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NTRK fusions are oncogenic drivers for multiple tumor types. Therefore, the development of selective tropomyosin receptor kinase (TRK) inhibitors, including larotrectinib and entrectinib, has been transformative in the context of clinical management, given the high rates of responses to these drugs, including intracranial responses in patients with brain metastases. Given their promising activity in pan-cancer cohorts, larotrectinib and entrectinib received U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for tissue-agnostic indications in patients with advanced solid tumors harboring NTRK fusions. The safety profiles for both drugs are quite manageable, although neurotoxicity driven by the on-target inhibition of normal NTRK can be a concern. Also, on- and off-target resistance mechanisms can arise during therapy with TRK inhibitors, but they can be addressed with the use of combination therapy and next-generation TRK inhibitors. More recently, the FDA approved the use of repotrectinib, a second-generation TRK inhibitor, in patients with NTRK fusions, based on data suggesting clinical efficacy and safety, which could offer another tool for the treatment of NTRK -altered cancers. In this review, we summarize the current evidence related to the use of TRK inhibitors in the tissue-agnostic setting. We also elaborate on the safety profiles and resistance mechanisms from a practical perspective.

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high ( MSI-H ) or deficient mismatch repair ( dMMR ) solid tumors in 2017. It was later approved for tumor mutational burden-high ( TMB-H ) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase ( NTRK ) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase ( NTRK ) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection ( RET ) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAF V600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

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., Competing Interests: Declaration of interests K.Z.T. served on the advisory board of Exelixis. M.G. declares no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: This study was presented as a poster presentation at the annual meeting of the American Society of Hematology in New Orleans in December 2022. The authors report no funding or conflicts of interest., (Copyright © 2023 Baylor University Medical Center.)

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., (© 2022 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.)

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., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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, KRAS G12C mutation has attracted special interest because it is now considered potentially druggable with recently developed covalent small-molecule KRAS G12C inhibitors. Nevertheless, to date, there have been no large-scale analyses of liquid biopsy that include testing for KRAS G12C . Here, we performed a comprehensive analysis of KRAS G12C mutations in multiple cancer types, as detected by circulating tumor DNA., Methods: We conducted a 5-year retrospective review of KRAS G12C 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: KRAS G12C mutations were identified in 2,985 of 80,911 patients (3.7%), across > 40 tumor types. KRAS G12C 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%). KRAS G12C 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 KRAS G12C mutations., Conclusion: Our study demonstrates the feasibility of using circulating tumor DNA to identify KRAS G12C mutations across solid tumors; the highest detection rate was in lung cancer, as previously reported in the literature.

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 )., (© 2021. The Author(s).)

Competing Interests: Conflict of Interest: Aung Naing reports the following: research funding from NCI, EMD Serono, MedImmune, Healios Inc. Nutrition, Atterocor, Amplimmune, ARMO BioSciences, Eli Lilly, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, BMS, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance Biosciences, Kymab, PsiOxus, Arcus Biosciences, NeoimmuneTech, ImmuneOncia, Surface Oncology; on advisory boards of CytomX Therapeutics, Novartis, Genome & Company, OncoSec KEYNOTE-695, and STCube; travel and accommodation expense from ARMO BioSciences. Jatin Shah is an employee of and stockholder of Karyopharm Therapuetics. The remaining authors have declared that they have no conflicts of interest.

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., (Copyright © 2022 Baylor University Medical Center.)

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., Competing Interests: Benjamin GarmezyUncompensated Relationships: AVEO (Inst) Xianli JiangPatents, Royalties, Other Intellectual Property: I am in the process of a patent application, which is nonrelevant to this study. The application is for United States Letters Patent, Serial No. 63/015,317 Patrick G. PiliéConsulting or Advisory Role: NovartisPatents, Royalties, Other Intellectual Property: Patent pending-biomarker Kenna R. ShawConsulting or Advisory Role: Guidepoint GlobalResearch Funding: Guardant Health (Inst), Tempus (Inst), Philips Healthcare (Inst) Jordi RodonConsulting or Advisory Role: Peptomyc, Kelun, Merck Sharp & Dohme, Spectrum Pharmaceuticals, Pfizer, Roche/Genentech, Ellipses Pharma, Ionctura, Novartis, Lilly, Orion, Servier, Molecular Partners, NovellusDx, Certara, Bayer, KisoJi BiotechnologyResearch Funding: Novartis, Bayer, Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, Genmab, CytomX Therapeutics, Kelun, Takeda/Millennium, GlaxoSmithKline, Ipsen, Blueprint MedicinesTravel, Accommodations, Expenses: ESMO, Department of Defense, Louisiana State University, Huntsman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute, King Abdullah International Medical Research Center, Molecular Partners, Merck Sharp & Dohme, Kelun Pharmaceuticals/Klus Pharma, Bayer, WIN Consortium, JanssenOther Relationship: European Journal of Cancer, Chinese University of Hong Kong, SOLTI, Elsevier, GlaxoSmithKline, Vall d'Hebron University Hospital Institute of Oncology, VHIO/Ministero De Empleo Y Seguridad Social John-Paul ShenStock and Other Ownership Interests: Agios, SyndaxConsulting or Advisory Role: Engine BiosciencesResearch Funding: Celsius Therapeutics Ying YuanHonoraria: Ono PharmaceuticalConsulting or Advisory Role: Boehringer Ingelheim, Amgen, AbbVie, Servier, Starpax Medical, Vertex, MicuRx Pharmaceuticals, BeyondSpring Pharmaceuticals, Bristol Myers Squibb/Celgene/Juno Funda Meric-BernstamEmployment: MD Anderson Cancer CenterHonoraria: Rutgers Cancer Institute of New JerseyConsulting or Advisory Role: Samsung Bioepis, Xencor, Debiopharm Group, Silverback Therapeutics, IBM Watson Health, Roche, PACT Pharma, eFFECTOR Therapeutics, Kolon Life Sciences, Tyra Biosciences, Zymeworks, Puma Biotechnology, Zentalis, Alkermes, Infinity Pharmaceuticals, AbbVie, Black Diamond Therapeutics, Eisai, OnCusp Therapeutics, Lengo Therapeutics, Tallac Therapeutics, Karyopharm Therapeutics, BiovicaSpeakers' Bureau: Chugai PharmaResearch Funding: Novartis (Inst), AstraZeneca (Inst), Taiho Pharmaceutical (Inst), Genentech (Inst), Calithera Biosciences (Inst), Debiopharm Group (Inst), Bayer (Inst), Aileron Therapeutics (Inst), PUMA Biotechnology (Inst), CytomX Therapeutics (Inst), Jounce Therapeutics (Inst), Zymeworks (Inst), Curis (Inst), Pfizer (Inst), eFFECTOR Therapeutics (Inst), AbbVie (Inst), Boehringer Ingelheim, Guardant Health (Inst), Daiichi Sankyo (Inst), GlaxoSmithKline (Inst), Seattle Genetics (Inst), Klus Pharma (Inst), Takeda (Inst)Travel, Accommodations, Expenses: Beth Israel Deaconess Medical Center Timothy A. YapConsulting or Advisory Role: Pfizer, EMD Serono, Clovis Oncology, Ignyta, AstraZeneca, Atrin Pharmaceuticals, Aduro Biotech, Merck, Almac Diagnstics, Bayer, Bristol Myers Squibb, Calithera Biosciences, Cybrexa Therapeutics, Janssen, Roche, Seattle Genetics, Axiom Biotechnologies, F-Star, Guidepoint Global, I-Mab, Repare Therapeutics, Rubius Therapeutics, Schrodinger, Varian Medical Systems, Zai LabResearch Funding: AstraZeneca (Inst), Vertex (Inst), Pfizer (Inst), Bayer (Inst), Tesaro (Inst), Jounce Therapeutics (Inst), Seattle Genetics (Inst), Kyowa Hakko Kirin (Inst), Constellation Pharmaceuticals (Inst), Lilly (Inst), Artios (Inst), Clovis Oncology (Inst), Cyteir (Inst), EMD Serono (Inst), Forbius (Inst), F-Star (Inst), GlaxoSmithKline (Inst), Genentech (Inst), ImmuneSensor Therapeutics (Inst), Ipsen (Inst), Karyopharm Therapeutics (Inst), Merck (Inst), Novartis (Inst), Ribon Therapeutics (Inst), Regeneron (Inst), Repare Therapeutics (Inst), Sanofi (Inst), Scholar Rock (Inst)No other potential conflicts of interest were reported.

Squamous cell cancer of the head and neck (HNSCC) is the sixth most common cancer and is associated with significant morbidity and mortality. The tumor microenvironment for HNSCC is a complex interplay of immune cells, stromal cells, and cytokines amongst others. Immunotherapy acts as an effective antineoplastic agent by influencing this complex environment and includes immune checkpoint inhibitors (ICI). ICI have been approved in the frontline setting for recurrent and metastatic (R/M) HNSCC as well as platinum-refractory (second line) R/M HNSCC. However, recent clinical studies highlight that the response to immunotherapy varies, and different ICI, as well as different combination strategies play a crucial role in augmenting the efficacy of immunotherapy. An in-depth analysis and focused study of the immune contexture in patients with HNSCC receiving ICI remains critical. Many novel immunotherapies including CAR-T cell therapy, oncolytic virus therapy, and vaccines are underway. Ongoing trials are testing ICI in the neoadjuvant and adjuvant settings. Furthermore, identifying better biomarkers to target population that benefits from immunotherapy is of paramount importance. Pioneering the optimal combination regimen utilizing new novel immunotherapy has recently become a paradigm shift in the HNSCC treatment landscape. Herein, we summarize the clinical development with all ongoing clinical trials of immunotherapy in HNSCC., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022. Published by Elsevier Ltd.)

Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks., Competing Interests: Declaration of interests V.S. reports research funding/grant support for clinical trials: Roche/Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Loxo Oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda and National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals; Travel: Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte. Consultancy/advisory board: Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis. Other: Medscape. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Source of Support: None. Conflict of Interest: None., (© 2022.)

Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a "basket type" expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22-68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2-48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., Competing Interests: Kyaw Zin Thein, Thura Win Htut, and Donald Quick declare no conflict of interest. Thein Hlaing Oo served on an advisory board for Bristol-Myers Squibb, not related to this manuscript., (Copyright © 2021 Baylor University Medical Center.)

In recent years, there has been remarkable progress in our understanding of cancer biology, host responses, and the concept of precision oncology. These advances have focused attention on biomarker-driven, tissue-agnostic drug development strategies. The recent approvals by the FDA of pembrolizumab for the treatment of unresectable or metastatic, microsatellite instability-high or deficient mismatch repair solid tumors, and more recently for the treatment of tumor mutational burden-high tumors; and of larotrectinib and entrectinib for the treatment of neurotrophic tyrosine kinase ( NTRK ) fusion-positive solid tumors, have further heightened interest in target-driven as opposed to histology-driven drug development. Herein, we focus on tissue-agnostic clinical drug development with an understanding of target modulation in the context of histology. The use of molecular genetics and biomarker-driven strategies rather than traditional histology based on organ of origin has reinforced the concept of tissue-agnostic drug development. Recent approvals in the United States, Europe, Japan, Australia, and other regions have further heightened interest in target-driven as opposed to histology-driven drug development., (©2021 American Association for Cancer Research.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38-76); median number of prior systemic therapies was 5(range 0-10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation.Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Pernicious anemia (PA) is the most common cause of vitamin B12 (cobalamin) deficiency anemia in the world. It is an autoimmune disease, comprising of salient features of autoimmune chronic atrophic gastritis (CAG) and cobalamin deficiency (CD). Although the anemia was first described as pernicious, it may well be controlled with vitamin B12 replacement. The onset and progression of PA is often insidious. Alternatively, patients may have no anemic symptoms since they become acclimatized to the subtle nature of the disease. Oftentimes, there is a possibility that the underlying disease may be missed unless a full blood count (FBC) is investigated, leading to hindrance in the treatment journey. Diagnostic challenges remain tangible for many practicing clinicians, since there is lack of reliable cobalamin assays to diagnose CD as well as clinical mimics, which simulate many other hematological conditions, such as myelodysplastic syndrome, acute leukemia, sideroblastic anemias, bone marrow failure states, thrombotic microangiopathy, and thromboembolism. Moreover, prompt recognition of the symptoms of CD is also vital, because some neurologic sequalae may become irreversible despite replenishing cobalamin. Herein, we discuss a literature review on the pathophysiology, challenging clinical presentations and diagnostic difficulties of PA. Since the cobalamin replacement therapy for PA is straightforward, it will not be discussed in this review., (© 2021 Chinese Cochrane Center, West China Hospital of Sichuan University and John Wiley & Sons Australia, Ltd.)

In this case report of a patient with angioimmunoblastic T-cell lymphoma (AITL), we describe the occurrence of three sequential complications that have been reported uncommonly in this disease subtype. Firstly, the patient developed hypercalcemia due to elevated 1,25-didydroxyvitamin D. Although hypercalcemia in AITL is not rare (1-2% incidence), this case was unusual in that the complication developed when disease appeared stable and symptomatically, he was doing well otherwise. Hypercalcemia surprisingly resolved a few months later at a time when his disease appeared to be progressing. A year later, the patient presented with digital ischemia necessitating partial amputation of a finger. Pathological exam revealed granulomatous vasculitis of small and medium arterioles with infiltrating malignant T lymphocytes. Although skin manifestations are common in AITL, necrotizing granulomatous vasculitis with accompanying tumor cells leading to severe digital ischemia appears rare. Subsequently the patient developed profound pancytopenia with bone marrow confirming severe aplastic anemia. To our knowledge only one other case of aplastic anemia has been reported in a patient with AITL. We discuss the diagnostic and management considerations involved in this patient care and review similar reported cases., (Copyright © 2020. Published by Elsevier Inc.)

Aberrations in rat sarcoma (RAS) viral oncogene are the most prevalent and best-known genetic alterations identified in human cancers. Indeed, RAS drives tumorigenesis as one of the downstream effectors of EGFR activation, regulating cellular switches and functions and triggering intracellular signaling cascades such as the MAPK and PI3K pathways. Of the three RAS isoforms expressed in human cells, all of which were linked to tumorigenesis more than three decades ago, KRAS is the most frequently mutated. In particular, point mutations in KRAS codon 12 are present in up to 80% of KRAS-mutant malignancies. Unfortunately, there are no approved KRAS-targeted agents, despite decades of research and development. Recently, a revolutionary strategy to use covalent allosteric inhibitors that target a shallow pocket on the KRAS surface has provided new impetus for renewed drug development efforts, specifically against KRAS G12C . These inhibitors, such as AMG 510 and MRTX849, show promise in early-phase studies. Nevertheless, combination strategies that target resistance mechanisms have become vital in the war against KRAS-mutant tumors.

Acalabrutinib is a second generation Bruton's tyrosine kinase inhibitor and was recently approved in the treatment of chronic lymphocytic leukaemia. We undertook a systematic review and meta-analysis of randomised controlled trials to determine the risks of acalabrutinib-related second primary malignancies (SPM) and nonmelanoma skin cancers (NMSC). The incidence of SPM was 4.7% higher in the acalabrutinib arm compared to control arm with risk ratio (RR) of 1.76 (5.32 vs 3.2 per 100 person-years). Notably, NMSC was the most common SPM, and the incidence was 2.56 per 100 person-years in the acalabrutinib group versus 1.12 per 100 person-years in the control group (RR 2.43). Long-term follow-up and future studies are necessary to define the actual relationship and their risk factors., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. AUTHOR CONTRIBUTIONSThura W. Htut and Kyaw Z. Thein contributed to the study conception and design. Material preparation, data collection and analysis were performed by Thura W. Htut, Myat M. Han and Kyaw Z. Thein. The first draft of the manuscript was written by Thura W. Htut. Kyaw Z. Thein commented on the manuscript. All authors read and approved the final manuscript., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Approximately 70% of patients with metastatic breast cancer (MBC) are hormone receptor (HR)-positive. Recent studies have shown that CDK4/6 inhibitors (CDKI) improve survival in combination with ET in HR-positive, HER2-negative MBC. The risk of venous thromboembolism (VTE) is 3-4 times higher in patients with breast cancer (BC) than in patients without cancer. The risk is even higher in BC patients receiving ET and chemotherapy. The aim of the study was to determine the VTE risk of CDKIs plus ET versus ET alone in patients with HR-positive, HER2-negative MBC., Methods: We performed a systematic review and meta-analysis to demonstrate the risk of VTE in patients with HR-positive HER2-negative MBC treated with combined CDKIs and ET versus ET alone., Results: Eight randomized controlled trials (RCT) with a total of 4,557 patients were eligible. The study arms comprised of palbociclib or ribociclib or abemaciclib plus ET while the control arms utilized placebo plus ET. The VTE events were 56 (2%) in the CDKIs plus ET group compared to 10 (0.5%) in the control group. Pooled relative risk (RR) for VTE was 2.62 (95% CI 1.21-5.65; P = 0.01) and the risk difference (RD) was 0.01 (95% CI 0.00-0.03; P = 0.02). Over a median follow-up of up to 36 months, RR was 3.18 (95% CI 1.22-8.24; P = 0.02) and RD was 0.03 (95% CI 0.01-0.06, P = 0.008)., Conclusions: Our meta-analyses demonstrated that the addition of CDKIs to ET in patients with HR-positive HER 2-negative MBC contribute to a higher incidence of VTE. Further trials are required to define the actual relation and definitive incidence of VTE with different CDKIs.

The use of the CD38 monoclonal antibody daratumumab in combination with standard myeloma chemotherapy regimens has been studied extensively in recent years. We undertook an updated meta-analysis of phase III randomized controlled trials (RCT) to determine the efficacy of daratumumab combination regimens. The relative risk for progression was significantly lower in daratumumab-treated cohorts (HR 0.46, 95% CI 0.38-0.55) and this was consistent across newly diagnosed and relapsed cases. No statistically significant improvement was identified in newly diagnosed patients with high-risk cytogenetics and this group remains a therapeutic challenge., Competing Interests: Gavin Preston has received honoraria or meeting sponsorship from Abbvie, Janssen‐Cilag, and Takeda, and has attended meetings sponsored by Celgene, Roche, Bristol‐Myers‐Squibb, Novartis, Gilead, Pfizer, and Napp pharmaceuticals. Jane Tighe has received educational support and travel for meetings from Amgen, Celgene, Sanofi Aventis, Takeda, and Janssen over the years. We had no financial support for this project., (© 2020 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Lung cancer (LC) is the leading cause of cancer mortality. PATP was provided in experimental trials to decrease the venous thromboembolism (VTE), with ultimate aim to improve overall survival (OS). We undertook an updated systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the impact of PATP with LMWHs on OS and VTE in patients with LC. 5443 patients with LC from nine RCTs were included. The pooled hazard ratio (HR) for OS was 1.02 (95% CI 0.83 to 1.26; P = 0.83) and for progression or metastasis-free survival was 1.03 (95% CI 0.86 to 1.24; P = 0.74). The pooled risk ratio (RR) for VTE was 0.54 (95% CI 0.43 to 0.69; P < 0.00001) and the risk difference (RD) was-0.03 (- 0.05 to - 0.02; P < 0.00001). Our analysis showed no survival advantage with the addition of PATP with LMWHs to standard chemotherapy in patients with LC, regardless of histology or stages of small cell LC.

Background: Angiogenesis and activation of the epidermal growth factor (EGFR) pathway play an essential role in tumor proliferation and metastasis. Targeting angiogenesis or EGFR alone does not yield adequate tumor control in most solid tumors. Overcoming intrinsic and/or acquired resistance may need a doublet or triplet therapy strategy. Herein, we report the safety and feasibility of dual EGFR blockade with EGFR monoclonal antibody and EGFR tyrosine kinase inhibitor combined with anti-VEGF antibody in advanced solid tumors., Methods: We conducted a phase I study combining erlotinib, cetuximab, and bevacizumab. Patients with advanced or metastatic solid tumors (excluding colorectal and non-small cell lung cancers) were analyzed for safety, toxicity profile, and response. Anti-tumor activity was evaluated per response evaluation criteria in solid tumors (RECIST 1.0)., Results: Thirty-six patients received treatment on a range of dose-levels. The most frequent tumor types enrolled were cervical (n = 10), head and neck squamous cell (n = 10), and follicular thyroid (n = 4) cancers. The most common treatment-related grade ≥ 2 adverse events were rash (56%), hypomagnesemia (17%), pruritus (11%), diarrhea (8%), and tumor-related bleeding (8%). Seventeen of 19 patients (89%) treated at the maximum tolerated dose did not present treatment-related dose-limiting toxicity. Fifteen (63%) of the 24 evaluable patients achieved a disease control (stable disease ≥ 4 months (n = 14) and partial response (n = 1). The median number of prior lines of therapies was 3 (range 1-10)., Conclusions: The triplet combination of erlotinib, cetuximab, and bevacizumab was well tolerated, conferring clinical benefit in heavily pretreated patients. Future studies are warranted with second or third-generation EGFR tyrosine kinase triplet combinations in the EGFR pathway aberrant patients. Trial Registration: ClinicalTrials.gov Identifier: NCT00543504. Sponsor(s): National Cancer Institute (NCI), MD Anderson Cancer Center., Competing Interests: Competing interestsA full list of the authors’ competing interests can be found in Additional file 1., (© The Author(s) 2020.)

Background: We conducted a meta-analysis to evaluate the efficacy and safety of upfront add-on immunotherapy for advanced non-small cell lung cancers (NSCLC)., Methods: We performed a literature search on first-line chemotherapy ± immunotherapy in NSCLC. We utilized Revman version 5.3 to calculate the estimated pooled hazard ratio for overall survival (OS) and progression-free survival (PFS) and pooled risk ratio for objective response rate (ORR), all-grade and high-grade adverse events with 95% CI., Results: We analyzed 4322 patients. The pooled hazard ratios for OS, PFS and ORR were 0.74 (95% CI: 0.62-0.88; p = 0.0007), 0.62 (95% CI: 0.57-0.68; p = 0.00001) and 1.51 (95% CI: 1.3-1.74; p = 0.00001), respectively. The pooled risk ratios for all-grade and high-grade adverse events were 1.01 (95% CI: 0.99-1.03; p = 0.27) and 1.17 (95% CI: 1.07-1.28; p = 0.0006), respectively., Conclusion: Add-on immunotherapy significantly improves PFS, OS and ORR for the first-line treatment of advanced NSCLC with a reasonable safety profile., Competing Interests: Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript., (© 2019 Tun et al.)

: Calcium-binding at the A2 domain protects von Willebrand factor (VWF) from cleavage by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS13) and is coordinated by five important residues (p.Asp1596, p.Arg1597, p.Ala1600, p.Asn1602, and p.Asp1498). Only variants of p.Arg1597 resulting in type 2A von Willebrand disease have been reported. We report a novel VWF variant, a heterozygous single nucleotide change, c.4493A>G, occurring at the p.Asp1498 residue of the calcium-binding site of the A2 domain in two sisters with type 2A von Willebrand disease. Modest increase in the VWF propeptide/VWF:Ag ratio (2.4 and 2.7) supports increased clearance of VWF. A literature review provided insight into the integral role of p.Asp1498 residue in calcium-binding and its role in the stabilization of other residues including p.Arg1597 and p.Asn1602. Studies done by other groups on engineered mutations involving p.Asp1498 reported increased susceptibility to ADAMTS13 proteolysis. Cellular studies are needed to confirm these mechanisms.

Study Objective: Cancer immunotherapy is evolving rapidly and is transforming cancer care. During the last decade, immune checkpoint therapies have been developed to enhance the immune response; however, specific adverse effects related to autoimmunity are increasingly apparent. This study aims to fill the knowledge gap related to the spectrum of immune-related adverse effects among cancer patients visiting emergency departments (EDs)., Methods: We performed a retrospective review of patients treated with immune checkpoint therapy who visited the ED of a comprehensive cancer center between March 1, 2011, and February 29, 2016. Immune-related adverse effects from the ED visits were identified and profiled. We analyzed the association of each immune-related adverse effect with overall survival from the ED visit to death., Results: We identified 1,026 visits for 628 unique patients; of these, 257 visits (25.0%) were related to one or more immune-related adverse effects. Diarrhea was the most common one leading to an ED visit. The proportions of ED visits associated with diarrhea, hypophysitis, thyroiditis, pancreatitis, or hepatitis varied significantly by immune checkpoint therapy agent. Colitis was significantly associated with better prognosis, whereas pneumonitis was significantly associated with worse survival., Conclusion: Cancer patients treated with ipilimumab, nivolumab, or pembrolizumab may have a spectrum of immune-related adverse effects that require emergency care. Future studies will need to update this profile as further novel immunotherapeutic agents are added., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Copper is a crucial micronutrient needed by animals and humans for proper organ function and metabolic processes such as hemoglobin synthesis, as a neurotransmitter, for iron oxidation, cellular respiration, and antioxidant defense peptide amidation, and in the formation of pigments and connective tissue. Multiple factors, either hereditary or acquired, contribute to the increase in copper deficiency seen clinically over the past decades. The uptake of dietary copper into intestinal cells is via the Ctr1 transporter, located at the apical membrane aspect of intestinal cells and in most tissues. Copper is excreted from enterocytes into the blood via the Cu-ATPase, ATP7A, by trafficking the transporter towards the basolateral membrane. Zinc is another important micronutrient in animals and humans. Although zinc absorption may occur by direct interaction with the Ctr1 transporter, its absorption is slightly different. Copper deficiency affects physiologic systems such as bone marrow hematopoiesis, optic nerve function, and the nervous system in general. Detailed pathophysiology and its related diseases are explained in this manuscript. Diagnosis is made by measuring serum copper, serum ceruloplasmin, and 24-h urine copper levels. Copper deficiency anemia is treated with oral or intravenous copper replacement in the form of copper gluconate, copper sulfate, or copper chloride. Hematological manifestations are fully reversible with copper supplementation over a 4- to 12-week period. However, neurological manifestations are only partially reversible with copper supplementation.

Background: Thromboembolism (TE) is a leading cause of death in cancer patients. Primary thromboprophylaxis (PTP) in ambulatory cancer patients receiving chemotherapy has been debated and considered to potentially improve survival by reducing TE occurrence., Objective: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) in ambulatory lung cancer (LC) patients on chemotherapy to determine the benefit and risk of PTP with low-molecular-weight heparins (LMWHs)., Method: A literature search using MEDLINE and EMBASE databases was performed through June 2016. RCTs with venous thromboembolism (VTE) reduction as primary or secondary endpoints were included. Mantel-Haenszel method was used to estimate the pooled event risk ratio as well as pooled absolute risk difference with 95% confidence interval (CI)., Result: A total of 4315 LC patients from six studies were available for analysis. PTP lasted for 4 to 6 months. The venous thromboembolism (VTE) incidence was 4.0% and 7.9% in LMWH and control groups, respectively (risk ratio, 0.510 (95% CI, 0.397-0.654, P < 0.001). The absolute risk difference in VTE was -0.039 (95% CI, -0.053 to -0.025, P < 0.001), with an estimated number needed to treat (NNT) of 25 to prevent one VTE event. The pooled risk ratio for major bleeding was 1.468 (95% CI, 0.785-2.746, P = 0.229). The pooled risk ratio for overall survival was statistically nonsignificant at 1.020 (95% CI, 0.938-1.109, P = 0.648)., Conclusion: Routine PTP for ambulatory LC patients receiving chemotherapy is not recommended and further studies are necessary to define a subset of ambulatory LC patients receiving chemotherapy who may benefit from PTP., (© 2017 John Wiley & Sons Australia, Ltd.)

Thrombosis is common in cancer patients and is associated with increased morbidity and mortality. Myeloproliferative neoplasms (MPN) are common malignancies in elderly individuals and are known for a high incidence of thrombotic complications. Different risk factors have been identified in studies, and risk models have been developed to identify patients with MPN at higher risk for thrombosis. Several pathophysiological mechanisms help explain the increased likelihood of thrombosis in these patients. Factors, such as leukocyte and platelet activation leading to the formation of leukocyte-platelet aggregates, activation of the coagulation cascade by microparticles, high levels of inflammatory cytokines, and endothelial dysfunction have a crucial role in thrombosis in MPN patients. Recent studies have demonstrated a significant association between the allele burden of specific genetic mutations (mainly JAK2V617F) associated with MPN and the incidence of thrombotic events, thus suggesting a possible role for these mutations in thrombogenesis.

Mushroom poisoning is common in the United States. The severity of mushroom poisoning may vary, depending on the geographic location, the amount of toxin delivered, and the genetic characteristics of the mushroom. Though they could have varied presentation, early identification with careful history could be helpful in triage. We present a case of a 69-year-old female of false morel mushroom poisoning leading to hepatotoxicity with painless jaundice and biochemical pancreatitis., Competing Interests: The authors have declared that no competing interests exist.