Contrary to the long held belief that chemotherapy is immunosuppressive, emerging evidence indicates that the anticancer activity of cisplatin is not limited to its ability to inhibit mitosis, but ...that cisplatin also has important immunomodulatory effects. We therefore methodically examined the relevant preclinical literature and identified four main mechanisms of cisplatin-induced antitumor immunomodulation: (i) MHC class I expression upregulation; (ii) recruitment and proliferation of effector cells; (iii) upregulation of the lytic activity of cytotoxic effectors; and (iv) downregulation of the immunosuppressive microenvironment. Cisplatin-based combination chemotherapy's antitumor immunomodulatory effects are also beginning to be harnessed in the clinic; we therefore additionally reviewed the applicable clinical literature and discussed how monitoring various components of the immune system (and their responses to cisplatin) can add new levels of sophistication to disease monitoring and prognostication. In summation, this growing body of literature on cisplatin-induced antitumor immunomodulation ultimately highlights the therapeutic potential of synergistic strategies that combine traditional chemotherapy with immunotherapy.
To evaluate the neuroprotection exerted by ketosis against acute damage of the mammalian central nervous system (CNS). Search engines were interrogated to identify experimental studies comparing the ...mitigating effect of ketosis (intervention) versus non‐ketosis (control) on acute CNS damage. Primary endpoint was a reduction in mortality. Secondary endpoints were a reduction in neuronal damage and dysfunction, and an ‘aggregated advantage’ (composite of all primary and secondary endpoints). Hedges' g was the effect measure. Subgroup analyses evaluated the modulatory effect of age, insult type, and injury site. Meta‐regression evaluated timing, type, and magnitude of intervention as predictors of neuroprotection. The selected publications were 49 experimental murine studies (period 1979–2020). The intervention reduced mortality (g 2.45, SE 0.48, p < .01), neuronal damage (g 1.96, SE 0.23, p < .01) and dysfunction (g 0.99, SE 0.10, p < .01). Reduction of mortality was particularly pronounced in the adult subgroup (g 2.71, SE 0.57, p < .01). The aggregated advantage of ketosis was stronger in the pediatric (g 3.98, SE 0.71, p < .01), brain (g 1.96, SE 0.18, p < .01), and ischemic insult (g 2.20, SE 0.23, p < .01) subgroups. Only the magnitude of intervention was a predictor of neuroprotection (g 0.07, SE 0.03, p 0.01 per every mmol/L increase in ketone levels). Ketosis exerts a potent neuroprotection against acute damage to the mammalian CNS in terms of reduction of mortality, of neuronal damage and dysfunction. Hematic levels of ketones are directly proportional to the effect size of neuroprotection.
Acute injuries (AI) to the central nervous system (CNS) are a leading cause of mortality and disability. We performed an advanced meta‐analysis and regression of the body of evidence regarding the neuroprotection offered by ketosis after AI of the CNS in experimental mammalian models. Ketosis reduced mortality, neuronal damage and dysfunction. The level of hematic ketones was an independent predictor of neuroprotection. Besides targeted dietary regimens, the neuroprotection was significant also when ketosis was achieved via exogenous supplements. The latter consideration can prompt clinical trials to test the neuroprotection of exogenous ketones in humans with AI of the CNS.
Background
Low socioeconomic status is a well-characterized adverse prognostic factor in large lung cancer databases. However, such characterizations may be confounded as patients of lower ...socioeconomic status are more often treated at low-volume, non-academic centers. We evaluated whether socioeconomic status, as defined by ZIP code median income, was associated with differences in lung cancer resection outcomes within a high-volume academic medical center.
Methods
Consecutive patients undergoing resection for non-small cell lung cancer were identified from a prospectively maintained database (2011–18). Patients were assigned an income value based on the median income of their ZIP code as determined by census-based geographic data. We stratified the population into income quintiles representative of SES and compared demographics (chi-square), surgical outcomes, and survival (Kaplan–Meier).
Results
We identified 1,693 patients, representing 516 ZIP codes. Income quintiles were Q1: $24,421–53,151; Q2:$53,152–73,982; Q3:$73,983–99,063; Q4:$99,064–123,842; and Q5:$123,843–250,001. Compared to Q5 patients, Q1 patients were younger (median 69 vs. 73,
p
< 0.001), more likely male (44 vs. 36%,
p
= 0.035), and more likely Asian, Black, or self-identified as other than white, Asian, or Black. (67 vs. 11%,
p
= < 0.001). We found minor differences in surgical outcomes and no significant difference in 5-year survival between Q1 and Q5 patients (5-year: 86 vs. 85%,
p
= 0.886).
Conclusions
Surgical care patterns at a high-volume academic medical center are similar among patients from varying ZIP codes. Surgical treatment at such a center is associated with no survival differences based upon socioeconomic status as determined by ZIP code. Centralization of lung cancer surgical care to high-volume centers may reduce socioeconomic outcome disparities.
BACKGROUND Immune cell infiltration associated with tumor capsule disruption and tumor budding has been shown to reflect invasiveness, metastasis, and unfavorable prognosis in colorectal cancer. We ...investigated the influence of tumor budding on prognosis and its association with the immune microenvironment in lung adenocarcinoma. METHODS Tumor slides from resected stage I lung adenocarcinomas were reviewed (n = 524 and n = 514, for training and validation cohorts, respectively) for assessment of tumor budding. CD3+ and forkhead box P3+ (FoxP3+ ) lymphocytes, CD68+ macrophages, IL-7 receptor, and IL-12 receptor β2 were analyzed using tissue microarrays constructed from tumor and stroma. Probability of recurrence was calculated using the competing risks method. RESULTS In the training cohort, risk of recurrence for high-grade tumor budding was higher than it was for low-grade tumor budding (32% vs 12%, P ≤ .001), which was confirmed in the validation cohort (P = .005). Tumor budding stratified the risk of recurrence for acinar-predominant (22% vs 9%, P≤ .001), papillary-predominant (22% vs 13%, P = .045), and solid-predominant (39% vs 19%, P = .022) tumors. Tumor budding was associated with higher stromal FoxP3+ lymphocyte infiltration, higher stromal FoxP3/CD3 risk index, higher tumoral and stromal CD68+ macrophage infiltration, and IL-7 receptor overexpression ( P ≤ .001, all associations). Tumor budding remained independently associated with recurrence on multivariate analysis (hazard ratio, 1.61; P = .008). CONCLUSIONS Tumor budding is an independent prognostic factor of stage I lung adenocarcinoma and correlates with the protumor immune microenvironment. Our findings advocate investigating tumor-immune cell interactions at the invading edge as a biologic driver of tumor aggressiveness.
The convergent maze procedure (CMP) is a new minimally invasive technique for the surgical treatment of atrial fibrillation (AF). Recently, multiple groups have published excellent results and few ...adverse events with CMP. However, we now report the second case of an intrapericardial diaphragmatic hernia with small bowel obstruction that resulted from CMP. This adverse event was managed successfully by laparoscopic repair of the hernia and the use of a polytetrafluoroethylene mesh closure with hepatic buttress, achieving an excellent result. With the expanding use of CMP for the treatment of AF, awareness of this adverse event and its appropriate management are increasingly important.
Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor ...(CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand PD-L1 pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.
Success in solid tumor chimeric antigen receptor (CAR) T-cell therapy requires overcoming several barriers, including lung sequestration, inefficient accumulation within the tumor, and target-antigen ...heterogeneity. Understanding CAR T-cell kinetics can assist in the interpretation of therapy response and limitations and thereby facilitate developing successful strategies to treat solid tumors. As T-cell therapy response varies across metastatic sites, the assessment of CAR T-cell kinetics by peripheral blood analysis or a single-site tumor biopsy is inadequate for interpretation of therapy response. The use of tumor imaging alone has also proven to be insufficient to interpret response to therapy. To address these limitations, we conducted dual tumor and T-cell imaging by use of a bioluminescent reporter and positron emission tomography in clinically relevant mouse models of pleural mesothelioma and non-small cell lung cancer. We observed that the mode of delivery of T cells (systemic versus regional), T-cell activation status (presence or absence of antigen-expressing tumor), and tumor-antigen expression heterogeneity influence T-cell kinetics. The observations from our study underscore the need to identify and develop a T-cell reporter—in addition to standard parameters of tumor imaging and antitumor efficacy—that can be used for repeat imaging without compromising the efficacy of CAR T cells in vivo.
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Imaging the kinetics—trafficking, biodistribution, infiltration, and accumulation—of adoptively transferred CAR T cells in heterogenous antigen-expressing solid tumors can reveal critical information to interpret the response to immunotherapy. The authors performed serial quantitative imaging of tumor burden and CAR T cells in clinically relevant models of thoracic cancers.
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