Combining Poly (ADP-Ribose) Polymerase (PARP) Inhibitors with Chemotherapeutic Agents: Promise and Challenges.

Better understanding of molecular drivers and dysregulated pathways has furthered the concept of precision oncology and rational drug development. The role of DNA damage response (DDR) pathways has been extensively studied in carcinogenesis and as potential therapeutic targets to improve response to chemotherapy or overcome resistance. Treatment with small molecule inhibitors of PARP has resulted in clinical response and conferred survival benefit to patients with ovarian cancer, BRCA-mutant breast cancer, HRD-deficient prostate cancer and BRCA-mutant pancreatic cancer, leading to US Food and Drug Administration (FDA) approvals. However, the observed clinical benefit with single agent PARP inhibitors is limited to few tumor types within the relevant genetic context. Since DDR pathways are essential for repair of damage caused by cytotoxic agents, PARP inhibitors have been evaluated in combination with various chemotherapeutic agents to broaden the therapeutic application of this class of drugs. In this chapter, we discuss the combination of PARP inhibitors with different chemotherapeutics agents, clinical experience to date, lessons learnt, and future directions for this approach.

Selinexor: Changing the paradigm in patients with TP53 wild-type endometrial cancer?

Recurrent endometrial cancer (EC) remains a therapeutic challenge despite advancements in personalized medicine. SIENDO trial showed the potential clinical benefit of selinexor in patients with TP53 wild-type advanced/recurrent EC. The quest for novel therapeutic avenues and approaches continues as researchers seek a glimmer of hope in an area of uncertainty.

Successful elimination of falciparum malaria following the introduction of community-based health workers in Eastern Myanmar: A retrospective analysis.

BACKGROUND: Myanmar has a large majority of all malaria in the Greater Mekong Subregion. In the past decade, substantial progress was made in malaria control. The residual burden of malaria is in remote areas where currently recommended malaria elimination approaches are generally not feasible. In such hard-to-reach communities in Mon state, East Myanmar, Medical Action Myanmar introduced community health workers (CHWs) to deliver early diagnosis and treatment for malaria. We conducted a retrospective analysis to assess the impact of this intervention. METHODS AND FINDINGS: This retrospective analysis involved data collected routinely from a CHW programme in Mon state conducted between 2011 and 2018. A network of 172 CHWs serving a population of 236,340 was deployed. These CHWs carried out 260,201 malaria rapid diagnostic tests (RDTs) to investigate patients with acute febrile illness. The median blood examination rate was 1.33%; interquartile range (IQR) (0.38 to 3.48%); 95% CI [1.28%, 1.36%] per month. The changes in malaria incidence and prevalence in patients presenting with fever were assessed using negative binomial regression mixed effects models fitted to the observed data. The incidence of Plasmodium falciparum malaria (including mixed infections) declined by 70%; 95% CI [65%, 75%]; p < 0.001 for each year of CHW operation. The incidence of P. vivax malaria declined by 56%; 95% CI [50%, 62%]; p < 0.001 per year. Malaria RDT positivity rates for P. falciparum and P. vivax declined by 69%; 95% CI [62%, 75%]; p < 0.001 and 53%; 95% CI [47%, 59%]; p < 0.001 per year, respectively. Between 2017 and 2018, only 1 imported P. falciparum case was detected in 54,961 RDTs. The main limitations of the study are use of retrospective data with possible unidentified confounders and uncharacterised population movement. CONCLUSIONS: The introduction of CHWs providing community-based malaria diagnosis and treatment and basic health care services in remote communities in Mon state was associated with a substantial reduction in malaria. Within 6 years, P. falciparum was eliminated and the incidence of P. vivax fell markedly.

Updated meta-analysis of randomized controlled trials on primary outpatient thromboprophylaxis in patients with gastric and gastroesophageal junction cancers receiving chemotherapy.

Advanced gastric cancer is a highly thrombogenic cancer per Khorana score. Recent clinical practice guidelines suggest primary outpatient thromboprophylaxis (POTP) for patients with a Khorana score ≥2. We performed an updated meta-analysis to evaluate the benefit of POTP in patients with gastric cancer and gastroesophageal junction cancers receiving chemotherapy. Randomized controlled trials with reduction in venous thromboembolism (VTE) as a primary or secondary endpoint were incorporated. A total of 631 patients from subgroups of three randomized controlled trials were included. The VTE incidence was 1.6% and 5.1% in POTP and control groups, respectively (risk ratio 0.31; confidence interval 0.11 to 0.83; P = 0.02), with a number needed to treat of 29 to prevent one VTE event. Even though the recent clinical practice guidelines suggest POTP in patients with gastric cancer and gastroesophageal junction cancers, our meta-analysis findings do not support the routine use of POTP in those patients.

The contemporary management of cancers of the sinonasal tract in adults.

Sinonasal malignancies make up <5% of all head and neck neoplasms, with an incidence of 0.5-1.0 per 100,000. The outcome of these rare malignancies has been poor, whereas significant progress has been made in the management of other cancers. The objective of the current review was to describe the incidence, causes, presentation, diagnosis, treatment, and recent developments of malignancies of the sinonasal tract. The diagnoses covered in this review included sinonasal undifferentiated carcinoma, sinonasal adenocarcinoma, sinonasal squamous cell carcinoma, and esthesioneuroblastoma, which are exclusive to the sinonasal tract. In addition, the authors covered malignances that are likely to be encountered in the sinonasal tract-primary mucosal melanoma, NUT (nuclear protein of the testis) carcinoma, and extranodal natural killer cell/T-cell lymphoma. For the purpose of keeping this review as concise and focused as possible, sarcomas and malignancies that can be classified as salivary gland neoplasms were excluded.

Workplace Violence among Nurses at a Tertiary Hospital in Myanmar: A Cross-sectional Study.

ABSTRACT: Among all types of health-care workers, nursing professionals are at the highest risk of violence since they have to deal with patients and their families directly and frequently. This study aimed to assess the magnitude of both physical and psychological workplace violence (WPV) among nurses at a public hospital in Myanmar and identify related factors. A cross-sectional study was carried out among 192 nurses with a minimum 1-year of working service at a large tertiary hospital using a standard self-administered questionnaire developed by the World Health Organization/International Labour Organization in 2003. The prevalence of overall WPV in the past 12 months was 29.2%. In particular, verbal abuse was the most frequent type (27.1%), followed by bullying/mobbing (7.8%) and physical violence (1.6%). Majority of perpetrators were patient's relatives (62.7%) for verbal abuse and staff members (64.3%) for bullying/mobbing. The reporting rate was very low for verbal abuse (13.5%) and bullying/mobbing were not reported. Logistic regression analysis showed that respondents who were older than 45 years' group (adjusted odds ratio [AOR]: 19.32; 95% confidence interval (CI): 1.99-186.95, P = 0.011), those who were staff nurses (AOR: 17.87; 95% CI: 1.05-33.20, P = 0.046), and those who 1-5 years and 5.1-10 years of working experiences (AOR: 18.68; 95% CI: 3.43-101.65, P = 0.001) (AOR: 15.74; 95% CI: 2.80-88.42, P = 0.002) were more likely to be exposed to WPV than their respective counterparts. Awareness generation about the importance of WPV, enforcing available legal instruments, and establishing management strategies for safe working environments should be emphasized.

Heparin-Induced Thrombocytopenia at the Emergency Department Due to Intermittent Heparin Flush in a Patient Undergoing Stem Cell Transplant.

Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin products, but not warfarin. HIT usually occurs 5‒10 days after exposure to heparin. Here, we report a case of HIT with multiple thrombotic events and severe thrombocytopenia resulting from intermittent intravenous heparin flushes for maintenance of a newly placed subclavian central venous catheter (CVC) for stem cell transplant. The patient is a woman in her forties with multiple myeloma who presented to the emergency department (ED) with dyspnea, pleuritic-type chest pain, hemoptysis, and worsening left-leg swelling. Heparin had been used to flush the CVC. Her platelet count began dropping approximately one week after insertion. The patient was receiving other medications known to cause thrombocytopenia. She had undergone multiple platelet transfusions. In the ED, her lab results showed thrombocytopenia), anemia; renal insufficiency; and elevated troponin, prothrombin time, and D-dimer levels. Because of the hemoptysis and thrombocytopenia, she initially received platelet transfusion and oxygen. She was found to have deep vein thrombosis of the lower extremity and started a referral to interventional radiology for inferior vena cava (IVC) filter placement. However, further review and consultation of the Benign Hematology service, discussion about the timing of decreased platelet count shortly after CVC placement and heparin administration, and the presence of thrombosis, suggested a high pre-test probability of HIT. Anticoagulation with argatroban was initiated, and IVC filter insertion was canceled. Further workup confirmed HIT diagnosis and saddle pulmonary embolism. During the patient's hospitalization, her platelets continued to improve and reached baseline upon discharge. She was transitioned to fondaparinux at the time of discharge. A few weeks later, she had successful stem cell transplantation. Emergency physicians treating patients with thrombocytopenia receiving heparin, even in small amounts, should consider the possibility of HIT and be familiar with its management.

Identification of KRASG12C Mutations in Circulating Tumor DNA in Patients With Cancer.

PURPOSE: KRAS is the most mutated proto-oncogene that has been identified in cancer, and treatment of patients with KRAS mutations remains an arduous challenge. Recently, KRASG12C mutation has attracted special interest because it is now considered potentially druggable with recently developed covalent small-molecule KRASG12C inhibitors. Nevertheless, to date, there have been no large-scale analyses of liquid biopsy that include testing for KRASG12C. Here, we performed a comprehensive analysis of KRASG12C mutations in multiple cancer types, as detected by circulating tumor DNA. METHODS: We conducted a 5-year retrospective review of KRASG12C mutations in patients with cancer who had undergone Guardant360 testing between July 1, 2014, and June 30, 2019; our study included treatment-naive and previously treated patients with metastatic solid tumors. RESULTS: KRASG12C mutations were identified in 2,985 of 80,911 patients (3.7%), across > 40 tumor types. KRASG12C mutations were detected most frequently in patients with nonsquamous non-small-cell lung cancer (NSCLC; 7.5%), NSCLC of all subtypes (6.9%), cancer of unknown primary (4.1%), colorectal cancer (3.5%), squamous NSCLC (2.0%), pulmonary neuroendocrine tumors (1.9%), and pancreatic ductal adenocarcinoma (1.2%) and cholangiocarcinoma (1.2%). KRASG12C mutations were predominantly clonal (clonality > 0.9%) in patients with lung adenocarcinoma, non-NSCLC, cancer of unknown primary, NSCLC, and pancreatic ductal adenocarcinoma, and patients with colorectal cancer and breast cancer had bimodal distribution of clonal and subclonal KRASG12C mutations. CONCLUSION: Our study demonstrates the feasibility of using circulating tumor DNA to identify KRASG12C mutations across solid tumors; the highest detection rate was in lung cancer, as previously reported in the literature.

Acalabrutinib-Related Cardiac Toxicities in Patients with Chronic Lymphocytic Leukemia: A Meta-Analysis of Randomized Controlled Trials.

Acalabrutinib, a second-generation and more selective Bruton's tyrosine kinase inhibitor, was developed to potentiate efficacy while minimizing ibrutinib-associated side effects. We undertook a systematic review and meta-analysis of randomized clinical trials to determine the risks of acalabrutinib-related cardiac toxicities in patients with chronic lymphocytic leukemia. Patients on acalabrutinib experienced higher risk of any-grade cardiac events (risk ratio, 1.75; p = 0.01) while there was a considerable trend toward statistical significance in the risk of any-grade atrial fibrillation (risk ratio, 2.56; p = 0.05). There was no significant increase in the risk of hypertension or high-grade cardiac events or atrial fibrillation in the acalabrutinib group.

Meta-analysis of randomized controlled trials on primary ambulatory thromboprophylaxis in patients with ovarian cancer receiving chemotherapy.

Ovarian cancer (OC) is highly associated with venous thromboembolism (VTE). The OC cells stimulate thrombin generation, and chemotherapy potentiates the prothrombotic effect of cancer cells by damaging endothelium and enhancing hypercoagulability. Recently, primary ambulatory thromboprophylaxis (PATP) has been studied as a potential treatment in cancer patients undergoing chemotherapy with an aim of reducing the incidence of VTE and potentially prolonging survival. A meta-analysis was performed of randomized controlled trials of PATP vs control in patients with OC receiving chemotherapy. The primary outcome measure was the incidence of VTE. The secondary outcome measure was the incidence of major bleeding complications. Two articles published between 2012 and 2020 fulfilled selection criteria. The incidence of VTE was 0.9% in the PATP group and 1.8% in the control group. However, the pooled risk ratio was not statistically significant at 0.69 (95% CI: 0.08 to 5.67; P = 0.73). The absolute risk difference was -0.03 (95% CI, -0.17 to 0.11; P = 0.66). There was no statistically significant reduction in VTE by providing PATP to patients with OC receiving chemotherapy. Routine PATP should not be recommended in ambulatory OC patients. Future randomized trials are necessary to define the high-risk subset of OC patients who may benefit from PATP.

Primary ambulatory thromboprophylaxis in patients with pancreatic cancer receiving chemotherapy: hope or hype?

Thrombosis is the second leading cause of death in cancer patients. Patients with pancreatic cancer (PC) have a very high risk of developing venous thromboembolism (VTE). Even though primary ambulatory thromboprophylaxis (PATP) could decrease this risk, there are uncertain issues with regard to the choice and dose of anticoagulants, duration of anticoagulant therapy, and patient selection criteria. In addition, the current practice guidelines on PATP in PC patients are equivocal. This review critically appraises the evidence on the use of PATP in PC patients receiving chemotherapy.

Clinical and Molecular Characterization of POLE Mutations as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors in Advanced Cancers.

PURPOSE: DNA polymerase epsilon is critical to DNA proofreading and replication. Mutations in POLE have been associated with hypermutated tumors and antitumor response to immune checkpoint inhibitor (ICI) therapy. We present a clinicopathologic analysis of patients with advanced cancers harboring POLE mutations, the pattern of co-occurring mutations, and their response to ICI therapy within the context of mutation pathogenicity. METHODS: We conducted a retrospective analysis of next-generation sequencing data at MD Anderson Cancer Center to identify patient tumors with POLE mutations and their co-occurring mutations. The pathogenicity of each mutation was annotated using InterVar and ClinVar. Differences in therapeutic response to ICI, survival, and co-occurring mutations were reported by POLE pathogenicity status. RESULTS: Four hundred fifty-eight patient tumors with POLE mutations were identified from 14,229 next-generation sequencing reports; 15.0% of POLE mutations were pathogenic, 15.9% benign, and 69.1% variant of unknown significance. Eighty-two patients received either programmed death 1 or programmed death ligand-1 inhibitors as monotherapy or in combination with cytotoxic T-cell lymphocyte-4 inhibitors. Patients with pathogenic POLE mutations had improved clinical benefit rate (82.4% v 30.0%; P = .013), median progression-free survival (15.1 v 2.2 months; P < .001), overall survival (29.5 v 6.8 months; P < .001), and longer treatment duration (median 15.5 v 2.5 months; P < .001) compared to those with benign variants. Progression-free survival and overall survival remained superior when adjusting for number of co-occurring mutations (≥ 10 v < 10) and/or microsatellite instability status (proficient mismatch repair v deficient mismatch repair). The number of comutations was not associated with response to ICI (clinical benefit v progressive disease: median 13 v 11 comutations; P = .18). CONCLUSION: Pathogenic POLE mutations were associated with clinical benefit to ICI therapy. Further studies are warranted to validate POLE mutation as a predictive biomarker of ICI therapy.

Thrombotic events in patients using cyclin dependent kinase 4/6 inhibitors, analysis of existing ambulatory risk assessment models and the potential influences of tumor specific risk factors.

Cyclin dependent kinase 4 of 6 inhibitors (CDKi) are key therapeutics in the treatment of advanced breast cancer and have recently been approved in small cell lung cancer for the prevention of myelosuppression. Thrombotic events have emerged as a significant treatment related adverse event in up to 5% of patients in clinical trials and has been reported at higher rates, up to 10%, in real world analysis. The prothrombotic mechanisms of CDKis, however, remain unknown. Cancer specific risk assessment models exist to identify who may be at highest risk of thrombosis and who could potentially benefit from prophylactic anticoagulation. However, these models may not be accurate in patients taking CDKis and may not fully capture recently identified thrombotic risk factors such as tumor specific somatic mutations. In the following manuscript, we summarize the literature on thrombotic events with CDKis in clinical trials and real-world settings, review the existing thrombosis risk assessment models for ambulatory cancer patients, and discuss the literature on tumor mutations and role in cancer associated thrombosis.

Meta-analysis of randomized controlled trials on primary ambulatory thromboprophylaxis in patients with nonpancreatic gastrointestinal cancers receiving chemotherapy.

Primary ambulatory thromboprophylaxis (PATP) in patients with solid malignancies is not routinely indicated. We performed a meta-analysis of randomized controlled trials (RCTs) to determine the benefit and risk of PATP in patients with nonpancreatic gastrointestinal cancers receiving chemotherapy. RCTs with venous thromboembolism (VTE) reduction as primary or secondary endpoints were included. A total of 1932 patients from subgroups of 3 RCTs were eligible. The VTE incidence was 1.26% and 2.55% in PATP and control arms, respectively (risk ratio 0.49; confidence interval 0.25 to 0.96; P = 0.04), with a number needed to treat of 78 to prevent one VTE event. In gastric and gastroesophageal junction cancer patients, the VTE incidence was 1.37% and 3.40% in PATP and control arms, respectively (risk ratio 0.40; confidence interval 0.13 to 1.24; P = 0.11). PATP should not be recommended in patients with nonpancreatic gastrointestinal cancers on chemotherapy.

Selinexor in combination with carboplatin and paclitaxel in patients with advanced solid tumors: Results of a single-center, multi-arm phase Ib study.

BACKGROUND: Carboplatin and paclitaxel (CT) is one of the standard chemotherapy regimens used in various tumor types. Preclinical models have suggested that selinexor, a first-in-class oral potent selective inhibitor of nuclear export Exportin-1, and CT exerts antitumor activity in multiple malignancies. METHODS: This was a single-center, multi-arm phase Ib study utilizing a "basket type" expansion. CT and selinexor was employed as one of the 13 parallel arms. Advanced relapsed/refractory solid tumors following standard therapy or where the addition of selinexor to standard regimens deemed appropriate, were eligible. RESULTS: Of 13 patients treated, 12 patients were evaluable for response. The most common cancers were breast (n = 4), esophageal (n = 2), ovarian (n = 2) and non-small cell lung cancers (n = 2). All 13 patients had at least one treatment-related adverse events (TRAEs) and the most common were neutropenia (85%), leukopenia (85%), thrombocytopenia (85%), anemia (69%), nausea (54%), vomiting (46%), and fatigue (46%). One patient at 60 mg QW experienced DLT with grade 3 nausea and vomiting lasting 3 days. Unconfirmed partial response (uPR) was observed in 3 patients; one patient each with esophageal, breast, and ovarian cancer. One patient with esophageal adenocarcinoma had confirmed PR, however, was discontinued from the study due to clinical progression. Five patients achieved stable disease (SD). Disease control rate was 8%. Majority of patients (77%), including two patients who had uPR, had prior exposure to carboplatin and/or paclitaxel. Time-to-treatment failure (TTF) ranged from 1 to 153 weeks. CONCLUSION: The RP2D of selinexor was 60 mg QW in combination with CT. The combination conferred viable clinical activity with durable objective responses which should further be explored in tumor types for which CT is used as standard of care. Trial information. CLINICALTRIALS: gov Identifier: NCT02419495. Sponsor(s): Karyopharm Therapeutics. (Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495 ).

Selinexor in combination with standard chemotherapy in patients with advanced or metastatic solid tumors.

Selinexor, an oral selective inhibitor of nuclear export (SINE), was demonstrated to hinder the DNA damage repair (DDR) system by reducing DDR proteins while enhancing the killing of cancer cells by DDR-based therapeutics in vivo studies. In this single-center, multi-arm phase 1b study, selinexor with carboplatin, doxorubicin and cyclophosphamide (DC), irinotecan with fluorouracil and folinic acid (FOLFIRI), irinotecan, and capecitabine and oxaliplatin (XELOX), were employed as separate parallel arms. Eligible patients have relapsed/ metastatic refractory solid tumors following standard therapy or addition of selinexor to systemic therapy was appropriate. Nineteen patients were treated in the 5 arms. Tumor types included were colorectal (n = 3), breast (n = 3), neuroendocrine (n = 2), ovarian (n = 2), and pancreas cancers (n = 2). All patients developed one treatment-related adverse events (TRAE). The most prevalent TRAE were thrombocytopenia (84%), nausea (68%), leukopenia (68%), neutropenia (63%), and fatigue (58%). The common grade 3/4 TRAE were neutropenia (42%), leukopenia (26%), and hyponatremia (21%). Three patients had dose-limiting toxicities (DLT) in 3 separate arms. Fourteen patients were evaluable for response. Although no patients achieved complete or partial response (CR or PR), seven patients attained stable disease (SD). Disease control rate (DCR) was 14%. The combination of oral selinexor with different standard chemotherapies showed limited clinical activity despite toxicity and DLT prevented further dose escalation. Optimizing supportive care, the utility of growth factors, and aggressive measures on antiemetics strategies remain tangible.Trial registration ClinicalTrials.gov Identifier: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495 ). Sponsor(s): Karyopharm Therapeutics.