Factor Xa inhibitors versus low molecular weight heparin for the treatment of cancer associated venous thromboembolism; A meta-analysis of randomized controlled trials and non-randomized studies.

INTRODUCTION: We compared the safety and efficacy of Xa-inhibitors to LMWH for treatment of venous thromboembolism in mixed and gastrointestinal cancer cohorts (CA-VTE). METHODS: A systematic search identified RCTs and non-randomized studies (NRS) comparing Xa-inhibitors to LMWH for treating CA-VTE. Relative risks were computed. Certainty was assessed using the GRADE approach. RESULTS: Xa-inhibitors reduced the risk of recurrent VTE (RR0.64;0.49-0.84) and NRS (RR0.74;0.60-0.92;Moderate-Low Certainty). There was no significant difference in recurrent PE in RCTs (RR0.72;0.50-1.02) and NRS (1.43;0.65-3.12;Low-Very Low Certainty). Xa-inhibitors increased the risk of overall bleeding events in RCTs (RR1.45;1.05-2.01) and NRS (RR1.72;1.42-2.08;Moderate-Low Certainty), and the risk of major bleeding events in NRS (RR1.56;1.17-2.07), but not in RCTs (RR1.33;0.94-1.89; Low-Very Low Certainty). Similar results were detected in gastrointestinal cancer patients. CONCLUSION: Xa-inhibitors may reduce the risk of recurrent VTE, but not recurrent PE compared to LMWH. A higher overall bleeding risk, and a questionably higher major bleeding risk was found with Xa-inhibitor use.

Cost-effective heart failure management: Meta-analysis of IV iron therapy in iron-deficient heart failure patients.

Background: Iron deficiency is an important co-morbidity in heart failure patients. IV iron may improve quality of life and reduce heart failure hospitalizations, but the results of the clinical trials are varied. Objective: The purpose of this meta-analysis is to assess not only the effect of IV iron in iron-deficient heart failure patients but also the quality of evidence. Methods: PubMed and Cochrane databases were searched from inception to Oct 2021. Randomized clinical trials in iron-deficient, heart failure patients assessing the effect of IV iron versus placebo and with at least 12 weeks of follow-up were included. The outcomes were pooled and analyzed using a random-effect model. The quality of evidence was assessed using the GRADE approach. Results: Seven studies were included in our meta-analysis. IV iron was associated with a 13.8 % decreased risk of HF hospitalizations (OR 0.59; 0.35-0.98, p = 0.040, GRADE = Low). All-cause mortality and CV mortality were not different between IV iron and placebo. But a composite outcome of HF hospitalizations or CV mortality was 17.5 % lower with IV iron (OR 0.51;0.31-0.84, p = 0.008, GRADE = Moderate). Conclusions: Among heart failure patients with iron deficiency, IV iron is associated with lower HF hospitalizations. It is a relatively inexpensive regimen that can potentially improve quality of life and decrease healthcare expenditure.

Spontaneous Tumor Lysis Syndrome Secondary to Small-Cell Neuroendocrine Carcinoma of Unknown Origin: A Rare Case Report and Literature Review.

Spontaneous tumor lysis syndrome (STLS), in the absence of prior chemo or radiation therapy, is rare with solid tumors. Here, we present a case of STLS secondary to a small-cell neuroendocrine tumor of unknown origin in a 66-year-old female patient who presented with abdominal discomfort. Computed tomography (CT) abdomen showed a large tumor mass with peritoneal metastasis, and she developed renal failure from STLS, resulting in the need for hemodialysis. Due to the progressive deterioration and the comorbidities, she opted for comfort care. Timely recognition and intervention of STLS is critical. Further studies evaluating STLS in solid tumor patients are recommended.

Large cell neuroendocrine carcinoma and adenocarcinoma of gallbladder with concomitant hepatitis C infection.

Neuroendocrinetumour (NET) of the gallbladder is an extremely rare tumour and with coexisting adenocarcinoma an even rarer occurrence. Mixed NETs have the tendency to invade the lymph nodes and the hepatic tissue from their high malignant potential, leading to poor prognosis. Survival rates of the patients with mixed NET can be improved with wide excision, adjuvant chemotherapy and radiation. We present a case of 62-year-old woman with history of hepatitis C infection, a risk factor for both hepatic and extrahepatic gastrointestinal malignancies. Patient underwent exploratory laparotomy with resection of the gallbladder and partial hepatectomy. Pathology showed high-grade larger cell neuroendocrine carcinoma 5×4×3 cm along with two separate lesions found out to be adenocarcinomas. In our patient, hepatitis C infection can be an inciting factor for the development of these carcinomas. We will discuss the presentation, treatment modalities and outcomes with this kind of coexisting tumours.

A perillyl alcohol-conjugated analog of 3-bromopyruvate without cellular uptake dependency on monocarboxylate transporter 1 and with activity in 3-BP-resistant tumor cells.

The anticancer agent 3-bromopyruvate (3-BP) is viewed as a glycolytic inhibitor that preferentially kills glycolytic cancer cells through energy depletion. However, its cytotoxic activity is dependent on cellular drug import through transmembrane monocarboxylate transporter 1 (MCT-1), which restricts its anticancer potential to MCT-1-positive tumor cells. We created and characterized an MCT-1-independent analog of 3-BP, called NEO218. NEO218 was synthesized by covalently conjugating 3-BP to perillyl alcohol (POH), a natural monoterpene. The responses of various tumor cell lines to treatment with either compound were characterized in the presence or absence of supplemental pyruvate or antioxidants N-acetyl-cysteine (NAC) and glutathione (GSH). Drug effects on glyceraldehyde 3-phosphate dehydrogenase (GAPDH) enzyme activity were investigated by mass spectrometric analysis. The development of 3-BP resistance was investigated in MCT-1-positive HCT116 colon carcinoma cells in vitro. Our results show that NEO218: (i) pyruvylated GAPDH on all 4 of its cysteine residues and shut down enzymatic activity; (ii) severely lowered cellular ATP content below life-sustaining levels, and (iii) triggered rapid necrosis. Intriguingly, supplemental antioxidants effectively prevented cytotoxic activity of NEO218 as well as 3-BP, but supplemental pyruvate powerfully protected cells only from 3-BP, not from NEO218. Unlike 3-BP, NEO218 exerted its potent cytotoxic activity irrespective of cellular MCT-1 status. Treatment of HCT116 cells with 3-BP resulted in prompt development of resistance, based on the emergence of MCT-1-negative cells. This was not the case with NEO218, and highly 3-BP-resistant cells remained exquisitely sensitive to NEO218. Thus, our study identifies a mechanism by which tumor cells develop rapid resistance to 3-BP, and presents NEO218 as a superior agent not subject to this cellular defense. Furthermore, our results offer alternative interpretations of previously published models on the role of supplemental antioxidants: Rather than quenching reactive oxygen species (ROS), supplemental NAC or GSH directly interact with 3-BP, thereby neutralizing the drug's cytotoxic potential before it can trigger ROS production. Altogether, our study introduces new aspects of the cytotoxic mechanism of 3-BP, and characterizes NEO218 as an analog able to overcome a key cellular defense mechanism towards this drug.