Modified frailty index predicts postoperative morbidity in adhesive small bowel obstruction: analyzing the National Inpatient Sample 2015-2019.

BACKGROUND: There are limited data identifying predictors of postoperative outcomes in adhesive small bowel obstruction (ASBO). This study used the National Inpatient Sample (NIS) to assess the efficacy of the modified frailty index (mFI) to predict postoperative morbidity among patients undergoing an operation for ASBO. METHODS: A retrospective analysis of the NIS between September 1, 2015, and December 31, 2019, was performed to identify adult patients who underwent nonelective operative intervention for ASBO. The mFI was used to stratify patients as either frail (mFI value ≥ 0.27) or robust (mFI value < 0.27). The primary outcomes were overall in-hospital postoperative morbidity and mortality. The secondary outcomes were system-specific morbidity, length of stay (LOS), total in-hospital healthcare cost, and discharge disposition. Univariable and multivariable regressions were used. RESULTS: Overall, 23251 robust patients and 6122 frail patients were included. Adjusted analyses demonstrated that frail patients had increased in-hospital mortality (adjusted odds ratio [aOR], 2.16; 95% CI, 1.80-2.60), postoperative morbidity (aOR, 1.63; 95% CI, 1.52-1.74), postoperative LOS (adjusted mean difference [aMD], 0.97 days; 95% CI, 0.73-1.21), and total in-hospital healthcare costs (aMD, $18,921; 95% CI, $14,608-$23,235) and were less likely to be discharged home (aOR, 0.59; 95% CI, 0.55-0.63). The findings were unchanged on subgroup analysis of patients undergoing open operation and those older than 65 years of age. CONCLUSION: The mFI may predict postoperative outcomes for ASBO. Stratifying patients based on frailty may assist clinicians and patients in making informed decisions, setting realistic expectations, and proactively planning postoperative disposition.

Nanoparticle-mediated Photodynamic Therapy as a Method to Ablate Oral Cavity Squamous Cell Carcinoma in Preclinical Models.

Photodynamic therapy (PDT) is a tissue ablation technique able to selectively target tumor cells by activating the cytotoxicity of photosensitizer dyes with light. PDT is nonsurgical and tissue sparing, two advantages for treatments in anatomically complex disease sites such as the oral cavity. We have previously developed PORPHYSOME (PS) nanoparticles assembled from chlorin photosensitizer-containing building blocks (∼94,000 photosensitizers per particle) and capable of potent PDT. In this study, we demonstrate the selective uptake and curative tumor ablation of PS-enabled PDT in three preclinical models of oral cavity squamous cell carcinoma (OCSCC): biologically relevant subcutaneous Cal-33 (cell line) and MOC22 (syngeneic) mouse models, and an anatomically relevant orthotopic VX-2 rabbit model. Tumors selectively uptake PS (10 mg/kg, i.v.) with 6-to 40-fold greater concentration versus muscle 24 hours post-injection. Single PS nanoparticle-mediated PDT (PS-PDT) treatment (100 J/cm2, 100 mW/cm2) of Cal-33 tumors yielded significant apoptosis in 65.7% of tumor cells. Survival studies following PS-PDT treatments demonstrated 90% (36/40) overall response rate across all three tumor models. Complete tumor response was achieved in 65% of Cal-33 and 91% of MOC22 tumor mouse models 14 days after PS-PDT, and partial responses obtained in 25% and 9% of Cal-33 and MOC22 tumors, respectively. In buccal VX-2 rabbit tumors, combined surface and interstitial PS-PDT (200 J total) yielded complete responses in only 60% of rabbits 6 weeks after a single treatment whereas three repeated weekly treatments with PS-PDT (200 J/week) achieved complete ablation in 100% of tumors. PS-PDT treatments were well tolerated by animals with no treatment-associated toxicities and excellent cosmetic outcomes. SIGNIFICANCE: PS-PDT is a safe and repeatable treatment modality for OCSCC ablation. PS demonstrated tumor selective uptake and PS-PDT treatments achieved reproducible efficacy and effectiveness in multiple tumor models superior to other clinically tested photosensitizer drugs. Cosmetic and functional outcomes were excellent, and no clinically significant treatment-associated toxicities were detected. These results are enabling of window of opportunity trials for fluorescence-guided PS-PDT in patients with early-stage OCSCC scheduled for surgery.

Metabolic flexibility determines human NK cell functional fate in the tumor microenvironment.

NK cells are central to anti-tumor immunity and recently showed efficacy for treating hematologic malignancies. However, their dysfunction in the hostile tumor microenvironment remains a pivotal barrier for cancer immunotherapies against solid tumors. Using cancer patient samples and proteomics, we found that human NK cell dysfunction in the tumor microenvironment is due to suppression of glucose metabolism via lipid peroxidation-associated oxidative stress. Activation of the Nrf2 antioxidant pathway restored NK cell metabolism and function and resulted in greater anti-tumor activity in vivo. Strikingly, expanded NK cells reprogrammed with complete metabolic substrate flexibility not only sustained metabolic fitness but paradoxically augmented their tumor killing in the tumor microenvironment and in response to nutrient deprivation. Our results uncover that metabolic flexibility enables a cytotoxic immune cell to exploit the metabolic hostility of tumors for their advantage, addressing a critical hurdle for cancer immunotherapy.

Expanded human NK cells from lung cancer patients sensitize patients' PDL1-negative tumors to PD1-blockade therapy.

Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1-blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients' tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1- patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.