Key Points Question Is total neoadjuvant therapy (TNT) associated with improved outcomes when compared with standard concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A) for locally advanced rectal cancer? Findings In this systematic review and meta-analysis of 7 unique studies including 2416 unique patients, TNT was found to be associated with a significantly higher rate of achieving a pathologic complete response and disease-free survival compared with the standard CRT plus A approach. No significant difference was found in rates of sphincter-preserving surgery or ileostomy requirements between the 2 approaches. Meaning Total neoadjuvant therapy was associated with improved pathologic complete response rates and has a potential disease-free survival advantage compared with the standard CRT plus A strategy in locally advanced rectal cancer.

Background: Nano-liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) is the regimen of choice in the 2 nd line setting for advanced pancreatic adenocarcinoma (PAC). However, realworld data is limited. Our objectives were to elicit the real-word effectiveness and safety of this combination as an advanced line of therapy in pancreatic cancer patients and analyze the impact of prior lines of therapy on survival outcomes with this regimen. Methods: We conducted a retrospective cohort study of 58 patients with locally advanced unresectable or metastatic PAC, who were treated with at least one dose of nal-IRI + 5-FU/LV following cancer progression on prior therapies between August 2015 and December 2018 at the Kansas University Medical Center (KUMC) and University of Alabama at Birmingham (UAB).Results: Median OS was 5.4 (range, 4.2-7) months. Disease control rate (DCR) was highest (84%) for patients given nal-IRI + 5-FU/LV as 2 nd line agent after progression on a 1 st line gemcitabine-based regimen. However, no significant survival difference was observed between those given nal-IRI + 5-FU/LV after 1 st line or beyond the 2 nd line (P=0.17). Among those given nal-IRI + 5-FU/LV as 2 nd line, use of gemcitabineinclusive chemotherapy as the 1 st line agent did not impact survival (P=0.68). Prior irinotecan exposure and baseline CA 19-9 level did not affect the overall survival (OS) but patients with a higher CA 19-9 level had a significant risk of progression (HR =3.2, P=0.02). Grade 3/4 toxicities were reported in only 19% patients.Conclusions: Our report suggests that nal-IRI + 5-FU/LV offers a modest survival benefit with a tolerable safety profile as an advanced line of treatment in patients with advanced PAC.

Androgen deprivation therapy or ADT is one of the cornerstones of management of locally advanced or metastatic prostate cancer, alongside radiation therapy. However, despite early response, most advanced prostate cancers progress into an androgen unresponsive or castrate resistant state, which hitherto remains an incurable entity and the second leading cause of cancer-related mortality in men in the US. Recent advances have uncovered multiple complex and intermingled mechanisms underlying this transformation. While most of these mechanisms revolve around androgen receptor (AR) signaling, novel pathways which act independently of the androgen axis are also being discovered. The aim of this article is to review the pathophysiological mechanisms that help bypass the apoptotic effects of ADT to create castrate resistance. The article discusses castrate resistance mechanisms under two categories: 1. Direct AR dependent pathways such as amplification or gain of function mutations in AR, development of functional splice variants, posttranslational regulation, and pro-oncogenic modulation in the expression of coactivators vs corepressors of AR. 2. Ancillary pathways involving RAS/MAP kinase, TGF-beta/SMAD pathway, FGF signaling, JAK/STAT pathway, Wnt-Beta catenin and hedgehog signaling as well as the role of cell adhesion molecules and G-protein coupled receptors. miRNAs are also briefly discussed. Understanding the mechanisms involved in the development and progression of castration-resistant prostate cancer is paramount to the development of targeted agents to overcome these mechanisms. A number of targeted agents are currently in development. As we strive for more personalized treatment across oncology care, treatment regimens will need to be tailored based on the type of CRPC and the underlying mechanism of castration resistance.

Metastatic castrate resistant prostate cancer (PCa) remains an incurable entity. In the era of immunotherapy, the complex PCa microenvironment poses a unique challenge to the successful application of this class of agents. However, in the last decade, a tremendous effort has been made to explore this field of therapeutics. In this review, the physiology of the cancer immunity cycle is highlighted in the context of the prostate tumor microenvironment, and the current evidence for use of various classes of immunotherapy agents including vaccines (dendritic cell based, viral vector based and DNA/mRNA based), immune checkpoint inhibitors, Chimeric antigen receptor T cell therapy, antibody-mediated radioimmunotherapy, antibody drug conjugates, and bispecific antibodies, is consolidated. Finally, the future directions for combinatorial approaches to combat PCa are discussed.

ObjectiveTo evaluate the effectiveness of noradrenaline for the treatment of hepatorenal syndrome (HRS).BackgroundHRS represents the development of renal failure in cirrhotic patients. The standard treatment for HRS is terlipressin, which, as opposed to noradrenaline, is more expensive and less accessible in most tertiary care centers.Patients and methodsThirty consecutive patients with HRS type 1 received noradrenaline (1–4.0 mg/hour) and albumin for 14 days. The parameters recorded were: serum creatinine levels, creatinine clearance, mean arterial pressure (MAP), urine output, and serum sodium levels evaluated at baseline and on treatment days 1, 3, 7, and 14.ResultsMost patients achieved serum creatinine levels <1.5 mg/dL and were considered responders (22/30, 73%), whereas eight patients (27%) were nonresponders. At baseline, responders and nonresponders differed only regarding initial bilirubin levels and international normalized ratio values. Treatment duration was 7.5±3.2 days. Responders experienced a significant (p<0.05) decrease in serum creatinine levels (from 3.26±0.48 to 1.28±0.14 mg/dL), as well as a significant increase (p<0.05) in creatinine clearance (from 21±4.1 to 67.7±12.1 mL/min), urine output (from 583±41.1 to 1163±105 mL/day), MAP (from 79.2±2.94 to 93.9±2.34 mmHg), and serum sodium levels (from 125±2.01 to 132.3±1.39 mEq/L). In nonresponders, the MAP increased, but serum creatinine levels also increased, reflecting a decrease in creatinine clearance and urine output, with no significant change in serum sodium levels over the duration of the treatment.ConclusionIn most patients, noradrenaline treatment induced systemic vasoconstriction resulting in HRS reversal, with acceptable safety, in agreement with previously reported outcomes of terlipressin treatment.