Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer.

Group 3 innate lymphoid cells (ILC3s) regulate immunity and inflammation, yet their role in cancer remains elusive. Here, we identify that colorectal cancer (CRC) manifests with altered ILC3s that are characterized by reduced frequencies, increased plasticity, and an imbalance with T cells. We evaluated the consequences of these changes in mice and determined that a dialog between ILC3s and T cells via major histocompatibility complex class II (MHCII) is necessary to support colonization with microbiota that subsequently induce type-1 immunity in the intestine and tumor microenvironment. As a result, mice lacking ILC3-specific MHCII develop invasive CRC and resistance to anti-PD-1 immunotherapy. Finally, humans with dysregulated intestinal ILC3s harbor microbiota that fail to induce type-1 immunity and immunotherapy responsiveness when transferred to mice. Collectively, these data define a protective role for ILC3s in cancer and indicate that their inherent disruption in CRC drives dysfunctional adaptive immunity, tumor progression, and immunotherapy resistance.

Integrative Molecular Analysis of Patients With Advanced and Metastatic Cancer.

PURPOSE: We developed a precision medicine program for patients with advanced cancer using integrative whole-exome sequencing and transcriptome analysis. PATIENTS AND METHODS: Five hundred fifteen patients with locally advanced/metastatic solid tumors were prospectively enrolled, and paired tumor/normal sequencing was performed. Seven hundred fifty-nine tumors from 515 patients were evaluated. RESULTS: Most frequent tumor types were prostate (19.4%), brain (16.5%), bladder (15.4%), and kidney cancer (9.2%). Most frequently altered genes were TP53 (33%), CDKN2A (11%), APC (10%), KTM2D (8%), PTEN (8%), and BRCA2 (8%). Pathogenic germline alterations were present in 10.7% of patients, most frequently CHEK2 (1.9%), BRCA1 (1.5%), BRCA2 (1.5%), and MSH6 (1.4%). Novel gene fusions were identified, including a RBM47-CDK12 fusion in a metastatic prostate cancer sample. The rate of clinically relevant alterations was 39% by whole-exome sequencing, which was improved by 16% by adding RNA sequencing. In patients with more than one sequenced tumor sample (n = 146), 84.62% of actionable mutations were concordant. CONCLUSION: Integrative analysis may uncover informative alterations for an advanced pan-cancer patient population. These alterations are consistent in spatially and temporally heterogeneous samples.

Sacituzumab govitecan: an antibody-drug conjugate.

INTRODUCTION: Despite advances in the diagnosis and treatment of patients with cancer, patients with metastatic cancer have limited therapeutic options after initial lines of therapy. Understanding tumor biology has translated into the identification of actionable targets that resulted in therapeutics. Antibody-drug conjugates (ADC) are capitalizing on this explosion of scientific information. ADCs allow an antibody to a unique target to be conjugated via an innovative linker, to a highly toxic drug which is delivered to its target. Sacituzumab govitecan is an ADC that combines the active molecule in irinotecan, SN-38, to an antibody targeting trop2. Areas covered: In this review, the authors introduce the reader to the ADC sacituzumab govitecan providing the reader with details about its pharmacokinetics, pharmacodynamics, efficacy and safety. The authors also give their expert analysis about its potential future use. Expert opinion: Sacituzumab govitecan is a novel and well-tolerated therapeutic showing promising results in difficult to treat cancers. Further studies are underway to optimize the group of patients that would benefit from it. Given its excellent performance, we are cautiously optimistic it will be approved by the FDA.

Inpatient hemodialysis without anticoagulation in adults.

BACKGROUND: Anticoagulation use during hemodialysis (HD) is standard practice but issues related to an increased risk of hemorrhage associated with inpatients make this a concern. METHODS: An anticoagulation-free protocol in which (i) the dialysis circuit is aggressively primed with normal saline (NS) in an attempt to flush it of all air, (ii) blood flow during the HD treatment is maximized to up to 400 mL/min, (iii) the dialysis circuit is flushed every 15 min with 100 mL of NS, and (iv) the use of bloodlines that lack a blood-air interface was developed and used for all adult inpatient HD treatments at Rush University Medical Center. The purpose of this study was to evaluate the rate of HD circuit clotting using this approach and to determine if factors such as access type, blood flow, arterial and venous bloodline pressures, the need for reversing the arterial and venous access lines for low blood flow or high venous or arterial bloodline pressures, or the amount of net ultrafiltration were associated with HD circuit clotting. Patients were excluded from analysis if they were on a heparin drip, clopidogrel, warfarin or direct thrombin inhibitors. We reviewed 400 HD treatments in 400 adult patients from 12/12 to 10/13. RESULTS: The HD access in these patients consisted of catheters in 45%, native AV fistulas in 40% and grafts in 15% of the patients. The average blood flow in the treatments was 378 ± 46 mL/min. In 5% of the treatments, the arterial and venous bloodlines were reversed. Only 4 of the 400 (1%) of the treatments clotted the dialysis circuit. Factors associated with clotting were lower achieved blood flows (225 ± 50 mL/min versus 379 ± 44 mL/min), higher arterial bloodline pressures (-198 ± 24 mmHg versus -151 ± 45 mmHg) and reversal of arterial and venous access lines. CONCLUSION: Our anticoagulation-free protocol allows inpatient HD to be performed in adults across all access types and with essentially no circuit clotting.

Eight-and-a-half syndrome.

Eight-and-a-half syndrome is a clinical entity comprised of one-and-a-half syndrome with ipsilateral facial palsy. We report a case who presented with this constellation of findings with diffusion weighted images (DWI) and apparent diffusion coefficient (ADC) changes corresponding to the anatomical correlate in the dorsal pontine tegmentum.