bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes of prognostic disclosure: Effects on advanced cancer patients’ prognostic understanding, mental health, and relationship with their oncologist.
Authors: Enzinger Andrea Catherine , Zhang Baohui , Balboni Tracy A. , Schrag Deborah , Prigerson Holly Gwen
Published: March 2020

9519

Background: Many oncologists are reluctant to discuss life expectancy with advanced cancer patients. We examined the frequency of prognostic disclosure and its impact on patients’ prognostic understanding, the patient-doctor relationship, and psychological distress. Methods: Coping with Cancer was an NCI-funded, multi-site prospective cohort of 726 patients with advanced incurable cancer, enrolled 2002-2008. At baseline, patients were asked if their oncologist had ever discussed prognosis, and if so what estimate was communicated. Patients also estimated their prognosis. The therapeutic alliance scale measured patient-doctor relationship, and the McGill QOL instrument assessed symptoms of depression and anxiety. Multivariable analyses (MVA) assessed relationships between prognostic disclosure and psychological symptoms, controlling for confounds. Results: Among this cohort of terminally ill patients (median survival 4mos), most (72%) wanted to be told their life expectancy. Only 19.8% (104/525) of patients had received a prognostic estimate from their oncologist (median estimate 6mos; IQR 6-15mos). When queried about factors informing their prognostic understanding, 85.9% of patients cited personal or religious beliefs; only 11.7% cited a physician’s estimate. Of the 299 patients willing to estimate their life expectancy, patients who had been previously informed of their prognosis were substantially more realistic in their own estimate (median 12mos v 48mos, Wilcoxon test p<0.001). Moreover, patients’ and oncologists’ prognostic estimates were significantly correlated (ρ=0.49, p<0.001). Prognostic disclosure was not associated with poor patient-doctor relationship rating (Fisher’s Exact, p=0.625), nor was it associated with depressive symptoms (β 0.06, p=0.242) or anxiety (β 0.06, p=0.234) in MVA. Conclusions: Few advanced cancer patients are informed of their life expectancy, although most want this information. Prognostic disclosure is associated with substantial improvement in patients’ prognostic understanding, without compromising the patient-doctor relationship or increasing psychological distress.
Comparison of preoperative screening tools predicting postoperative complications in oncogeriatric surgical patients.
Authors: Huisman Monique , Van Leeuwen Barbara , Ugolini Giampaolo , Montroni Isacco , Stabilini Cesare , Spiliotis John , de'Liguori Carino Nicola , Farinella Eriberto , Stanojevic Goran , Nestorovic Milica , Veering Dettie , Salawu Abdulazeez , de Bock G. , Audisio Riccardo A.
Published: March 2020

9557

Background: In the onco-geriatric surgical population it is important to identify patients at increased risk of adverse post-operative outcome in order to effectively implement preventive measures and to improve outcome in this population. There is need for a time saving and efficient screening tool. Our aim was to determine the predictive ability of the Mini Mental State Examination (MMSE), Brief Fatigue Inventory (BFI) and Timed “Up & Go” (TUG) concerning the occurrence of a major post-operative complication in a series of elderly patients undergoing elective surgery for solid tumors. Methods: In an international cohort, 329 patients ≥70years undergoing elective surgery for solid tumors were prospectively included. Primary endpoint was the incidence of a major complication during the first 30 days after surgery. Pre-operatively the MMSE, BFI and TUG were scored. TUG depicts the time needed to stand up from a chair, walk 3 meters, turn around, walk back and sit down. Data were analyzed using multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95%-CI). Results: The majority of patients underwent major surgery (n=219; 66.6%). A total of 71 (22.1%) patients experienced major complications. TUG, MMSE and BFI, adjusted for center, gender and minor or major surgery, were independent predictors of the occurrence of major post-operative complications (see Table). Conclusions: Screening tools are able to predict major post-operative complications in onco-geriatric surgical patients. TUG is most specific in identifying patients at risk and could be considered to allocate preventive measures effectively. [Table: see text]
Provider-patient communication about cost of care: Results from a national patient education program.
Authors: Ahmed Ivy A. , Harvey Allison , Amsellem Marni , Smith Thomas J.
Published: March 2020

9578

Background: A 2010 NIH study indicates direct cancer care expenditures will reach $158 billion in the U.S. by 2020, impacting millions of Americans. The cost of insurance for a family of 4 has increased from $6000 (2000) to over $16,000 (2011). Medical debt is a significant cause of personal bankruptcy, even if insured. The financial realities posed by costs associated with cancer care greatly complicate a cancer diagnosis. The most recent American College of Physicians Ethics Manual recommends all parties must interact honestly, openly, and fairly. (Snyder L, et al. Ann Int Med 2012, p86) This analysis explores the occurrence and value of patient-provider communication surrounding costs associated with care in a national survey of those affected by cancer. Methods: From 2011-12, 505 individuals attending Frankly Speaking About Cancer: Coping with the Cost of Care workshops completed a survey assessing experiences about the costs of cancer care. This is a Cancer Support Community national evidence-based educational program. All attendees (n=708) were eligible to complete survey. Results: Most attendees (71.3%) responded. The majority (62.4%) were people with cancer/survivors; the remainder included spouses/partners, family members, and 8.7% were health care professionals. Most (80.8%) were Caucasian, and averaged 57.2 years. Of those with cancer, 89.9% were insured at diagnosis. 59.4% reported no one on their health care team initiated a discussion about the financial aspects of their care. Included in this figure, 22.7% actively sought information from health care team, and 36.7% received no information about cost. When topic was initiated, it was by social workers (16.2%), physicians (12.3%), nurses (6.3%) or financial specialists (8.2%). When information was provided, 72.1% found it somewhat or very useful. Also, regardless of provider discussion, respondents independently sought resources for managing costs, such as other patients (44.2%), the Internet (41.5%), and patient support organizations (38.1%). Conclusions: Patients want financial information but do not receive it. These data highlight the need and value of providers initiating a dialogue about the cost of cancer care with patients.
Prevalence of cardiovascular disease (CVD) risk factors and preventive care among U.S. cancer survivors.
Authors: Pearlstein Kevin A. , Hendrix Laura H. , Chen Ronald C.
Published: March 2020

9592

Background: CVD is a major cause of mortality in cancer survivors. Prior claims-based studies suggested underutilization of preventive care in cancer survivors, but most CVD preventive care items are not available in claims data. We directly examined the prevalence of CVD risk factors and receipt of care in survivors compared to the non-cancer general population (control) using the National Health Interview Survey. Methods: 32,934 cancer survivors interviewed between 1999 and 2011 were matched to 65819 controls based on age, race, and history of CVD events (angina, myocardial infarction, stroke). Statistical analysis accounted for population sampling weight. Results: CVD risk factors were prevalent among cancer survivors (Table), and 33% continued to smoke. Primary care visits were reported more often among survivors compared to controls (83% vs 74%, p<0.001). A high proportion of survivors and controls received monitoring for diagnosed CVD risk factors, while rates of interventions to modify the risk factors were more modest. On multivariable logistic regression models, having a general doctor visit was associated with increased monitoring for all CVD risk factors examined (hypertension, hyperlipidemia, diabetes, obesity, smoking), but there was no significant difference between cancer vs control. Conclusions: Cancer survivors in the US receive comparable monitoring and interventions for CVD risk factors compared to non-cancer individuals. Survivorship care involving a general doctor was associated with improved monitoring of CVD risk factors. [Table: see text]
Do patients with cardiovascular diseases have earlier relapse in stage I-III non-small cell lung cancer?
Authors: Crescentini Robert M. , Reich Richard R. , Bardhan Pooja , Extermann Martine
Published: March 2020

9603

Background: Diabetes mellitus (DM) has been reported to be an independent risk factor in the development of recurrence of NSCLC following treatment of early stage disease. We evaluated to see if there was a similar effect of cardiovascular disease in patients with newly diagnosed NSCLC. Methods: Using the Moffitt Cancer Center (MCC) databases, patients were identified who were treated for stage I, II and III NSCLC at MCC from 2001-2003. Charts were reviewed and descriptive data were recorded including histories of DM, coronary artery disease (CAD), hypertension, cerebrovascular disease and congestive heart failure (CHF). The use of aspirin and antihypertensive agents at the time of diagnosis were also recorded. Primary endpoint was disease free survival (DFS). Overall survival (OS) was a secondary endpoint. Kaplan Meier curves and Cox regression analyses were used for DFS and OS. Results: A total of707 patients were identified. Ninety-seven patients had DM, 158 had CAD, 396 had hypertension, 43 had cerebrovascular disease and 56 had CHF. DFS was worse in patients with DM (p<0.001, OR 0.63, 95% CI 0.50-0.80), CAD (p<0.001, OR 0.70, 95% CI 0.57-0.85), hypertension (p=0.016, OR 0.81, 95% CI 0.67-0.96), cerebrovascular disease (p=0.006, OR 0.62, 95% CI 0.45-0.87) and CHF (p<0.001, OR 0.56, 95% CI 0.42-0.75). Bivariate analysis showed that CAD, cerebrovascular disease and CHF were associated with shorter DFS independent of DM. OS was also worse in patients with DM (p<0.001, 95% CI 0.50-0.81), CAD (p<0.001, OR 0.62, 95% CI 0.51-0.78), hypertension (p=0.004, OR 0.77, 95% CI 0.64-0.92), cerebrovascular disease (p=0.02, OR 0.66, 95% CI 0.47-0.94) and CHF (p<0.001, OR 0.54, 95% CI 0.41-0.73). In patients with hypertension, there was an improvement in DFS (p=0.047, OR 1.35, 95% CI 1.004-1.819) for those treated with thiazide diuretics. There were no other statistically significant differences in patients based on antihypertensive regimens or aspirin use. Conclusions: DM,CAD, hypertension, cerebrovascular disease and CHF are associated with shorter DFS and worse overall prognosis in patients with non-metastatic NSCLC. CAD, cerebrovascular disease and CHF are associated with shorter DFS independent of DM.
Electro-acupuncture for joint pain related to aromatase inhibitors among breast cancer survivors: A randomized placebo-controlled trial.
Authors: Mao Jun J , Xie Sharon , Farrar John T , Stricker Carrie Tompkins , Bowman Marjorie , Bruner Deborah , DeMichele Angela
Published: March 2020

9639

Background: Arthralgia is a common and debilitating symptom in a significant proportion of breast cancer patients receiving aromatase inhibitors (AIs). Methods: We conducted a randomized, placebo-controlled trial of electro-acupuncture compared to waitlist control (WLC) and sham acupuncture in postmenopausal women with breast cancer who self-attributed their arthralgia to taking AIs. Acupuncturists delivered ten treatments of tailored acupuncture with 2 Hz electro-stimulation via a TENS unit. Sham acupuncture used non-penetrating Streitberger needles at non-traditional acupuncture points and lacked electro-stimulation. The primary endpoint was pain severity measured by the Brief Pain Inventory (BPI) between electro-acupuncture and WLC at Week 8; durability of response at Week 12 and comparison of electro to sham acupuncture were secondary aims. Results: Sixty-seven patients were randomized to the three arms. The mean reduction in BPI pain severity was significantly greater in the electro-acupuncture group than WLC group at both Week 8 (-2.2 vs. -0.2 p=0.0004) and Week 12 (-2.4 vs. -0.2, p<0.0001). The BPI pain-related interference also improved significantly in the electro-acupuncture group compared to WLC group at Weeks 8 (-2.0 vs. +0.2, p=0.0006) and 12 (-2.1 vs. -0.1, p=0.0034). Sham acupuncture reduced pain severity (-2.3) and pain-related interference (-1.5) at Week 8 similar to electro-acupuncture (p= non-significant); however, the effect of sham acupuncture appeared to decrease at Week 12 for pain severity (-1.7) and pain-related inference (-1.3). Conclusions: Electro-acupuncture significantly improved AI-related arthralgia over “usual care” with clinically important and durable changes in symptoms. Treatment effects were similar between the electro and sham groups at Week 8, suggesting that a large component of acupuncture effect is mediated through the process of acupuncture delivery rather than the specificity of needle placement or needle penetration of skin. Research is needed to evaluate the long term effects of electro-acupuncture to improve AI-related arthralgia. Clinical trial information: NCT01013337.
Assessment of neratinib-resistance and cross-resistance in HER2-overexpressing breast cancer cells.
Authors: Breslin Susan , Corcoran Claire , Rani Sweta , Crown John , O'Driscoll Lorraine
Published: March 2020

e11520

Background: While current therapies approved for HER2-overexpressing breast cancer (BC) treatment has led to advances in treatment of this BC subtype, issues of innate/acquired drug resistance are evolving. Neratinib (N) is an irreversible EGFR, HER2 and HER4 tyrosine kinase inhibitor currently in phase III clinical trials for BC treatment. We aimed to investigate the ability of BC cells to acquire resistance to N and the implications of this in terms of potential cross-resistance to other drugs and phenotypic changes in cells. Methods: Neratinib-resistant (NR) cell line variants were developed by exposing HER2-overexpressing BC cell lines, HCC1954 and SKBR3, to increasing concentrations of N over several months. Proliferation assays were used to establish IC50 values for N in parent and NR variants; as well as to assess possible cross-resistance to lapatinib (L), afatinib (A) and docetaxel (D). Phenotypic changes in NR cell variants were examined using invasion, migration and anoikis assays. IGF1R expression was determined using immunoblots. Results: HCC1954-NR and SKBR3-NR cell variants were 6.5±0.4 and 194±47 fold more resistant to neratinib than parent cells, respectively. Furthermore, HCC1954-NR variants were cross-resistant to afatinib (37±7.23 fold) and lapatinib (10±0.8 fold). SKBR3-NR variants were cross-resistant to afatinib by >163.3±22.7 fold (IC50 not reached at 9µM afatinib where, on average, 65.5 % cell growth is maintained) and lapatinib (162.3±22 fold). No cross-resistance to docetaxel was observed. Cells that have acquired N resistance are more invasive, migratory and resistant to anoikis than their parent controls. IGF1R expression is increased in NR cell variants compared to parent cells. Conclusions: Chronic exposure of BC cells to N results in acquired resistance to the drug. N resistance conferred cross-resistance to other HER2-targeting drugs and induced a more aggressive phenotype. Overexpression of IGF1R in NR variants suggested its role in the mechanism of N resistance.
Overall survival according to tumoral clusterin expression in breast cancer.
Authors: Mouillet Guillaume , Chaigneau Loic , Michy Thierry , Villanueva Cristian , Bazan Fernando , Almotlak Hamadi , Curtit Elsa , Cals Laurent , Montcuquet Philippe , Meneveau Nathalie , Algros Marie-Paule , Pivot Xavier B.
Published: March 2020

e11579

Background: Clusterin (CLU) is a glycoprotein expressed constitutively in many tissues and involved in various physiopathological processes. Despite CLU expression is dysregulated in many types of cancer, the specific role of CLU in tumorigenesis remains unclear. The identification of several forms of the protein, with multiple roles is an explanation for these conflicting results. Cytoplasmic CLU (cCLU) has a role in breast tumorigenesis, cancer progression and is associated with breast cancer cell lines death in vitro. However contradictory data are reported about prognostic value of cCLU on survival and clinical progression. Our objective was to estimate patient’s overall survival (OS) according to the expression of cCLU. Methods: Histological and clinical data of 158 patients diagnosed with breast cancer were retrospectively recorded. Every patients were treated in a single French university hospital between 1993 and 2001. Histological samples had been reviewed to determine hormonal status, HER2 and clusterin expression. Immunohistochemical techniques were based on standards and recommendations applied at the time of analysis. Tumors were defined as cCLU positive (cCLU +) if its expression was superior to 10%. Overall Survival rates along with standard deviations were estimated using the Kaplan-Meier method. Differences in OS according to cCLU expression were tested for significance using the log-rank test. Results: Patients had a median age of 56 years (31 – 82 years). Among the 158 patients analyzed, cCLU was overexpressed in 31 patients (19.62%). The histopathologic and clinical characteristics were not statistically different according to clusterin expression even if a trend favouring less favourable tumoural characteristics were observed in cCLU positive tumour. The median follow-up was 14.1 years (11.3 - 19.3). In univariate analysis, cCLU overexpession were not related to OS (HR = 0.86; CI95%: 0.43 - 1.70). Ten-year OS was 76% (± 4) among patients with cCLU - tumors vs 77% (± 7) in patients with cCLU + tumor (p = 0.66). Conclusions: cCLU expression does not seem to be a pronostic factor of overall survival.
Anastrozole in combination with fulvestrant in the first line treatment of hormone receptor positive advanced breast cancer: A meta-analysis.
Authors: Tan Pui San , Haaland Benjamin , Montero Alberto J. , Lopes Gilberto
Published: March 2020

e11591

Background: Emerging resistance to single agent aromatase inhibitors (AI) or fulvestrant as first line treatment for postmenopausal women with advanced hormonal receptor positive breast cancer calls for alternative therapeutic options. This meta-analysis studies the effectiveness of combination therapy with fulvestrant and an AI, as compared to an AI alone in first line treatment of postmenopausal patients with hormonal receptor positive relapsed or metastatic breast cancer. Methods: Literature search was performed using PubMed, Google Scholar, Embase, ASCO and ESMO to search for studies published during the last 10 years using relevant keywords. Two prospective randomized clinical trials were found to fulfill the search criteria for combination of fulvestrant + AI vs. AI alone (both studied anastrozole in combination with fulvestrant). Meta-estimates were calculated by combining study estimates using the DerSimonian and Laird random effects model. The linear mixed-effects model was used to generate 95% prediction intervals for study-specific hazard and odds ratios. Results: Pooled hazard ratio for progression free survival was 0.88 (95% CI 0.72-1.09, 95% prediction interval [PI] 0.65-1.21). Pooled HR for overall survival was 0.88 (95% CI 0.72-1.08, 95% PI 0.68-1.14). Pooled odds ratio for response rate was 1.13 (95% CI 0.79-1.63, 95% PI 0.78-1.65). Conclusions: Pooled results showed a small, non-statistically significant, improvement in progression-free and overall survival. These results do not support the use of combination therapy with fulvestrant and anastrozole in the first line treatment of postmenopausal patients with hormonal receptor positive relapsed or metastatic breast cancer.
Molecular pattern of breast cancer among a series of Egyptian patients.
Authors: Elmesidy Salah Eldeen , Elsherief Wessam , Abdelshafy Mohamed , Hammam Walid
Published: March 2020

e11614

Background: Triple negative (TN) breast cancer has a bad prognosis. It is associated with a poor progression-free and overall survivals. Accordingly, we explored the outcome of different molecular subtypes among a series of Egyptian breast cancer patients. Methods: A total of 661 non-metastatic breast cancer patients' files with were reviewed from Kasr Al-Aini Center of Clinical Oncology and Nuclear Medicine of Cairo University between January 2005 and December 2010. Data were analyzed for age; menopausal status, tumour size, nodal status, pathological type, grade; estrogen status, progesterone status, and human epidermal growth factor receptor 2 (HER2) status. Disease free survival (DFS) was the primary end point. Results: The median age was 50 years. 50.4% of patients were premenopausal, 93.1% had invasive duct carcinoma, 93.3% had grade II tumours, 79.4% had early tumours (T1&T2), 70.4% had positive lymph nodes, 51.7% had luminal A subtype, 21.3% had luminal B, 10.2% had HER2-enriched and 16.6% had TN. Disease free survival after 3 years for each subtype was 87.8% for luminal A, 86% for luminal B, 69% for TN and 66% for HER2 (p= .008). The 3-year disease-free survival was significantly better for postmenopausal patients 92.1% as compared with premenopausal patients 80.1% (P= <0.001), with early tumours (T1&T2) 92.1% & 87.3% respectively as compared with advanced tumours (T3+T4) 80.1% (p= <0.001), LN negative (N0) 98.1% as compared with LN positive (N1+N2) 85.2% and (N3) 68% (p= <0.001), (ER) positive 90.2% as compared with (ER) negative 78.2% (p= <0.001), (PR) positive 90% as compared with (PR) negative 80.2% (p= 0.003), non TNBC 89.8% as compared with TN 72.1% (p= 0.012). The 3-year disease-free survival for TN patients who received adjuvant platinum-based chemotherapy was 46% and for those who received adjuvant non-platinum chemotherapy was 78% (p= 0.135). Conclusions: In our series of Egyptian patients luminal breast cancer subtypes (A and B) had the highest 3-year disease-free survival followed by TN then HER2-enriched type. Adjuvant platinum based chemotherapy had no impact on the 3-year disease-free survival when compared with non-platinum chemotherapy in TN patients.
Benzene-poly-carboxylic acids complex with Cis-diammineplatinum (II) dichloride (BP-C1), a novel anticancer agent, induces apoptosis in human breast cancer cells through caspase activation.
Authors: Fares Fuad , Fares Basem , Larsen Stig , Lindkair-Jensen Steen
Published: March 2020

e12029

Background: Breast cancer is the most frequent malignancy in women in western countries and despite progress in the treatment options surgery, radiation, chemotherapy and hormonal therapy it is still the leading cause of cancer death. BP-C1 is a novel anti-cancer complex of benzol-polycarbonic acids with ammonium-platinum salt developed by Meabco ltd, Denmark. Methods: In the present study, the effect of BP-C1 on growth of human breast cancer cells, MCF7 and T47D, was studied. Cells were exposed to different doses of BP-C1, 100-1000 µg/ml, and cell viability, toxicity (LDH release), cell cycle, apoptosis, caspase activation and gene expression were examined. Results: No toxicity was observed. Exposure of the cells to BP-C1 for 48h, significantly (P<0.001) reduced cell viability by approxematly 90% with IC50 of 400 µg/ml. In cell cycle studies cells were accumulated in sub-G1 phase, which may indicate induction of apoptosis. Annexin 5 assay demonstrated that BP-C1 induces apoptosis of MCF-7 and T47D cell by 65% and 34%, respectively, after 48h of treatment. Detection of caspases by western blot analysis revealed that BP-C1 activates caspase 8 and caspase 9. Moreover, gene expression experiments following BP-C1 treatment and using the Applied Biosystems TaqMan Array Plates indicated that BP-C1 caused an increase in the the expression of pro-apoptotic genes; CASP8AP2, TNFRSF21, RELB, NFKB2, BIRC8 and FADD when compared to the expression level of the House keeping genes, HPRT1 and GAPDH. On the other hand, lower levels of mRNA transcripts of the inhibitory apoptotic genes; BCL2L2 and XIAP were detected. Conclusions: These results may indicate that BP-C1 reduced cell viability of human cancer cells by a unigue induction of apoptosis through activation of the extrinsic (death receptors) and the intrinsic (mitochondrion) apoptotic pathways. These findings may lead to the development of new therapeutic strategies for treatment of cancer using BP-C1 or analogs.
Searching for new genes responsible for unexplained hereditary breast and ovarian cancer patients.
Authors: Teule Alex , Quiles Francisco , Valdes-Mas Rafael , Pujana Miguel Angel , Salinas Monica , Feliubadalo Lidia , Capella Gabriel , Brunet Joan , Blanco Ignacio , Puente Xose S , Lazaro Conxi
Published: March 2020

e12516

Background: About 10-20% of breast and ovarian cancer patients show family history of the disease. Germline mutations in the BRCA1 and BRCA2 genes are usually found in 20-25% of these cases, while the remaining ones are commonly known as BRCAX. Next generation sequencing (NGS) studies have the promise to expedite the identification of the genetic basis underlying BRCAX cases. Aim: To identify gene mutations associated with BRCAX cases by means of whole exome sequencing. Methods: Five selected BRCAX families with more than three affected individuals across at least three generations, and with an apparent dominant pattern of inheritance of the disease were selected in this study. All type of potential alterations of BRCA1/2and linkage to the corresponding loci were excluded in these families. For sequencing, libraries representing the whole exome of multiple affected individuals were obtained using the SureSelect Human All Exon 50 Mb Kit (Agilent) together with the Paired-End Sample Preparation Kit (Illumina) following manufacturers' protocols. Bioinformatics analysis to identify candidate variants present in each family was performed as previously described (PubMed ID: 21549337). Selected rare variants have been analyzed in a set of 288 controls and are currently being evaluated in 500 additional BRCAX cases. Results: By using the described workflow we have identified 16 candidate genes. They were selected based on the presence of rare missense variants that were not found in our control group, predicted as pathogenic using several algorithms (SIFT, PoplyPhen2, Condel and Mutation Taster). Currently, we are re-sequencing these genes in a set of BRCAX samples and complementarily performing loss-of-heterozigosity studies in tumor samples. Conclusions: Exome sequencing of 20 patients from 5 independent Spanish BRCAX families identified a list of putative new BRCAX genes that are currently in the process of validation. Identification of the genetic causes underlying breast and ovarian cancer in BRCAX families is paramount to perform genetic counseling and individual risk assessment in these patients.
Adverse events in non-AIDS-defining cancer patients receiving chemotherapy and combined antiretroviral therapy.
Authors: Sandhu Sonia , Cisak Kamila , Sreenivasappa Shylandra B. , Batra Kumar Kunnal , Gupta Shweta , Mullane Michael Russell , Blumetti Jennifer , Rubinstein Paul G.
Published: March 2020

e12523

Background: From 1991 to 2005, the number of cases of non-AIDS defining cancers (NADC) rose from 3,192 to 10,059 in the USA. Studies have shown an improvement in survival for many HIV-associated malignancies in the post HAART era. Drug-drug interactions between HIV therapy and chemotherapy (CTX) are not well understood. HIV medications can inhibit or induce the cytochrome p450 system, modulating CTX clearance. To understand CTX-HIV medication interactions, we performed a retrospective analysis of all patients (pts) diagnosed with a solid NADC who took CTX with combined antiretroviral therapy (cART). Methods: 157 pts with solid NADC were identified via a computer search at County Hospital. Adverse events (AE) during CTX in pts taking cART were assessed by chart review and graded per the NCI Common Terminology Criteria. Statistics: A Fisher's exact test was used to examine the differences in AE incidence. Results: Patients who did not take cART in conjunction with, or did not require CTX, were excluded. The number of pts analyzed for anal cancer (n=25), lung carcinoma (n=9), breast (n=7), and head and neck carcinoma (HNSCC) (n=4) represents 94% of pts taking cART with CTX in our cohort. Interestingly, Forty-two pts (50%) never received cART during therapy. All pts with anal carcinoma were treated with mitomycin/5FU/radiotherapy. 46 % of the patients taking ritonavir-based cART (6 pts of 13) developed a G4 neutropenia versus 8% (1 pt of 12) taking non-ritonavir cART (p<0.07). Anemia all grades with ritonavir, 54%, versus non-ritonavir cART 16% (p<0.09). All grades neutropenia for lung carcinoma while taking ritonavir was 83% versus 33% while taking non-ritonavir cART. No other correlations were identified. In this cohort, 17 pts received platinum (37%), taxanes (n=5) (11%), anthracyclines (n=5) 11%, gemcitabine (n=2) (4%), and pemetrexed (n=1). No difference in AE was noted between any CTX class, AE, and cART. Conclusions: Ritonavirinduced a 38% increase in G4 neutropenia and anemia during treatment of anal carcinoma with mitomycin/5FU. More trials including HIV-associated cancer pts are needed to assess the role of cART when given in conjunction with CTX.
Saliva samples for genomic testing for preventive oncology: Improving the yield.
Authors: Manschreck Christopher , Stratton Kelly Lynn , Sullivan John , Schrader Kasmintan A. , Vijai Joseph , Offit Kenneth
Published: March 2020

e12555

Background: Germline DNA procurement is an integral step in cancer genomic studies. Saliva collection has numerous benefits over blood draws, including lower cost, easier storage, less risk to patients, and ability to mail samples. However a major limitation to saliva is lower yield per extraction, limiting its use in whole genome sequencing studies. We present a modification of the standard protocol for extracting DNA from saliva collected in Oragene Discover 250 kits (DNA Genotek, Kanata, ON) that reduces both labor and reagent costs while providing yields sufficient for whole genome sequencing. Methods: Nineteen saliva samples were collected using the Oragene Discover 250 kit. Randomly, 10 were selected for extraction using the standard protocol. The remaining nine samples were allocated to the modified protocol. In the modified group, the cell mix was enriched by pelleting, removal of supernatant, followed by resuspension. At this point the sample was enriched for cellular material but at a volume suitable for processing according to the standard protocol. Standard quality control (QC) was performed using a spectrophotometer. Statistical analysis used Student’s T-test and Fisher’s Exact test. Results: All extracted samples attained appropriate quality measures with no significant difference between sample purities (mean 260:280 ratio: 1.72 vs 1.73). Samples undergoing modified extraction provided a mean concentration 50% higher than standard protocol (14.9 µg vs 9.9 µg, p=0.0038, 95% CI: 1.8 – 8.0). Comparing yields required to perform whole genome sequencing, the modified protocol provided significantly more samples meeting QC requirements (p=0.011). Conclusions: The advent of next generation sequencing has made DNA procurement vital to performing studies for preventive oncology. Noninvasive methods are preferred by patients and clinicians. Here we present a modification to a common DNA extraction protocol that provides labor and cost savings while producing sufficient yields for whole genome sequencing.
Variations of DICER1 sequence in Chinese women with BRCA1/BRCA2 negative familial breast cancer.
Authors: Cao Wenming , Gao Yun , Yang Hongjian , Xie Shang-Nao , Meng Xuli , Pan Zhi-Wen , Chen zhan-Hong , Jian Huang , Ye Wei-Wu , Xiying Shao , Jia Wang Xiao
Published: March 2020

e12557

Background: Germline mutations in identified breast cancer susceptibility genes account for less than 20% of Chinese familial breast cancers. Dicer is an essential component of the microRNA producing machinery and germline mutations of DICER1 gene have been confirmed in familial pleuropulmonary blastoma, ovarian sex cord-stromal tumor and so on. Moreover, low expression of DICER1 is frequently detected in breast cancer. However, whether germline mutations of DICER1 occur in familial breast cancers remains unknown. Methods: 65 breast cancer probands from BRCA1/BRCA2 negative Chinese breast cancer families were used for screening of germline mutations in DICER1. In addition, 100 unrelated healthy females were enrolled as the controls. Polymerase chain reaction (PCR)-sequencing assay was employed to screen mutations in the entire coding regions and exon-intron boundaries of DICER1. Genotype and haplotype analyses were studied by widely available programs. Results: No deleterious mutations were identified in the 65 breast cancer probands. However, we found 12 germline variations and 4 of which were novel. In addition, the G allele frequency of rs2297730 (IVS12-91 A>G) was higher in familial breast cancer patients group than that in healthy controls group (OR = 1.873, 95% CI: 1.174-2.988, P = 0.008), and the A/G genotype were significantly associated with familial breast cancer (OR = 3.133; 95% CI: 1.562-6.287, P = 0.004). According to the minimum value of Akaike’s Information Criterion (AIC), the best genetic model was dominant. In addition, the haplotype GCGGAT was significantly associated with familial breast cancer (OR = 2.17, 95% CI: 1.20-3.91, P = 0.011). Conclusions: Although none of deleterious mutations were identified in the DICER1 gene, the current study provided a haplotype analysis of the DICER1 gene polymorphisms. We showed a significantly increased risk of BRCA1/BRCA2 negative familial breast cancer for DICER1 IVS12-91 A>G variant. It might be a potential risk marker for breast cancer in thus population.
Clinical and morphological characteristics of BRCA-associated and sporadic breast cancer in fertile female in the Altai territory.
Authors: Petrova Valentina Dmitrievna , Terekhova Svetlana Aleksandrovna , Sinkina Tatiyana Vladimirovna , Selezneva Inna Anatolievna , Dimitriadi Ylija Nikolaevna , Ermolenko Natalya Aleksandrovna , Boyarskih Ulyana Aleksandrovna , Filipenko Maxim Leonidovich , Lazarev Alexander Fedorovit
Published: March 2020

e12560

Background: Breast cancer (BC) for more than 10 years is the most frequent cancer in females in the Altai territory of Russian Federation. The share of patients under 40 years old varies from 2.6% to 16.0%. Genetically dependent nature of BC in young female is scientifically confirmed fact. The aim of this study was to analyze characteristics of BRCA-associated and sporadic BC in fertile females. Methods: 161 female patients of fertile age (under 40 years old) with BC were examined. Clinical, morphological and genetic (BRCA1) factors were analyzed. BRCA1 mutation was revealed in 22 patients (139 patients did not have it). Results: 82.0% of patients with BRCA1 mutations had positive family cancer history. In this group BC was diagnosed more frequently at the age of 31-35 y.o. (40.9%), while in the group of sporadic cancer – at the age of 36-40 y.o. (58.2%). Pathomorphological forms of BC were analyzed and in both groups infiltrative forms of BC were the most frequent (95.5% and 91.4% correspondingly). I stage cases of BC were diagnosed more frequently the group of sporadic cancers than in the group of BRCA-associated cancers (23.0% and 4.5% correspondingly, P<0.05). Hormone status of the tumours was analyzed. BRCA-associated cancers were significantly more often ER and PR negative (87.5%, P<0.05). Hyperexpression of Her2neu was not revealed in this group. In the group of patients without BRCA mutation ER and PR negative tumours were also prevalent (60.5%, P<0.05). Hyperexpression of Her2neu (+++) was revealed in 6.9%. Triple negative cancers were prevalent in the both groups, while in the group of BRCA-associated cancers there were 91.7% of such tumours. The percentage of polyneoplasia in the group of patients with BRCA mutations was higher than in the group without them (12.0 and 1.0 correspondingly, P<0.05). Conclusions: In females of fertile age carriage of BRCA mutations in 82.0% connected with family cancer history. In the group of sporadic cancers I stage cases of BC are more frequent. In both groups hormone receptor negative and triple negative cancer are prevalent, but in the group of BRCA-associated cancers the percentage of such tomours and polyneoplasia are significantly higher.
The number of metastatic lymph node in N3M0 breast cancer and influence on survival.
Authors: Solak Mustafa , Turkoz Fatma P. , Keskin Özge , Petekkaya Hilbrahim , Sarici Saim Furkan , Babacan Taner , Esin ECE , Aksoy Sercan , Altundag Kadri
Published: March 2020

e12563

Background: To evaluate the impact of the number of metastatic lymph node (MLN) in N3M0 breast cancer patients with a sufficient lymph node sampling. Methods: 200 patients with histopathologically confirmed N3M0 breast cancer were analyzed. Patients were divided into three groups according to the MLN; i) MLN:10-15, ii) MLN:16-20, iii) MLN:>20. Pearson Chi-square test and Kaplan-Meier test were used. Results: 25 patients had T1, 91 had T2, 69 had T3 and 15 had T4 tumor. The number of median MLN was 15 (10-48). HER-2, ER and PR status were similar. There were no significant differences in age at diagnosis, menopausal status, stage, grade and treatment among groups (p>0,05). The median follow-up period was 41.5 months. The median OS was 100, 98 and 58 months in group I, II and III, respectively (p=0.06). When we analyzed for two groups; the median OS was significantly shorter in patients with >20 MLN than patients with 10-15 MLN (98 vs. 58 months; p=0.04). We found no significant difference in DFS (p=0.52). The patients with >20 MLN had increased risk of mortality compared to patients with 10-15 MLN (adjusted-HR 1.96 (95%CI 1.1-3.5); p=0.025). Conclusions: To define the subgroups according to MLN in N3 disease may help determining the high-risk patients and making decision in clinical practice. However this finding should be supported by larger studies.
Twenty-five year anniversary of a successful rural, community hospital, comprehensive cancer screening program.
Authors: Waheed Shahid , Linthacum Tonya A
Published: March 2020

e12569

Background: A 25 year successful comprehensive cancer screening program at a rural community hospital in Mexico, MO, USA, provides a multi-organ cancer detection clinic for asymptomatic women over age of 35. Methods: The Screening Program consists of a Medical Director, day to day oversight by a Family Nurse Practitioner, with nurse practitioner and specialty trained registered nurse examiners. This multi-organ screening program focuses on breast, colon, skin, cervical and prostate cancer early detection. One-hour screening exams for women include detailed cancer risk assessment, prevention education, head-to-toe physical exams including an examination of the skin, clinical breast exam, mammogram, pelvic and Pap test. Additionally, site-specific exams of the abdomen, thyroid, peripheral lymph nodes and rectum are conducted. Male exams include a physical examination of the skin, abdomen, peripheral lymph nodes, thyroid, external genital, digital rectal exam of the prostate and PSA blood education. For all tobacco users, the screening includes an oral examination. Extensive education is provided to participants on prevention modalities, current screening guidelines, and new research findings. Detected abnormalities are referred to the patient’s primary care physician for follow up. A phone call to the patient and the primary care provider four to six weeks after the initial exam obtains the results of the referral visit. Results: 25-year participation rates total 51,223 visits with a ratio of 1 male to 19 females. Return rates over the past year were 94%. 626 cancers have been detected since the inception of the program with 1 breast cancer for every 41 women participating, most identified at early stages. Over 2,500 participants, with a 95% satisfaction rating, from 48 Missouri counties, as well as 21 states of the nation are seen annually for cancer screening. Conclusions: Comprehensive screening programs are effective at decreasing cancer mortality and morbidity through education, prevention, and early detection. Nurse run clinics offer a satisfying, cost effective alternate approach, while continuing to provide competent expertise in the specialized field of cancer prevention.
Training and validation cohort analysis for predicting radiation therapy response in human glioblastoma.
Authors: Corwin David , Rockne Russell , Mrugala Maciej M. , Rockhill Jason K. , Swanson Kristin
Published: March 2020

e13018

Background: Glioblastomas comprise 50% of primary brain tumors and are the most fatal, with a median survival time of 14 months despite aggressive treatment. Due to disease heterogeneity and the presence of subclinical disease, there is a large variability in treatment response among patients, making it difficult to assess treatment efficacy and confounding clinical decision making. Methods: A patient-specific, mathematical model of glioblastoma has been shown to predict untreated growth as well as the effect of radiation therapy. We expand on the technique presented in Rockne 2010 to determine patient-specific radiosensitivity and post therapy radial growth using only pretreatment data. From a potential cohort of 44 patients we randomly chose a training set of 30 to compute the relationship for the radiosensitivity parameter (alpha) versus the net proliferation rate. We then used that relationship to compute an individualized alpha for the remaining 14 test patients based only on pretreatment information. For each of the test patients we compared the observed T1Gd visible radius at the first post radiotherapy timepoint with the simulated prediction. Results: Half of the patients demonstrated average absolute differences between the observed and simulated post radiotherapy T1Gd radii of less than 5 mm, within the measurement error associated with contouring the tumor on MRI, with a maximum difference of 2.5 cm. The largest errors were observed in patients with significant resection. Conclusions: This patient-specific, mathematical model of glioma growth and response to radiotherapy can potentially predict radioresponse in vivo, prior to the commencement of therapy. As a clinical tool, this can have prognostic applications and separate responders from non-responders before deciding to treat with radiotherapy. The larger error for patients with more extensive resections is not unexpected given the difficulties in contouring and assessing tumor burden post surgery. This can be improved by including other imaging modalities such as pre-gadolinium T1 and improving the quantification of extent of resection.
Application of mechanism-based PKPD model to identify optimal dosing regimens for future development of oraxol.
Authors: Fetterly Gerald J. , Gaudy Allison , Liu Biao , Meholick Patricia D. , Kwan Min-Fun Rudolf , Hangauer David G. , Park Kyung-Mi , Son Jeewoong , Bang Yung-Jue
Published: March 2020

e13505

Background: Paclitaxel (PTX) is a widely used potent anticancer drug that blocks mitosis by stabilization of microtubules. Previous attempts for oral administration of PTX have been unsuccessful at least partly due to its affinity for the efflux pump, P-gp. Oraxol is an oral formulation of PTX combined with a novel potent P-gp inhibitor, HM30181A, to maximize absorption of paclitaxel without itself being systemically absorbed. A population PK/PD model was developed to characterize the temporal relationship between PTX exposure and neutropenia, and subsequently model-based simulations were utilized to determine the optimal dosing strategy for oraxol. Methods: Oraxol was administered to 68 (51M/17F) patients with various malignancies. Oraxol dose levels ranged from 60 to 420 mg/m2 QW, and 90-150 QWx2 for 3/4 weeks. Population PKPD modeling was performed with the following patient factors: [BSA (1.29-2.15 m2), ECOG PS scores (97% pts ≤ 1), age (36-81.4 yrs), CrCL (39.6-132.8 ml/min), ALB (2.3-4.8 mg/dL), ALT (6-61 IU/L), TBIL (0.2-1.6 mg/dL), and smoking status (NS:57%)]; followed by model validation. Simulations assessed the influence of dose and schedule on the time course and the extent of neutropenia. Results: A precursor-dependent indirect PKPD response model, including three transit compartments was employed to describe the time course of ANC after oraxol administration. Mean predicted (%SEM) baseline ANC and MTT of neutrophils in plasma were 3.6 (3.9) x109 cells/L and 6.3 (4.2) days. The magnitude of the inhibition on marrow cells was 3.3% per 100 ng/mL of PTX. Model validation results showed excellent concordance with the observed and simulated ANC profiles at the 150 mg/m2 dose level. Simulations showed that severity of neutropenia was dose- and schedule-dependent. The optimal dosing scenarios for oraxol 150 mg/m2QDx3 and QDx5 showed the incidence of grade ³3 neutropenia to be 53.8% and 58%, respectively. Simulated grade 4 neutropenia was 25 and 34.6% for the same regimens; similar to IV PTX. Conclusions: A PKPD model quantifying the neutropenic effect of oraxol has been developed. The model predicts that the QDx3 or QDx5 oraxol dosing 3/4 weeks may optimize efficacy with manageable toxicity.
Effect of Sonic hedgehog activation on CXCR7 expression and CXCR4 signaling in medulloblastoma.
Authors: Ward Stacey Anne , Sengupta Rajarshi , Rubin Joshua
Published: March 2020

e13537

Background: Stratification of pediatric medullolastoma into molecular subtypes elevates hopes that subtype-specific therapy can be more efficacious and less toxic. To realize this goal, the molecular targets that distinguish each subtype must be defined. We found that Sonic hedgehog (Shh)-subtype medulloblastoma can be further divided by CXCR4 expression and that CXCR4 inhibition has potent anti-tumor effects. Here we present data that Shh regulates CXCR4 activity through CXCR7, whose differential expression between normal granule cells and medulloblastoma cells makes its function an ideal therapeutic target. Methods: Single-cell suspensions were plated with or without Shh or cyclopamine followed by treatment with CXCL12. SmoA1 brain tumors were dissociated into single cells and transplanted into nude mice and treated with vehicle, AMD3100, GDC-0449, or both. Tumors were measured and harvested at the conclusion of treatment. Results: Using primary cultures of Shh-driven medulloblastoma we found that Shh activation enhances CXCR4 surface localization and promotes CXCL12-induced signaling, similar to effects of Shh on normal granule cells. We evaluated expression of CXCR4 internalization regulators and found that Shh activation altered the levels of GRKs, arrestins and CXCR7. Among these, CXCR7 expression exhibited the greatest differential response to Shh pathway activation between normal cells and medulloblastoma: CXCR7 expression was highly expressed in normal cells despite Shh effects, but almost completely absent in tumor cells. Conclusions: We conclude that activation of the Shh pathway in medulloblastomas promotes CXCR4 surface localization through inhibition of internalization mediators. This cross-talk is also evident in developing GPCs but with one notable difference: CXCR7 expression (high in normal cells, absent in tumor cells). This distinction suggests that CXCR7 antagonists, which are moving towards clinical trials, may be detrimental to normal cerebellar development and inactive against medulloblastoma. We propose that restoring CXCR7 activity would have negligible effects on granule cells and potently block CXCR4 function in medulloblastoma.