Clinical and economic outcomes of serious postoperative infections following resection of common respiratory and gastrointestinal solid tumors

Unlike infections occurring during periods of chemotherapy-induced neutropenia, postoperative infections in patients with solid malignancy remain largely understudied. The purpose of this population-based study was to evaluate the clinical and economic burden, as well as the relationship of hospital surgical volume and outcomes associated with serious postoperative infection (SPI) – i.e., bacteremia/sepsis, pneumonia, and wound infection – following resection of common solid tumors.^ From the Texas Discharge Data Research File, we identified all Texas residents who underwent resection of cancer of the lung, esophagus, stomach, pancreas, colon, or rectum between 2002 and 2006. From their billing records, we identified ICD-9 codes indicating SPI and also subsequent SPI-related readmissions occurring within 30 days of surgery. Random-effects logistic regression was used to calculate the impact of SPI on mortality, as well as the association between surgical volume and SPI, adjusting for case-mix, hospital characteristics, and clustering of multiple surgical admissions within the same patient and patients within the same hospital. Excess bed days and costs were calculated by subtracting values for patients without infections from those with infections computed using multilevel mixed-effects generalized linear model by fitting a gamma distribution to the data using log link.^ Serious postoperative infection occurred following 9.4% of the 37,582 eligible tumor resections and was independently associated with an 11-fold increase in the odds of in-hospital mortality (95% Confidence Interval [95% CI], 6.7-18.5, P < 0.001). Patients with SPI required 6.3 additional hospital days (95% CI, 6.1 - 6.5) at an incremental cost of $16,396 (95% CI, $15,927–$16,875). There was a significant trend toward lower overall rates of SPI with higher surgical volume (P=0.037). ^ Due to the substantial morbidity, mortality, and excess costs associated with SPI following solid tumor resections and given that, under current reimbursement practices, most of this heavy burden is borne by acute care providers, it is imperative for hospitals to identify more effective prophylactic measures, so that these potentially preventable infections and their associated expenditures can be averted. Additional volume-outcomes research is also needed to identify infection prevention processes that can be transferred from higher- to lower-volume providers.^

Novel Imaging-Based Techniques Reveal a Role for PD-1/PD-L1 in Tumor Immune Surveillance in the Lung

The binding of immune inhibitory receptor Programmed Death 1 (PD-1) on T cells to its ligand PD-L1 has been implicated as a major contributor to tumor induced immune suppression. Clinical trials of PD-L1 blockade have proven effective in unleashing therapeutic anti-tumor immune responses in a subset of patients with advanced melanoma, yet current response rates are low for reasons that remain unclear. Hypothesizing that the PD-1/PD-L1 pathway regulates T cell surveillance within the tumor microenvironment, we employed intravital microscopy to investigate the in vivo impact of PD-L1 blocking antibody upon tumor-associated immune cell migration. However, current analytical methods of intravital dynamic microscopy data lack the ability to identify cellular targets of T cell interactions in vivo, a crucial means for discovering which interactions are modulated by therapeutic intervention. By developing novel imaging techniques that allowed us to better analyze tumor progression and T cell dynamics in the microenvironment; we were able to explore the impact of PD-L1 blockade upon the migratory properties of tumor-associated immune cells, including T cells and antigen presenting cells, in lung tumor progression. Our results demonstrate that early changes in tumor morphology may be indicative of responsiveness to anti-PD-L1 therapy. We show that immune cells in the tumor microenvironment as well as tumors themselves express PD-L1, but immune phenotype alone is not a predictive marker of effective anti-tumor responses. Through a novel method in which we quantify T cell interactions, we show that T cells are largely engaged in interactions with dendritic cells in the tumor microenvironment. Additionally, we show that during PD-L1 blockade, non-activated T cells are recruited in greater numbers into the tumor microenvironment and engage more preferentially with dendritic cells. We further show that during PD-L1 blockade, activated T cells engage in more confined, immune synapse-like interactions with dendritic cells, as opposed to more dynamic, kinapse-like interactions with dendritic cells when PD-L1 is free to bind its receptor. By advancing the contextual analysis of anti-tumor immune surveillance in vivo, this study implicates the interaction between T cells and tumor-associated dendritic cells as a possible modulator in targeting PD-L1 for anti-tumor immunotherapy.

Scanned Ion Beam Therapy for Thoracic Tumors

Although frequently cured of Hodgkin lymphoma, adolescents and young adults can develop radiation induced second cancers. These patients could potentially benefit from scanned ion radiotherapy yet likely would require motion mitigation strategies. In theory, four-dimensional (4D) optimization of ion beam fields for individual motion states of respiration can enable superior sparing of healthy tissue near moving targets, compared to other motion mitigation strategies. Furthermore, carbon-ion therapy can sometimes provide greater relative biological effectiveness (RBE) for cell sterilization in a target but nearly equivalent RBE in tissue upstream of the target, compared to proton therapy. Thus, we expected that for some patients with Hodgkin lymphoma, carbon-ion therapy would reduce the predicted risk of second cancer incidence in the breast compared with proton therapy. The purpose of this work was to determine whether 4D-optimized carbon-ion therapy would significantly reduce the predicted risk of radiation induced second cancers in the breast for female Hodgkin lymphoma patients while preserving tumor control compared with proton therapy. To achieve our goals, we first investigated whether 4D-optimized carbon beam tracking could reduce dose to volumes outside a moving target compared with 3D-optimized carbon beam tracking while preserving target dose coverage. To understand the reliability of scanned carbon beam tracking, we studied the robustness of dose distributions in thoracic targets to uncertainties in patient motion. Finally, we investigated whether using carbon-ion therapy instead of proton therapy would significantly reduce the predicted risk of second cancer in the breast for a sample of Hodgkin lymphoma patients. We found that 4D-optimized ion beam tracking therapy can reduce the maximum dose to critical structures near a moving target by as much as 53%, compared to 3D-optimized ion beam tracking therapy. We validated these findings experimentally using a scanned carbon ion synchrotron and a motion phantom. We found scanned carbon beam tracking to be sensitive to a number of motion uncertainties, most notably phase delays in tracking, systematic spatial errors, and interfractional motion changes. Our findings indicate that a lower risk of second cancer in the breast might be expected for some Hodgkin lymphoma patients using carbon-ion therapy instead of proton therapy. For our reference scenario, we found the ratio of risk to be 0.77 ± 0.35 for radiogenic breast cancer after carbon-ion therapy versus proton therapy. Our findings were dependent on the RBE values for tumor induction and the radiosensitivity of breast tissue, as well as the physical dose distribution.