Prevalence of germline TP53 mutation among early onset middle eastern breast cancer patients.

BACKGROUND: The data on prevalence and clinical relevance of TP53 germline mutations in early onset Middle-Eastern breast cancer (BC) is limited. METHODS: We determined TP53 germline mutations in a cohort of 464 early onset BC patients from Saudi Arabia using capture sequencing based next generation sequencing. RESULTS: Germline TP53 pathogenic mutations were found in 1.5% (7/464) of early onset Saudi BC patients. A total of six pathogenic missense mutations, one stop gain mutation and two variants of uncertain significance (VUS) were detected in our cohort. No TP53 pathogenic mutations were detected among 463 healthy controls. TP53 mutations carriers were significantly more likely to have bilateral breast cancer (p = 0.0008). At median follow-up of 41 months, TP53 mutations were an unfavorable factor for overall survival in univariate analysis. All the patients carrying TP53 mutations were negative for BRCA1 and BRCA2 mutations. Majority of patients (85.7%; 6/7) carrying TP53 mutation had no family history suggestive of Li-Fraumeni Syndrome (LFS) or personal history of multiple LFS related tumors. Only one patient had a positive family history suggestive of LFS. CONCLUSIONS: TP53 germline mutation screening detects a clinically meaningful risk of early onset BC from this ethnicity and should be considered in all early onset BC regardless of the family history of cancer, especially in young patients that are negative for BRCA mutations.

Telomerase reverse transcriptase promoter mutations in cancers derived from multiple organ sites among middle eastern population.

Sanger Sequencing and immunohistochemistry was employed to investigate the TERT promoter mutations and TERT protein expression with their association to clinicopathological characteristics in over 2200 samples of Middle Eastern origin from 13 different types of cancers. The TERT promoter mutations were most frequently present in bladder cancer (68.6%), followed by central nervous system tumors (28.7%), thyroid cancer (15.4%), prostate cancer (9.3%), endometrial carcinoma (3.7%), rhabdomyosarcoma (1.4%), colorectal cancer (1%), epithelial ovarian carcinoma (0.7%) and breast cancer (0.7%). No mutations were observed in other types of cancers. In bladder cancer, we found significant inverse association with metastasis and a trend to good survival in patients with TERT mutations. In gliomas, TERT promoter mutations predicted poor prognosis. In thyroid cancer, high frequency of TERT mutation was observed in poorly differentiated carcinoma. In addition, TERT promoter mutations were associated with aggressive markers and poor outcome in follicular thyroid carcinomas.

Does the Timing of Surgery after Neoadjuvant Therapy in Breast Cancer Patients Affect the Outcome?

BACKGROUND: There is a paucity of literature examining the impact of timing of surgery after neoadjuvant chemotherapy. OBJECTIVE: This study aimed to analyze the impact of the time taken to initiate surgical treatment following completion of neoadjuvant chemotherapy on patients' outcomes by evaluating their pathological response, overall survival (OS), and disease-free survival (DFS). METHODS: This is a retrospective review of 611 patients diagnosed with stage II and III breast cancer that received neoadjuvant chemotherapy and surgery between January 2004 and December 2014. The data was collected from a prospectively gathered registry. The patients were stratified into three cohorts according to the time of surgery after neoadjuvant chemotherapy: <4 weeks, 4-7 weeks, or ≥8 weeks. Outcomes were assessed using Kaplan-Meier curves, and the variables were compared using log-rank statistics. RESULTS: The 5-year OS rate was 89.6% and the 5-year DFS rate was 74%. OS and DFS were not significantly different when stratified according to timing of surgery; however, the trends of OS and DFS were poor when surgery was delayed for ≥8 weeks. Median OS and median DFS have not yet been reached. Of the 17% of patients that had surgery after ≥8 weeks, 12.9% had pathological complete response (pCR), while among those that received surgery 4-7 weeks and <4 weeks after neoadjuvant chemotherapy, 26% and 21% had pCR, respectively (p = 0.02). ER+/HER-2+ patients had a statistically significant decrease in pCR if surgery was performed after ≥8 weeks. CONCLUSION: Our patients showed improved pCR if surgery was performed within 8 weeks, especially for ER+/HER-2+ patients. All patients had better OS and DFS trends if surgery was performed between 4 and 7 weeks after neoadjuvant chemotherapy.

Expanding the spectrum of germline variants in cancer.

Our ability to identify germline variants in hereditary cancer cases remains challenged by the incomplete cataloging of relevant genes and lack of consensus on who should be tested. We designed a panel [hereditary oncogenesis predisposition evaluation (HOPE)] that encompasses most of the genes known to be associated with cancer development and tested its yield on more than 1300 samples of cancer patients. Pathogenic or likely pathogenic variants in high and intermediate risk genes were identified in 16, 23.9, 9.7 and 2.7%, respectively, of peripheral blood or normal tissue samples taken from patients with breast, ovarian, colorectal and thyroid cancer. To confirm specificity of these findings, we tested an ethnically matched cohort of 816 individuals and only identified pathogenic or likely pathogenic variants in 1.59% (0.98% in high risk and 0.61% in intermediate risk). Remarkably, pathogenic or likely pathogenic alleles in DNA repair/genomic instability genes (other than BRCA2, ATM and PALB2) accounted for at least 16.8, 11.1, 50 and 45.5% of mutation-positive breast, ovarian, thyroid and colorectal cancer patients, respectively. Family history was noticeably lacking in a substantial fraction of mutation-positive cases (63.7, 81.5, 42.4 and 87.5% in breast, ovarian, colorectal and thyroid, respectively). Our results show high contribution of germline mutations to cancer predisposition that extends beyond "classical" hereditary cancer genes. Family history was lacking in 63.5% mutation-positive cases, shows that hereditary cancer need not appear familial and suggests that relaxed selection of cancer patients for hereditary cancer panels should be considered.

XIAP over-expression is an independent poor prognostic marker in Middle Eastern breast cancer and can be targeted to induce efficient apoptosis.

BACKGROUND: Breast cancer is the most common cancer in females and is ranked second in cancer-related deaths all over the world in women. Despite improvement in diagnosis, the survival rate of this disease has still not improved. X-linked Inhibitor of Apoptosis (XIAP) has been shown to be over-expressed in various cancers leading to poor overall survival. However, the role of XIAP in breast cancer from Middle Eastern region has not been fully explored. METHODS: We examined the expression of XIAP in more than 1000 Middle Eastern breast cancer cases by immunohistochemistry. Apoptosis was measured by flow cytometry. Protein expression was determined by western blotting. Finally, in vivo studies were performed on nude mice following xenografting and treatment with inhibitors. RESULTS: XIAP was found to be over-expressed in 29.5% of cases and directly associated with clinical parameters such as tumor size, extra nodal extension, triple negative breast cancer and poorly differentiated breast cancer subtype. In addition, XIAP over-expression was also significantly associated with PI3-kinase pathway protein; p-AKT, proliferative marker; Ki-67 and anti-apoptotic marker; PARP. XIAP over-expression in our cohort of breast cancer was an independent poor prognostic marker in multivariate analysis. Next, we investigated inhibition of XIAP using a specific inhibitor; embelin and found that embelin treatment led to inhibition of cell viability and induction of apoptosis in breast cancer cells. Finally, breast cancer cells treated with combination of embelin and PI3-kinase inhibitor; LY294002 synergistically induced apoptosis and caused tumor growth regression in vivo. CONCLUSION: These data suggest that XIAP may be playing an important role in the pathogenesis of breast cancer and can be therapeutically targeted either alone or in combination with PI3-kinase inhibition to induce efficient apoptosis in breast cancer cells.

Identification of novel BRCA founder mutations in Middle Eastern breast cancer patients using capture and Sanger sequencing analysis.

Ethnic differences of breast cancer genomics have prompted us to investigate the spectra of BRCA1 and BRCA2 mutations in different populations. The prevalence and effect of BRCA 1 and BRCA 2 mutations in Middle Eastern population is not fully explored. To characterize the prevalence of BRCA mutations in Middle Eastern breast cancer patients, BRCA mutation screening was performed in 818 unselected breast cancer patients using Capture and/or Sanger sequencing. 19 short tandem repeat (STR) markers were used for founder mutation analysis. In our study, nine different types of deleterious mutation were identified in 28 (3.4%) cases, 25 (89.3%) cases in BRCA 1 and 3 (10.7%) cases in BRCA 2. Seven recurrent mutations identified accounted for 92.9% (26/28) of all the mutant cases. Haplotype analysis was performed to confirm c.1140 dupG and c.4136_4137delCT mutations as novel putative founder mutation, accounting for 46.4% (13/28) of all BRCA mutant cases and 1.6% (13/818) of all the breast cancer cases, respectively. Moreover, BRCA 1 mutation was significantly associated with BRCA 1 protein expression loss (p = 0.0005). Our finding revealed that a substantial number of BRCA mutations were identified in clinically high risk breast cancer from Middle East region. Identification of the mutation spectrum, prevalence and founder effect in Middle Eastern population facilitates genetic counseling, risk assessment and development of cost-effective screening strategy.

Impact of Surgery on Survival in Stage IV Breast Cancer.

We aimed to assess retrospectively the survival outcome in patients with stage IV breast cancer who underwent surgery. In a retrospective, nonrandomized study of stage IV breast cancer patients diagnosed in a single institution between 2000 and 2012, we assessed patient's survival in the context of baseline characteristics. A total 678 patients with metastatic breast cancer were included; 412 (60.77%) underwent surgery for the primary tumor (Surgery group), and 266 (39%) did not underwent surgery for the primary tumor (Nonsurgery group), with a median follow-up of 41 months. Patients in the Surgery group had longer survival (41 versus 27 months, p < 0.0029). The 5-year survival rate for Surgery group was 34% compared with 14% for the Nonsurgery group. A multivariate analysis revealed surgery (p = 0.0003), large tumor size (p = 0.0195), ER-positive (p < 0.0001), and metastasis at presentation (p = 0.0032) were prognostic variables. Loco-regional surgery does confer a survival advantage in stage IV breast cancer, however, selection bias cannot be excluded, a well-designed and powerful randomized, controlled trial would be valuable to answer whether surgery can improve survival.

ALK alteration is a frequent event in aggressive breast cancers.

INTRODUCTION: Breast cancer is the most common female malignancy worldwide and, despite improvements in treatment modalities, there are increased chances of recurrence and metastasis in a substantial number of cases and it remains one of the major causes of mortality among female cancer patients. Anaplastic lymphoma kinase (ALK) gene has been found to be altered in several solid and hematologic tumors. We aimed to comprehensively study the prevalence of ALK expression, and changes in copy number and translocation in a large cohort of breast cancer cases in a Middle Eastern population. METHODS: ALK protein expression was investigated by immunohistochemistry and numerical and structural variations of the ALK gene were analyzed by fluorescence in situ hybridization (FISH) in a tissue microarray format in a cohort of more than 1000 Middle Eastern breast cancers. The data were correlated with clinicopathologic parameters and other important molecular biomarkers. RESULTS: Immunohistochemical analysis showed ALK overexpression in 36.0 % of the breast cancer patients and gene amplification was present in 13.3 % of cases, seen by FISH analyses. ALK overexpression was significantly associated with ALK gene amplification (p = 0.0031). ALK-overexpressing tumors showed significant association with high-grade tumors (p = 0.0039), ductal histologic subtype (p = 0.0076), triple-negative phenotype (p = 0.0034), and high Ki-67 (p = 0.0001) and p-AKT (p <0.0001). CONCLUSIONS: Immunohistochemical analysis showed ALK is overexpressed in a substantial proportion of breast cancers and possibly plays a significant role in the aggressive behavior of this cancer. Gene amplification is hypothesized to be a possible cause for a significant proportion of this overexpression. Based on these findings, a potential role for an ALK inhibitor, as a therapeutic agent targeting aggressive subtypes of breast cancer, merits further investigation.

Loss of PTEN expression is associated with aggressive behavior and poor prognosis in Middle Eastern triple-negative breast cancer.

PTEN is a tumor suppressor that negatively regulates the PI3 K-AKT signaling pathway which is involved in the pathogenesis of many different tumor types and serves as a prognostic marker in breast cancer. However, the significance of the role of PTEN in Middle Eastern ethnic breast cancer has not been explored especially with the fact that breast cancer originating from this ethnic population tend to behave more aggressively than breast cancer in the west. In this study, we analyzed PTEN alteration in a tissue microarray format containing more than 1000 primary breast cancers with clinical follow-up data. Tissue Microarray sections were analyzed for protein expression and copy number change using immunohistochemistry and fluorescence in situ hybridization. Loss of PTEN immunostaining was observed in 77 % of the cases. PTEN loss was significantly associated with large tumor size (p = 0.0030), high grade (p = 0.0281), tumor recurrence (p = 0.0333), and triple-negative breast cancers (p = 0.0086). PTEN loss in triple-negative breast cancers was significantly associated with rapid tumor cell proliferation (p = 0.0396) and poor prognosis (p = 0.0408). PTEN deletion was found only in 60 cases (6.4 %). Loss of PTEN protein expression occurs at high frequency in Middle Eastern breast cancer. PTEN inactivation may potentially lead to an aggressive behavior of tumor cells through stimulation of tumor cell proliferation. Furthermore, PTEN signaling pathway might be used as potential therapeutic target in triple-negative breast cancers since loss of its expression is shown to be significantly associated with this aggressive subtype of breast cancer.

Obesity is a significant risk factor for breast cancer in Arab women.

BACKGROUND: Breast cancer (BC) is the most common malignancy and the leading cause of cancer-related death amongst women worldwide. The risk factors of this disease are numerous, and their prevalence varies between racial and ethnic groups as well as geographical regions. Therefore, we sought to delineate the association of socio-demographic, reproductive and life-style related risk factors with breast cancer in the Arab population. METHODS: Unmatched case-control study was conducted in the kingdom of Saudi Arabia using 534 cases of histologically confirmed breast cancer and 638 controls. Controls were randomly selected from primary health care visits and were free of breast cancer. Unconditional logistic regression analysis was performed to estimate odds ratios (ORs) and to examine the predictive effect of each factor on risk for BC. All study participants were interviewed by trained interviewers at hospital (cases) or at primary health care centers (controls). RESULTS: A total of 1172 women were eligible for this study, of which 281 (24.0%) were aged ≤35 years, 22.9% illiterate, 43.6% employed, 89.5% married, and 38.1% were obese. Grade III tumors constituted 38.4% of cases. Tumor stage I was 7.5%; II, 50.7%; II, 30.9%; IV, 11.1%. We have shown strong association between breast cancer among Arab females and obesity (OR =2.29, 95% CI 1.68-3.13), positive family history of breast cancer (OR =2.31, 95% CI 1.60 - 3.32), the use of hormonal replacement therapy (OR =2.25, 95% CI 1.65 - 3.08), post-menopause (OR =1.72, 95% CI 1.25 - 2.38), lack of education (OR =9.09, 95% CI 5.88 - 14.29), and never breastfeed (OR =1.89, 95% CI 1.19 - 2.94). CONCLUSION: These results indicate the presence of classical risk factors established in the western countries, and also some specific ones, which may result from genetic and/or environmental factors. Thereby, these findings will be of great value to establish adequate evidence-based awareness and preventative measures in the Arab world.

Factors Associated with Health-Related Quality of Life Among Breast Cancer Survivors in Saudi Arabia: Cross-Sectional Study.

BACKGROUND: Assessment of health-related quality of life (HRQOL) is a major concern among breast cancer survivors. Little is known about HRQO and its determinants in Saudi women with breast cancer (BC). This study aimed to describe the HRQOL of Saudi women with breast cancer and the association between HRQO and sociodemographic and clinical variables. METHODS: This cross-sectional study involved 147 BC participants who completed the 36-item Short Form Health Survey (SF-36). Multivariable linear logistic regression analysis was conducted to determine factors associated with HRQOL. RESULTS: For the physical component scale, general health scored the highest (55.41±17.99) while, role physical function scored the lowest (48.61±22.51). The mean scores in the mental component were higher for social function (56.91±20.84), while the lowest score was observed for energy and vitality (49.62±20.84). Significant differences were observed in many SF-36 domains across the sociodemographic and clinical variables. Older age, having had a mastectomy as well as comorbid conditions, and receiving chemotherapy and hormonal therapy were associated with decreased HRQOL. However, being physically active, employed, and having more education were associated with higher HRQOL. CONCLUSION: HRQOL is generally poor among breast cancer survivors in Saudi Arabia, depending on a variety of factors. These findings highlight the need for routine QOL assessment. Furthermore, recognizing these predictors may play a key role in maximizing HRQOL for breast cancer participants.

Successful Recovery of COVID-19 Associated With Cardiomyopathy in Advanced Breast Cancer Patient With Pulmonary Lymphangitis Carcinomatosis.

SARS-CoV-2 infection induces myocardiopathy in 19% of severe cases, with a mortality rate of up to 51%. The mainstay of treatment is supportive care, steroids, and tocilizumab (anti-IL-6). This is a case of a 43-year-old woman diagnosed with hormone-positive breast cancer with lung metastasis and pulmonary lymphangitis carcinomatosis (PLC). Her baseline cardiac function was within normal limits. She presented to the emergency department with respiratory distress. Chest CT showed multiple bilateral ground-glass opacities consistent with COVID-19 pneumonia and confirmed by COVID-19-PCR nasal swab. Her condition deteriorated, and she was urgently admitted to the intensive care unit with evidence of a cytokine storm. She was started on tocilizumab, dexamethasone, and meropenem. Echocardiogram (echo) showed a severely reduced ejection fraction with severe global hypokinesis. A second dose of tocilizumab was given, and the dexamethasone dose was increased. Fortunately, the patient had significant clinical and biochemical improvement and regained her normal cardiac function. In conclusion, dexamethasone and tocilizumab could be promising aids in treating cardiomyopathy secondary to SARS-CoV-2 infection.

Gemcitabine-Induced Myositis in a Luminal B Breast Cancer patient: A Case Report.

Human epidermal growth factor receptor-positive breast cancer is an aggressive cancer which represents approximately a quarter of all breast cancers worldwide. Recent advances have led to the development of targeted therapies, such as trastuzumab (H), which have significantly improved prognosis. Such therapies are currently used alongside other chemotherapeutic agents, such as paclitaxel (P) and gemcitabine (G). The most common side effects of PGH combination therapy include thrombocytopenia and anemias. However, there have been no previous reports of myositis resulting from this combination. We report the case of a 54-year-old metastatic breast cancer patient on PGH therapy who developed muscle weakness. The patient was initially treated with trastuzumab, pertuzumab, and paclitaxel. However, pertuzumab was changed to gemcitabine due to severe diarrhea. After the fourth cycle of PGH, the patient presented with muscle weakness and creatine kinase levels of up to 6755 U/L. Magnetic resonance imaging of the femur and pelvis revealed diffuse bilateral myositis, suggesting a diagnosis of gemcitabine-induced myositis. The patient was placed on intravenous fluids and corticosteroids, which resolved her condition. To our knowledge, this is the first report of gemcitabine-induced myositis in a breast cancer patient. Further studies are needed to determine the underlying mechanisms of gemcitabine-induced myositis and develop preventative measures.

PALB2 germline mutations in a large cohort of Middle Eastern breast-ovarian cancer patients.

The PALB2 gene is a breast cancer (BC) and ovarian cancer (OC) predisposition gene involved in the homologous recombination repair pathway. However, the prevalence and clinicopathological association of PALB2 pathogenic/likely pathogenic (PV/LPV) variants in Middle East is still not fully explored. Total 918 BC/OC patients from Saudi Arabia were selected for PALB2 mutations screening using capture sequencing technology. Five heterozygous PVs or LPVs were identified in six cases, accounting for 0.65% (6/918) of entire cohort. Two cases (33.3%) harbored PVs and four cases (66.7%) carried LPVs. Four PVs/LPVs (80%) were frameshift along with one novel splicing LPV (c.2835-2_2835-1delinsTT). One recurrent LPV (c.3425delT: p.L1142fs) was identified in two cases. All six affected carriers have breast cancer diagnosis with median age of 39.5 years (range 34-49 years). Only two cases (33%) have documented family history of cancer. Breast cancer phenotype was invasive ductal unilateral cancer in all cases with 66.7% of hormone receptor positive and 16% of triple negative tumors. Germline PVs/LPVs in the PALB2 gene were observed in low frequency of 0.65% in Saudi BC and/or OC. Our study confirms one recurrent LPV and one novel LPV in Saudi breast cancer patients.

The biological and clinical impact of inhibition of NF-κB-initiated apoptosis in diffuse large B cell lymphoma (DLBCL).

NF-κB is frequently over-expressed in a variety of non-Hodgkin's lymphomas (NHLs) and has been implicated in lymphomagenesis; however, its role in diffuse large B cell lymphoma (DLBCL) as a prognostic biomarker has not been fully elucidated. Therefore, we investigated the role of NF-κB and its association with clinicopathological features in a tissue microarray cohort of 230 DLBCL patient samples. We then elucidated the role of NF-κB inhibition on cell viability and apoptosis in vitro, using DLBCL cell lines. Using immunohistochemistry, NF-κB was detected in 25.6% (52/203) DLBCL tumours, was associated with activated B cell (ABC) phenotype (p = 0.0054), Epstein-Barr virus (EBV; p = 0.0080) and over-expression of the anti-apoptotic marker XIAP (p = 0.0013). DLBCL cases with nuclear expression of NF-κB showed a significantly poorer overall survival as compared to those without NF-κB expression (p = 0.0236). In a multivariate analysis using a Cox proportional hazard model for IPI and NF-κB expression, the relative risk was 2.97 for high NF-κB expression (95% CI 1.27-6.94; p = 0.0113) and 7.55 for the high-IPI group (95% CI 3.34-18.35; p < 0.0001). In vitro, Bay 11-7085 inhibited constitutively active NF-κB expression in a dose-dependent manner and inhibition of NF-κB also down-regulated expression of the downstream target gene products Bcl-2, Bcl-XL (BCL2L1), XIAP and Survivin, leading to apoptosis via activation of the mitochondrial apoptotic pathway. NF-κB over-expression was found to be an independent prognostic marker for poor survival in DLBCL. Altogether, these results suggest that NF-κB may be a useful prognostic biomarker and a potential target for therapeutic intervention in DLBCL.

Association Between Obesity and Clinicopathological Profile of Patients with Newly Diagnosed Non-Metastatic Breast Cancer in Saudi Arabia.

Purpose: Obesity is prevalent in Saudi Arabia and is associated with adverse clinical features and poor breast cancer (BC) outcomes. We determined the distribution of body mass index (BMI) and evaluated its association with disease characteristics and outcomes in women with non-metastatic BC. Patients and Methods: We conducted a retrospective analysis of a prospectively collected database of consecutive patients treated for non-metastatic BC between 2002 and 2014. Patients were categorized into the following groups: underweight/normal weight (BMI <25 kg/m2), overweight (BMI 25-29.9 kg/m2), and obese (BMI ≥30 kg/m2). Regression analysis was used to evaluate clinicopathological factors associated with BMI and clinical stage. Results: A total of 2212 patients were enrolled. The median age was 45 years (interquartile range [IQR], 39-52 years), and the median BMI was 30 kg/m2 (IQR, 26-34 kg/m2). Most patients were premenopausal (63.6%), nearly half of the patients had stage III disease, and 11.2% were screen-detected. The prevalence of obesity was 53.4%, with a significant difference between the peri/premenopausal (49.4%) and postmenopausal (61.7%) groups (p < 0.001). Obese patients were more likely to be aged >40 years, be postmenopausal, have a history of oral contraceptive pills, have advanced-stage disease, and have undergone radiation therapy, and were less likely to have human epithelial growth factor 2 (HER2)+ disease than non-obese patients. Premenopausal obese women had fewer hormone receptor-positive and more triple-negative cancers than postmenopausal obese women did. Obesity, non-screening-detected BC, and HER+ status were independent prognostic factors for advanced-stage presentation. Conclusion: The prevalence of obesity and its significant association with advanced BC justify the upscaling of screening services and instituting weight-reduction strategies.

Using the Appropriate Formula for QT Measurement Can Save Lives.

CDK 4/6 inhibitors, in combination with endocrine therapy, are the standard of care for patients with endocrinesensitive advanced breast cancer. This class of drug, however, is associated with QT prolongation, which serves as a surrogate marker for Torsades de Pointes (TdP), a cause of life-threatening ventricular arrhythmias and sudden cardiac death. The ICH E14 guidance document uses the Bazett formula for reporting of cardio-dynamic and safety ECG data in clinical trials. While there is substantial familiarity with the Bazett (QTcB) formula (QT/(RR) 1/2), the Fridericia (QTcF) formula (QT/(RR) 1/3 ) is preferred in the cancer population as it is often more accurate at heart rate extreme. Accordingly, the Fridericia formula is currently the standard adopted by the FDA when submitting QT data for review. At the King Faisal Specialist Hospital and Research Center, a total of 82 patients with advanced breast cancer, had a baseline ECG on day 1 before the initiation of ribociclib based therapy. Of the enrolled 82 patients, 19 (23%) were initially excluded from receiving ribociclib based due to a prolonged QTc >450ms, however, when the QTc-interval was manually measured and recalculated using Fridericia and Framingham formulae using MDCalC (https://www.mdcalc.com),17 of 19 patients successfully received their treatment without any arrhythmogenic effects. Repeat ECG on day14, and day 1 of cycle 2 demonstrated that none of these patients had QTc exceeding 480 ms. Our data highlights the complexities of evaluating the QT interval in oncology patients and the utility of the Fridericia/Framingham formulae in this population. Given these findings, we recommend the adoption of the Fridericia or Framingham formulae for measurement of QTc in all cancer patients exposed to potentially QT-prolonging cancer therapy.

Prognostic significance of XIAP expression in DLBCL and effect of its inhibition on AKT signalling.

The inhibitor of apoptosis protein (IAP) family member X-linked inhibitor of apoptosis protein (XIAP) is essential for cell survival in lymphoma. However, the role of XIAP overexpression in diffuse large B-cell lymphoma (DLBCL) is not fully elucidated. Therefore, we analysed the expression of XIAP protein and its clinicopathological correlation in a large cohort of DLBCLs by immunohistochemistry in a tissue micro-array format. XIAP was found to be overexpressed in 55% of DLBCLs and significantly associated with poor clinical outcome (p = 0.0421). To further elucidate the role of XIAP in DLBCL and the inter-relationship with PI3-kinase/AKT signalling, we conducted several in vitro studies using a panel of DLBCL cell lines. We found that pharmacological inhibition of XIAP led to caspase-dependent apoptosis in DLBCL cells. We also detected an inter-relationship between XIAP expression and activated AKT in DLBCL cells that may explain cellular resistance to PI3-kinase/AKT inhibition-mediated apoptosis. Finally, this anti-apoptotic effect was overcome by simultaneous pharmacological inhibition of XIAP and PI3-kinase/AKT signalling leading to a more potent synergistically induced apoptosis. In summary, our data suggest that XIAP expression is a poor prognostic factor in DLBCL and the XIAP-AKT relationship should be explored further as a potential therapeutic target in DLBCL.