Emerging Risk Factors and Prevention of Perioperative Pulmonary Complications

Modern surgery is faced with the emergence of newer “risk factors” and the challenges associated with identifying and managing these risks in the perioperative period. Obstructive sleep apnea and obesity hypoventilation syndrome pose unique challenges in the perioperative setting. Recent studies have identified some of the specific risks arising from caring for such patients in the surgical setting. While all possible postoperative complications are not yet fully established or understood, the prevention and management of these complications pose even greater challenges. Pulmonary hypertension with its changing epidemiology and novel management strategies is another new disease for the surgeon and the anesthesiologist in the noncardiac surgical setting. Traditionally most such patients were not considered surgical candidates for any required elective surgery. Our review discusses these disease entities which are often undiagnosed before elective noncardiac surgery

The Hedgehog Signaling Pathway: A Viable Target in Breast Cancer?

The hedgehog (Hh) pathway plays a key role in embryonic development and stem cell programs. Deregulation of the Hh pathway is a key driver of basal cell carcinoma, and therapeutic targeting led to approval of Hh inhibitor, vismodegib, in the management of this cancer. The Hh pathway is implicated in other malignancies including hormone receptor (HR+) positive and triple negative breast cancer (TNBC). Hh signaling, which is activated in human mammary stem cells, results in activation of glioma-associated oncogene (GLI) transcription factors. High GLI1 expression correlates with worse outcomes in breast cancer. Non-canonical GLI1 activation is one mechanism by which estrogen exposure promotes breast cancer stem cell proliferation and epithelial–mesenchymal transition. Tamoxifen resistant cell lines show aberrant activation of Hh signaling, and knockdown of Hh pathway inhibited growth of tamoxifen resistant cells. As in other cancers Hh signaling is activated by the PI3K/AKT pathway in these endocrine resistant cell lines. Hh pathway activation has also been reported to mediate chemotherapy resistance in TNBC via various mechanisms including paracrine signaling to tumor micro-environment and selective proliferation of cancer stem cells. Co-activation of Hh and Wnt signaling pathways is a poor prognostic marker in TNBC. Early phase clinical trials are evaluating the combination of smoothened (SMO) inhibitors and chemotherapy in TNBC. In addition to SMO inhibitors like vismodegib and sonidegib, which are in clinical use for basal cell carcinoma, GLI1 inhibitors like GANT58 and GANT61 are in preclinical drug development and might be an effective mechanism to overcome drug resistance in breast cancer. Gene signatures predictive of Hh pathway activation could enrich for patients likely to respond to these agents

Postoperative Complications in Patients with Unrecognized Obesity Hypoventilation Syndrome Undergoing Elective Non-cardiac Surgery

BACKGROUND: Among patients with obstructive sleep apnea (OSA) a higher number of medical morbidities are known to be associated with those that have obesity hypoventilation syndrome (OHS) compared to OSA alone. OHS can therefore pose a higher risk of postoperative complications after elective non-cardiac surgery (NCS) and is often unrecognized at the time of surgery. The objective of this study was to retrospectively identify patients with OHS and compare their postoperative outcomes with those who have OSA alone. METHODS: Patients meeting criteria for OHS were identified within a large cohort of patients with OSA who underwent elective NCS at a major tertiary care center. We identified postoperative outcomes associated with OSA and OHS as well as the clinical determinants of OHS (BMI, AHI). Multivariable logistic or linear regression models were used for dichotomous or continuous outcomes, respectively. RESULTS: Patients with hypercapnia from definite or possible OHS, and overlap syndrome are more likely to develop postoperative respiratory failure [OR: 10.9 (95% CI 3.7-32.3), p<0.0001], postoperative heart failure (p<0.0001), prolonged intubation [OR: 5.4 (95% CI 1.9-15.7), p=0.002), postoperative ICU transfer (OR: 3.8 (95% CI 1.7-8.6), p=0.002]; longer ICU (beta coefficient: 0.86; SE: 0.32, p=0.009) and hospital length of stay (beta coefficient: 2.94; SE: 0.87, p=0.0008) when compared to patients with OSA. Among the clinical determinants of OHS, neither BMI nor AHI showed associations with any postoperative outcomes in univariable or multivariable regression. CONCLUSIONS: Better emphasis is needed on preoperative recognition of hypercapnia among patients with OSA or overlap syndrome undergoing elective NCSRevisión por pare

Retinoblastoma mutation predicts poor outcomes in advanced non small cell lung cancer

Abstract The retinoblastoma gene (RB1) encodes the retinoblastoma (RB) pocket protein that plays an important role in cell cycle progression. Here we determine the frequency and prognostic significance of RB1 mutation in non small cell lung cancer (NSCLC), restricting inclusion to Stage III and IV patients with linked genomic and clinical data. The primary outcome was median overall survival (OS). We identified RB1 mutation in 8.2% of NSCLC patients. The median OS for wild‐type (wt) RB1 was 28.3 months vs 8.3 months for mutant RB1 (Hazard Ratio = 2.59, P = 0.002). Of special interest, RB1 mutation also correlated with lack of response to immunotherapy. Our study focused on RB1 mutation in locally advanced and advanced non small cell lung cancer to better facilitate comparisons with small cell lung cancer (SCLC). In our SCLC cohort, RB1 mutation was identified in 75% of patients and wt RB1 was associated with significantly shorter OS (P = 0.002). The different outcomes of RB1 mutation observed among lung cancer subtypes suggest a more complicated mechanism than simple regulation of cell cycle or response to chemotherapy

Palliative Quad Shot Radiation Therapy with or without Concurrent Immune Checkpoint Inhibition for Head and Neck Cancer

Objectives: Patients with recurrent and metastatic head and neck cancer (HNC) have limited treatment options. ‘QuadShot’ (QS), a hypofractionated palliative radiotherapy regimen, can provide symptomatic relief and local control and may potentiate the effects of immune checkpoint inhibitors (ICIs). We compared outcomes of QS ± concurrent ICIs in the palliative treatment of HNC. Materials and Methods: We identified patients who received ≥three cycles of QS from 2017 to 2022 and excluded patients without post-treatment clinical evaluation or imaging. Outcomes for patients who received QS alone were compared to those treated with ICI concurrent with QS, defined as receipt of ICI within 4 weeks of QS. Results: Seventy patients were included, of whom 57% received concurrent ICI. Median age was 65.5 years (interquartile range [IQR]: 57.9–77.8), and 50% patients had received prior radiation to a median dose of 66 Gy (IQR: 60–70). Median follow-up was 8.8 months. Local control was significantly higher with concurrent ICIs (12-month: 85% vs. 63%, p = 0.038). Distant control (12-month: 56% vs. 63%, p = 0.629) and median overall survival (9.0 vs. 10.0 months, p = 0.850) were similar between the two groups. On multivariable analysis, concurrent ICI was a significant predictor of local control (HR for local failure: 0.238; 95% CI: 0.073–0.778; p = 0.018). Overall, 23% patients experienced grade 3 toxicities, which was similar between the two groups. Conclusions: The combination of QS with concurrent ICIs was well tolerated and significantly improved local control compared to QS alone. The median OS of 9.4 months compares favorably to historical controls for patients with HNC treated with QS. This approach represents a promising treatment option for patients with HNC unsuited for curative-intent treatment and warrants prospective evaluation

Identification of Clinical and Socioeconomic Predictors of Adjuvant Therapy after Trans-Oral Robotic Surgery in Patients with Oropharyngeal Squamous Cell Carcinoma

Trans-oral robotic surgery (TORS) has emerged as an important surgical treatment option in the management of human papillomavirus (HPV)-positive and -negative oropharynx cancer. However, treatment selection is paramount to ensure that patients will not require multimodality adjuvant therapy. In this study, we determined predictors of adjuvant therapy in TORS-treated patients. The National Cancer Database (NCDB) was used to identify patients with newly diagnosed clinical T1-T4, N0-N3 oropharyngeal squamous cell carcinoma who underwent TORS between 2010&ndash;2016. Kaplan&ndash;Meier survival analysis was used to estimate overall survival (OS). A total of 2999 patients were studied, and the five-year OS for the entire cohort was 82.5%, and for HPV-positive and -negative cohorts it was 88.3% and 67.9%, respectively (p &lt; 0.001). Among all patients treated with TORS, 35.1% of patients received no additional treatment, 33.5% received adjuvant radiation alone (RT), and 31.3% received adjuvant chemoradiation. The N stage was pathologically upstaged in 629 (20.9%) patients after TORS. Patients treated at higher-volume centers were more likely to have negative surgical margins (OR: 0.96, 95% CI: 0.94, 0.98, p &lt; 0.001), but this did not influence the receipt of adjuvant therapy. The high rate of adjuvant multimodality treatment after TORS suggests a need for improved patient selection. Limitations of this study, including lack of data on loco-regional control, progression free survival, acute and late toxicities, and utilization of pretreatment PET/CT imaging, should be addressed in future studies