Comparative Immunogenomics of Canine Natural Killer Cells as Immunotherapy Target.

Natural killer (NK) cells are key effectors of the innate immune system, but major differences between human and murine NK cells have impeded translation. Outbred dogs offer an important link for studies of NK biology and immunotherapy. We analyzed gene expression of putative NK populations from healthy dogs and dogs with naturally-occurring cancers examining differential gene expression across multiple conditions, including steady-state, in vitro activation with cytokines and co-culture, and in vivo activation with inhaled IL-15 in dogs receiving IL-15 immunotherapy. We also compared dog, mouse and human CD3-NKp46+ NK cells using a novel orthologous transcriptome. Distinct transcriptional profiles between NK populations exist between conditions and in vitro versus in vivo treatments. In cross-species analysis, canine NK cells were globally more similar to human NK cells than mice. These data define canine NK cell gene expression under multiple conditions and across species, filling an important gap in translational NK studies.

Adrenal Tumors Found During Staging and Surveillance for Colorectal Cancer: Benign Incidentalomas or Metastatic Disease?

OBJECTIVE: To evaluate the incidence of adrenal metastases in patient with colorectal cancer (CRC) and determine the clinical and radiographic features associated metastatic CRC to the adrenal glands. MATERIALS AND METHODS: The review of consecutive adults with newly diagnosed CRC found to have adrenal tumors > 1 cm in size on staging or surveillance CT scans with at least two scans to evaluate progression or stability of disease. RESULTS: Fifty-eight of 856 (6.8%) CRC patients had an adrenal tumor. Forty-three patients (74%) with 46 adrenal tumors had benign adrenal tumors, and 15 (26%) patients with 17 adrenal tumors had metastatic disease. On univariate analysis, patients with metastatic CRC had larger adrenal tumors (26.7 mm vs 12.4 mm, p < 0.01), a higher mean CEA (239 ng/mL vs 14.2 ng/mL, p = 0.03), and were more likely to have other sites of metastatic disease seen on imaging 8/43 (19%) vs 14/15 (93%), p < 0.01. On multivariable analysis, adrenal tumor size > 1.8 cm (OR 49.6 CI 8-306), CEA > 2.5 ng/mL (OR 15.8 CI 1.7-144) and other metastatic disease seen on imaging (OR 68.1 CI 7-661) were independently associated with adrenal metastases. CONCLUSION: CRC patients with small adrenal tumors, normal CEA levels and no evidence of other metastatic disease are unlikely to have spread to the adrenal glands. Adrenal tumors found during staging and surveillance of CRC patients should be evaluated with appropriate imaging and biochemical analysis.

Blood and tissue biomarker analysis in dogs with osteosarcoma treated with palliative radiation and intra-tumoral autologous natural killer cell transfer.

We have previously reported radiation-induced sensitization of canine osteosarcoma (OSA) to natural killer (NK) therapy, including results from a first-in-dog clinical trial. Here, we report correlative analyses of blood and tissue specimens for signals of immune activation in trial subjects. Among 10 dogs treated with palliative radiotherapy (RT) and intra-tumoral adoptive NK transfer, we performed ELISA on serum cytokines, flow cytometry for immune phenotype of PBMCs, and PCR on tumor tissue for immune-related gene expression. We then queried The Cancer Genome Atlas (TCGA) to evaluate the association of cytotoxic/immune-related gene expression with human sarcoma survival. Updated survival analysis revealed five 6-month survivors, including one dog who lived 17.9 months. Using feeder line co-culture for NK expansion, we observed maximal activation of dog NK cells on day 17-19 post isolation with near 100% expression of granzyme B and NKp46 and high cytotoxic function in the injected NK product. Among dogs on trial, we observed a trend for higher baseline serum IL-6 to predict worse lung metastasis-free and overall survival (P = 0.08). PCR analysis revealed low absolute gene expression of CD3, CD8, and NKG2D in untreated OSA. Among treated dogs, there was marked heterogeneity in the expression of immune-related genes pre- and post-treatment, but increases in CD3 and CD8 gene expression were higher among dogs that lived > 6 months compared to those who did not. Analysis of the TCGA confirmed significant differences in survival among human sarcoma patients with high and low expression of genes associated with greater immune activation and cytotoxicity (CD3e, CD8a, IFN-γ, perforin, and CD122/IL-2 receptor beta). Updated results from a first-in-dog clinical trial of palliative RT and autologous NK cell immunotherapy for OSA illustrate the translational relevance of companion dogs for novel cancer therapies. Similar to human studies, analyses of immune markers from canine serum, PBMCs, and tumor tissue are feasible and provide insight into potential biomarkers of response and resistance.

Implementation of a Post-mastectomy Home Recovery Program in a Large, Integrated Health Care Delivery System.

BACKGROUND: The number of outpatient mastectomies, with and without reconstruction, has increased nationwide. In well-selected patient populations, same-day surgery for mastectomy is a safe option. A pilot project was initiated within the Kaiser Permanente Northern California healthcare system to facilitate surgical home recovery (SHR) for mastectomy patients, including patients undergoing implant-based reconstruction and bilateral mastectomies. METHODS: Surgical home recovery for mastectomy patients was implemented in October 2017. Specific measures in this initiative included management of patient expectations at initial consultation, education about postoperative home care, multimodality pain management, and timely post-discharge follow-up. All patients undergoing mastectomy were included, except those undergoing autologous tissue reconstructions. After a 6-month implementation period, rate of same day discharge over 6 months was compared before and after the SHR initiative. We also compared emergency department (ED) visits, reoperations, and readmissions within 7 days. RESULTS: Twenty-one medical centers participated in this initiative. Before implementing SHR, 164 of the 717 (23%) mastectomies were outpatient procedures, compared with 403 of the 663 (61%) after the implementation period. Although the rate of outpatient mastectomy increased significantly, there were no statistically significant differences in ED visits (5.2% vs. 5.1%, p = 0.98), reoperation (3.5% vs. 3.5%, p = 0.99), or readmission rates (1.4% vs. 2.7%, p = 0.08). CONCLUSIONS: By implementing standard expectations and sharing best practices, there was a significant increase in the rate of home recovery for mastectomy without compromising quality of patient care. The success of this pilot program supports SHR for mastectomy.

Morbidity, mortality and temporal trends in the surgical management of retroperitoneal sarcoma: An ACS-NSQIP follow up analysis.

BACKGROUND: Calls for multivisceral resection (MVR) of retroperitoneal sarcoma (RPS) are increasing, although the risks and benefits remain controversial. We sought to analyze current 30-day morbidity and mortality rates, and trends in utilization of MVR in a national database. METHODS: Overall morbidity, severe morbidity, mortality rates, and temporal trends were analyzed utilizing the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). RESULTS: From 2012 to 2015, a total of 564 patients underwent RPS resection with 233 patients (41%) undergoing MVR. The MVR group had a higher rate of preoperative weight loss and larger tumors overall. When comparing MVR to non-MVR, there was no significant difference in overall morbidity (22% vs 17%, P = .13), severe morbidity (11% vs 8%, P = .18), or mortality (<1% vs 2%, P = .25). On multivariate analysis, MVR was not associated with increased overall morbidity or severe morbidity. Mortality rates were too low for meaningful statistical analysis. Annual rates of MVR ranged from 37% to 46% with no significant change over time (P = .47). RESULTS: Short-term morbidity and mortality rates after MVR for RPS remain acceptable, but rates of MVR show little change over time in NSQIP hospitals. Concerns about increased morbidity and mortality should not be viewed as a contraindication to wider implementation of MVR for RPS.

Serum C-reactive Protein and Neutrophil/Lymphocyte Ratio After Neoadjuvant Radiotherapy in Soft Tissue Sarcoma.

BACKGROUND/AIM: The predictive value of serum C-reactive protein (CRP) and neutrophil/lymphocyte (N/L) ratio in soft tissue sarcoma (STS) patients receiving neoadjuvant radiotherapy (RT) has not been analyzed. PATIENTS AND METHODS: From 2007 to 2015, we identified 98 STS patients from a prospective database. Using multivariate analysis, we analyzed CRP and N/L ratios as predictors of overall survival (OS). RESULTS: Mean age of patients was 59 years, 46% were female, and 55% of tumors were located at the extremity. A total of 15 histologies were represented. Fifty percent received preoperative RT. Except for extremity location, characteristics were similar between the preoperative RT and upfront surgery cohorts, including baseline CRP levels and N/L ratios. Multivariate analysis of upfront surgery revealed histological grade, tumor size, and baseline N/L ratio to be predictors of OS, while for preoperative RT, baseline CRP and N/L ratio were not predictive. CONCLUSION: Baseline CRP and N/L ratio did not predict poor clinical outcome in STS patients receiving neoadjuvant RT.