3DCRT), intensity modulated radiotherapy (IMRT), and volumetric modulated arc therapy (VMAT) for treatment in pituitary adenomas.
Authors: Gupta Subhash , Laviraj M. A , Kunhiparambath Haresh , Sharma Dayanand , M Rajendran , Julka Pramod Kumar , Rath Goura Kishor
Published: March 2020

e13043

Background: Radiotherapy is usually delivered after surgery in pituitary adenomas. Usually stereotactic radiotherapy is used in their treatment. The studies evaluating the recent advances like IMRT, VMAT for pituitary adenomas are rare. Present study evaluates 3DCRT, IMRT, and VMAT for the treatment of pituitary adenomas. Methods: Ten patients of pituitary adenomas who were planned for post operative adjuvant radiotherapy were included. Planning CT was done with the patient supine with a customized thermoplastic cast of head on Philips wide bore CT (for 3 mm). The CT images were transferred online to the Pinnacle TPS V.8.0M. Tumor and the critical structures like brain stem and optic nerves were contoured on pinnacle. 3DCRT was planned on pinnacle. The CT images with the contoured structures were sent to Monaco TPS V.3.10.02. IMRT and VMAT were planned on Monaco. Dose: 50 Gy in 25 fractions. PTV indices analyzed: D mean, D2 (dose received by the hottest 2 percent volume), D98 (dose received by 98 percent), homogeneity index HI [(D2-D98)/D50)], and conformity index CI (PTV volume/volume of PTV covered by 95 percent isodose). Dmax and D2 (dose received by hottest 2cc) for the brain stem, right and left optic nerve PRV were evaluated. The average were calculated and compared. Statistical analysis was done by SPSS Version 14. Results: The Table shows that VMAT is better in terms of PTV indices. For the normal structures also VMAT provides the least dose. Conclusions: VMAT is superior to IMRT and both are better than 3DCRT for the radiotherapeutic treatment of pituitary adenoma. [Table: see text]
Linking kinases to adverse events through kinase inhibitors.
Authors: Iqbal Afsheen , Zhao Shan , Reichert Sonia Evelyn , Maki Robert G.
Published: March 2020

e13524

Background: Small molecule oral kinase inhibitors (SMOKIs) are anticancer agents with unique activity and toxicity. We sought to determine if specific kinases blocked by SMOKIs could be linked to specific adverse events (AEs). Methods: We identified studies in which cancer indications for SMOKIs were compared to placebo or other therapy, and collected prevalence data of grade 3, 4, and 5 AEs for each study arm. Targets of each SMOKI were screened from existing data on kinase specificity, selecting Kd<500nM. Each SMOKI was mapped to its respective kinases. We compared the frequency of AEs from all studies when the kinase of interest was involved to AE frequency when the kinase was not involved, and computed the probabilities for attributed risk for each kinase and the significance of association between AE and drug of interest via t-test. We evaluated the significance in a pair-wise manner, computing the difference in probability for a single AE for each study independently, and then evaluating the significance of the average probability, assuming unequal variance across studies. Results: 67 trials fit our criteria, and led to the identification of AEs associated with varying number of kinases, e.g. diarrhea (45 kinases), asthenia (43), hypertension (30), rash (30), thrombocytopenia (plts, 29), and neutropenia (21). Most associations, while statistically significant, had low attributable risk (≤5%), except diarrhea (24 kinases), hand-foot syndrome (19), and plts (13). BRAF (5.4% attributable risk) and VEGFR1 (4.9%) inhibition were most strongly associated with hypertension; AXL (5.3%), FGFR3 (5.3%), MAP4K5 (5%), and YES1 (5%) were associated with neutropenia; and TNIK (5.4%), PLK4 (5.3%), STK16 (5.3%), RPS6KA1 (5.1%), and FGFR3 (5%) were associated with asthenia. Conclusions: Certain AEs are common to many SMOKIs and thus many kinases. Other AEs such as neutropenia and asthenia were more tightly linked to specific kinases. By developing SMOKIs that block the target of interest but not kinases identified from these data, it may be possible to decrease the toxicity burden of future generations of SMOKIs.
Effect of cilastatin on cisplatin-induced nephrotoxicity and on antitumoral activity.
Authors: Blanco-Codesido Montserrat , Humanes Blanca , Lazaro Alberto , Camaño Sonia , Jado Juan Carlos , Tejedor Alberto
Published: March 2020

e13535

Background: Cisplatin (CDDP) is a very effective and common treatment in solid malignancies used mostly in breast, ovarian, bladder, esophageal, gastric, head and neck cancer and germ cell tumors. One of the most important side effects of CDDP is the nephrotoxicity, a limitating side effect, especially with high CDDP doses, affecting as much as 30% of the patients. Cilastatin (Cls) is a specific inhibitor of renal dedydrodipeptidase I which prevents hydrolysis of imipenem and its accumulation in the proximal tubule. In this work we show that Cls acts as a nephroprotector against CDDP-induced damage without compromising its antitumor activity. Methods: Primary cultures of proximal tubular cells (PTCs) and cell lines of different malignancies (colon, breast, ovarian, bladder) were cultured with CDDP (1, 10 and 30 μM) in the presence or absence of Cls. Cell viability was assessed with MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide) assay. Wistar rats were treated with 5 mg/Kg of CDDP (single dose) and 75 mg/Kg/12 hours of Cls. We measured body weight, serum albumin, ALT, AST, creatinine, BUN, serum iones and GAP anion as well as urinary creatinine, osmolality, potassium, sodium and urea. Results: Concomitant treatment with Cls reduced CDDP-induced changes in PCTs. Several tumoral cell lines were tested with CDDP and Cls together. Cls did not increase or decreased tumor growth alone or in combination with CDDP. CDDP sensitivity was not affected by Cls. Wistar rats treated with CDDP alone showed loss of weight and significant worsening in renal function tests. Wistar rats experienced less loss of weight and a significant reduction in renal function worsening when treated simultaneously with CDDP and Cls. Liver function tests were not altered by the addition of Cls to the treatment. Conclusions: Our findings suggest that Cls administration might represent a novel strategy in the prevention of CDDP-induced acute renal injury without compromising its antitumor activity. Cls treatment could potentially increase the number of patients undergoing CDDP treatment or maintaining treatment. Further clinical trials for renal function preservation in cancer patients are on development.
Identification of pharmacogenetic target genes associated with chemotherapy-induced peripheral neuropathy.
Authors: Komatsu Masaaki , Wheeler Heather E. , Wing Claudia , Delaney Shannon , Dolan M. Eileen
Published: March 2020

e13541

Background: Chemotherapy-induced Peripheral Neuropathy (CIPN) is a dose-limiting toxicity of many anticancer drugs, including taxanes, vinca alkaloids and platinating agents. There are no effective means to predict which patients are at risk for CIPN nor are there effective treatments. Therefore, we have used a whole genome approach in lymphoblastoid cell lines (LCLs) alone or combined with clinical study data to identify target genes associated with CIPN that we tested further in Neuroscreen-1 (NS-1: rat pheochromocytoma) cells and human neurons derived from induced pluripotent stem cells (iCell neurons). Methods: For selecting candidate target genes, we compared published genome-wide association studies (GWAS) results of sensory peripheral neuropathy in cancer patients receiving paclitaxel with GWAS results of pharmacologic phenotypes in LCLs after paclitaxel treatment. We evaluated neurotoxic drug-induced cell growth inhibition using Cell Titer Glo and neurite parameters of outgrowth, processes and branching through imaging following transient knockdown of target genes in NS-1 cells and iCell neurons. Results: After treatment of paclitaxel, vincristine and cisplatin, iCell neurons showed decrease of neurite outgrowth, processes and branching. Whereas, these parameters did not decrease for hydroxyurea, which is not reported to induce neuropathy. Through transient knockdown in NS-1 cells of RFX2, a gene identified through clinical and preclinical studies to be associated with paclitaxel-induced neuropathy, sensitivity to paclitaxel increased as measured by a decrease of neurite outgrowth. Conclusions: These findings imply our model system could identify pharmacogenetic target genes associated with CIPN. These genes have potential for biomarkers or therapeutic targets and enable future personalized treatments for cancer patients at risk for CIPN.
Preclinical characterization of a potent and selective inhibitor of the histone demethylase KDM1A for MLL leukemia.
Authors: Maes Tamara , Tirapu Iñigo , Mascaró Cristina , Ortega Alberto , Estiarte Angels , Valls Nuria , Castro-Palomino Julio , Buesa Arjol Carlos , Kurz Guido
Published: March 2020

e13543

Background: The lysine-specific demethylase KDM1A catalyzes the removal of methyl groups from mono and dimethylated H3K4/K9, changes that have inductive or inhibitory effects on gene expression. KDM1A is a key regulator of leukemia stem cell (LSC) potential and is required for MLL-AF9 oncogenic transformation. Inhibition of KDM1A expression or activity overcomes the differentiation block in AML. Mixed lineage leukemia (MLL) is a form of AML that is especially sensitive to inhibition of KDM1A. Methods: Gene expression was analyzed using microarrays, cell differentiation was assessed by FACS, viability and apoptosis were assessed by MTT assay and PI staining, me2H3K4 levels were quantified by qPCR and ChIPseq. Results: We used computational models based on reported X-ray structures fine-tuned with the SAR of a first series of molecules to design and synthesize >800 KDM1A inhibitors. ORY-1001 is an enantiomerically pure KDM1A inhibitor (IC50 <20nM) with high selectivity against related FAD dependent aminoxidases (MAO-A/B, IL4I1, KDM1B >100uM, SMOX 7uM). ORY-1001 does not inhibit non-related histone modifiers, and is clean in a CEREP diversity panel. Treatment of THP-1 (MLL-AF9) cells with ORY-1001, results in a time/dose dependent me2H3K4 accumulation at KDM1A target genes and concomitant induction of differentiation markers (EC50 me2H3K4 and FACS CD11b <1nM). Microarray analysis of treated THP-1 cells reveals differentiation towards a monocyte-like phenotype. ORY-1001 induces apoptosis in THP-1 and inhibits proliferation and colony formation of MV(4;11) (MLL-AF4) cells (EC50 <1nM). Daily oral administration of doses <0.020mg/kg leads to significantly reduced tumor growth in rodent MV(4;11) xenografts. In vivo and in vitro IND/IMPD enabling studies have shown that ORY-1001 presents excellent oral bioavailability, target exposure and activity in vivo. The compound is stable in hepatocytes (Clint<0.6 mL/min/g liver, @1uM) and does not exhibit CYP (IC50>100uM) or hERG (%inhib.<2%, @10uM) inhibition. No off-target activity has been detected in 28d rat toxicology studies. Conclusions: A potent and selective KDM1A inhibitor is described with in vitro and vivo anti-leukemic efficacy.