A randomized controlled trial of spinal morphine with an enhanced recovery pathway and its effect on duration of analgesia after cesarean delivery.

BACKGROUND: Intrathecal morphine is frequently administered after cesarean delivery to provide pain relief lasting up to 24 h. An enhanced recovery after cesarean pathways reduces the amount of postoperative opioids needed. The ideal dose of intrathecal morphine when combined with a pathway has not been determined. METHODS: This was a non-inferiority trial in 72 healthy women undergoing a scheduled cesarean delivery. Women were randomized to receive either 50 mcg, 150 mcg, or 250 mcg of intrathecal morphine during spinal anesthesia, with a standardized postoperative enhanced recovery pathway. The time to request supplemental opioids was the primary outcome. Secondary outcomes included pain scores, side effects, and quality of recovery at 24 h. RESULTS: The duration of analgesia with 50 mcg of morphine (median 24.5 h [IQR: 3.5-34.4]) was inferior to 150 mcg (29.4 h [24.5-72]), and both doses were inferior to 250 mcg (32 h [30.5-72]). Women who received 50 mcg morphine had higher pain scores than the other doses, received more supplemental opioids, and had lower quality recovery scores. The secondary outcomes between 150 mcg and 250 mcg were similar. Side effects were similar among all groups. 63% of women who received 250 mcg remained opioid-free at 72 h, compared to 150 mcg (52%) and 50 mcg (30%). CONCLUSIONS: The duration of analgesia using intrathecal morphine with an enhanced recovery pathway was longer with 250 mcg than with lower doses, and side effects were similar. 50 mcg provided inferior pain relief over 24 h. More than half of our patients avoided additional opioids for up to 72 h with either 150 mcg or 250 mcg doses. REGISTRATION: Clinical trial number NCT05069012.

Bridging and downstaging with TACE in early and intermediate stage hepatocellular carcinoma: Predictors of receiving a liver transplant.

Background and Aims: In patients with surgically unresectable early and intermediate stage hepatocellular carcinoma (HCC), only liver transplant (LT) offers a cure. Locoregional therapies, such as transarterial chemoembolization (TACE), are widely used to bridge patients waiting for an LT or downstage tumors beyond Milan Criteria (MC). However, there are no formal guidelines on the number of TACE procedures patients should receive. Our study explores the extent to which repeated TACE might offer diminishing gains toward LT. Approach: We retrospectively analyzed 324 patients with BCLC stage A and B HCC who had received TACE with the intention of disease downstaging or bridging to LT. In addition to baseline demographics, we collected data on LT status, survival, and the number of TACE procedures. Overall survival (OS) rates were estimated using the Kaplan-Meier method, and correlative studies were calculated using chi-square or Fisher's exact test. Results: Out of 324 patients, 126 (39%) received an LT, 32 (25%) of whom had responded favorably to TACE. LT significantly improved OS: HR 0.174 (0.094-0.322, P < .001). However, the LT rate significantly decreased if patients received ≥3 vs < 3 TACE procedures (21.6% vs 48.6%, P < .001). If their cancer was beyond MC after the third TACE, the LT rate was 3.7%. Conclusions: An increased number of TACE procedures may have diminishing returns in preparing patients for LT. Our study suggests that alternatives to LT, such as novel systemic therapies, should be considered for patients whose cancers are beyond MC after three TACE procedures.

TKIs beyond immunotherapy predict improved survival in advanced HCC.

PURPOSE: For patients with advanced HCC, predictors of immunotherapy response are scarce, and the benefits of tyrosine kinase inhibitor (TKI) treatment after immunotherapy are unclear. We explored whether clinical features, such as target lesion response, immune-mediated toxicity, or subsequent TKI therapy predict immunotherapy response. METHODS: We retrospectively studied 77 patients with advanced HCC receiving immunotherapy. Patient characteristics and outcomes were assessed using various statistical methods, including the log-rank test and Kaplan-Meier methods. Cox proportional hazard modeling was used for multivariable survival analysis. RESULTS: For all patients, median overall survival (mOS) was 13 months (95% CI 8-19), and median progression-free survival (mPFS) was 6 months (95% CI 4-10). Patients with partial response (PR) and stable disease (SD) compared to progressive disease (PD) had prolonged mPFS (27 vs. 5 vs. 1 month(s), p < 0.0001) and mOS (not met vs. 11 vs. 3 months, p < 0.0001). Patients with vs. without immune-mediated toxicities trended towards longer mPFS (9 vs. 4 months p = 0.133) and mOS (17 vs. 9 months; p = 0.095). Patients who did vs. did not receive a tyrosine kinase inhibitor (TKI) after immunotherapy had a significantly improved mOS (19 vs. 5 months, p = 0.0024)). Based on multivariate modeling, the hazard ratio (HR) of overall survival (OS) of patients receiving TKI vs. no TKI was 0.412 (p = 0.0043). CONCLUSION: We show that disease control predicts prolonged mOS and mPFS. Furthermore, TKI therapy administered after immunotherapy predicts prolonged mOS in patients with advanced HCC.

Burnout, stress and resilience of an Australian regional hospital during COVID-19: a longitudinal study.

Coronavirus disease 2019 (COVID-19) has placed huge strain on hospital staff around the world. The aim of the current longitudinal study was to investigate the resilience, stress and burnout of hospital staff located at a large, regional hospital in Victoria, Australia during the COVID-19 pandemic over time via cross-sectional surveys. The surveys were disseminated six times from August 2020 to March 2021, with the first three data collection points distributed during a state-wide lockdown. A total of 558 responses from various professional roles within the hospital over the survey period were included in the sample. Analysis of variance indicated significant main effects for the psychological variables across time, age, and workload. Hospital staff reported an increase in burnout levels throughout the eight-months. Significant negative relationships were observed between resilience and burnout, and between resilience and stress. A backward regression highlighted the contribution of resilience, stress, age, and nursing roles on burnout. Hierarchical regression analysis indicated that resilience contributed to the stress-burnout relationship. This study strengthens the evidence between resilience and burnout among healthcare workers and hospital staff and highlights the need for psychological wellbeing programs to be implemented for hospital staff impacted by a prolonged worldwide pandemic.

Molecular characterization of squamous cell carcinoma of the anal canal.

BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is an uncommon malignancy with limited therapeutic options. Nivolumab and pembrolizumab show promising results in patients with SCCA. Human papillomavirus (HPV)-negative tumors are frequently TP53-mutated (TP53-MT) and often resistant to therapy. METHODS: We present a large molecularly-profiled cohort of SCCA, exploring the underlying biology of SCCA, differences between TP53-wild type (TP53-WT) and TP53-MT tumors, and differences between local and metastatic tumors. SCCA specimens (n=311) underwent multiplatform testing with immunohistochemistry (IHC), in situ hybridization (ISH) and next-generation sequencing (NGS). Tumor mutational burden (TMB) was calculated using only somatic nonsynonymous missense mutations. Chi-square testing was used for comparative analyses. RESULTS: The most frequently mutated genes included PIK3CA (28.1%), KMT2D (19.5%), FBXW7 (12%), TP53 (12%) and PTEN (10.8%). The expression of PD-1 was seen in 68.8% and PD-L1 in 40.5% of tumors. High TMB was present in 6.7% of specimens. HER2 IHC was positive in 0.9%, amplification by chromogenic in situ hybridization (CISH) was seen 1.3%, and mutations in ERBB2 were present in 1.8% of tumors. The latter mutation has not been previously described in SCCA. When compared with TP53-WT tumors, TP53-MT tumors had higher rates of CDKN2A, EWSR1, JAK1, FGFR1 and BRAF mutations. PD-1 and PD-L1 expression were similar, and high TMB did not correlate with PD-1 (P=0.50) or PD-L1 (P=0.52) expression. CONCLUSIONS: Molecular profiling differences between TP53-MT and TP53-WT SCCA indicate different carcinogenic pathways which may influence response to therapy. Low frequency mutations in several druggable genes may provide therapeutic opportunities for patients with SCCA.

A phase I trial of the mTOR inhibitor temsirolimus in combination with capecitabine in patients with advanced malignancies.

BACKGROUND: Temsirolimus is an mTOR antagonist with proven anticancer efficacy. Preclinical data suggest greater anticancer effect when mTOR inhibitors are combined with cytotoxic chemotherapy. We performed a Phase I assessment of the combination of temsirolimus and capecitabine in patients with advanced solid tumors. METHODS: Patients were enrolled in an alternating dose escalation of temsirolimus (at 15 or 25 mg IV weekly) and capecitabine (at 750, 1000, and 1250 mg/m2 twice daily) in separate Q2-week and Q3-week cohorts. At the recommended Phase II doses (RP2Ds) of temsirolimus and capecitabine (Q2), seven patients were also treated with oxaliplatin (85 mg/m2 , day 1) to determine triplet combination safety and efficacy. RESULTS: Forty-five patients were enrolled and 41 were evaluable for dose-limiting toxicities (DLTs). The most common adverse events (AEs) were mucositis, fatigue, and thrombocytopenia. The most common grade 3/4 AEs were hypophosphatemia and anemia. Five patients had DLTs, including hypophosphatemia, mucositis, and thrombocytopenia. The RP2Ds were temsirolimus 25 mg +capecitabine 1000 mg/m2 (Q2); and temsirolimus 25 mg +capecitabine 750 mg/m2  (Q3). Of the 38 patients evaluable for response, one had a partial response (PR) and 19 had stable disease (SD). The overall disease control rate was 52%. Five of the 20 patients with SD/PR maintained disease control for >6 months. CONCLUSIONS: The combination of temsirolimus and capecitabine is safe on both a Q2-week and a Q3-week schedule. The combination demonstrated promising evidence of disease control in this highly refractory population and could be considered for testing in disease-specific phase II trials.

Immuno-oncology for Hepatocellular Carcinoma: The Present and the Future.

Hepatocellular carcinoma is a highly prevalent and lethal cancer that many therapeutics are being tested for this disease. It has the potential to be a highly immune-responsive tumor given its inflammatory origins. The first immunotherapies were anti-programmed death-1 monotherapies, which improved response rates and survival. Novel immunotherapy combinations and immunotherapy show promise in frontline treatment. The novel antibody therapy combination of atezolizumab and bevacizumab may be practice changing. Although these landmark studies seem to offer new treatment options, the role of immunotherapy in the liver transplant setting is uncertain until the safety of this approach is defined.

Molecular Profiling in Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is a commonly diagnosed malignancy. Although chemotherapy remains the backbone of treatment, the landscape of treating metastatic CRC (mCRC) is changing with the understanding of its heterogeneity and molecular blueprint. Colon cancer sidedness has proven to hold prognostic implications, with right-sided tumors having higher incidence of BRAF and KRAS mutations and being microsatellite instability-high (MSI-H); overall, they have a worse prognosis compared with left sided-tumors. Results of molecular research have demonstrated the need to profile each mCRC patient for RAS and BRAF mutations, MSI-H status, HER2 amplifications, and NTRK fusions. Ongoing clinical trials using targeted agents aim to further improve survival outcomes. We emphasize the epidemiology, knowledge of primary tumor location, and mutational landscape of mCRC, as well as novel treatment options for patients harboring unique subtypes of these characteristics.

Dashing Decades of Defeat: Long Anticipated Advances in the First-line Treatment of Extensive-Stage Small Cell Lung Cancer.

PURPOSE OF REVIEW: Small cell lung cancer (SCLC) is an exceptionally lethal subtype of lung cancer. For patients with extensive-stage (ES) disease, which is the majority of patients, platinum-doublet chemotherapy has been the standard of care for decades. Dozens of phase III trials have failed to improve survival over standard platinum plus etoposide. Recent results, however, have met with long-overdue success. This manuscript reviews the new standards of care for ES-SCLC. RECENT FINDINGS: Two recent phase III trials have shown an improvement in overall survival with concurrent immunotherapy and chemotherapy. In IMpower 133, the addition of the anti-PD-L1 antibody atezolizumab to carboplatin plus etoposide significantly improved both progression-free survival (PFS) and overall survival (OS). This was the first trial in over 30 years to improve survival. In CASPIAN, concurrent durvalumab, another anti-PD-L1 antibody, also led to an improvement in survival. While there is clearly a need to further improve outcomes, the improvement in survival with the addition of atezolizumab or durvalumab to platinum-doublet chemotherapy is a major advance. We now have new standards of care and the potential of a more meaningful benefit for patients with advanced SCLC.

ATM Dysfunction in Pancreatic Adenocarcinoma and Associated Therapeutic Implications.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid malignancies with very few therapeutic options to treat advanced or metastatic disease. The utilization of genomic sequencing has identified therapeutically relevant alterations in approximately 25% of PDAC patients, most notably in the DNA damage response and repair (DDR) genes, rendering cancer cells more sensitive to DNA-damaging agents and to DNA damage response inhibitors, such as PARP inhibitors. ATM is one of the most commonly mutated DDR genes, with somatic mutations identified in 2% to 18% of PDACs and germline mutations identified in 1% to 34% of PDACs. ATM plays a complex role as a cell-cycle checkpoint kinase, regulator of a wide array of downstream proteins, and responder to DNA damage for genome stability. The disruption of ATM signaling leads to downstream reliance on ATR and CHK1, among other DNA-repair mechanisms, which may enable exploiting the inhibition of downstream proteins as therapeutic targets in ATM-mutated PDACs. In this review, we detail the function of ATM, review the current data on ATM deficiency in PDAC, examine the therapeutic implications of ATM alterations, and explore the current clinical trials surrounding the ATM pathway.

Immune Checkpoint Inhibitors in Small Cell Lung Cancer: A Partially Realized Potential.

Small cell lung cancer (SCLC) is a highly lethal subtype of lung cancer that has seen few therapeutic advances, despite ongoing concerted efforts. Immunotherapy has been an effective option in other carcinogen-related cancers and has shown modest activity in SCLC. Monotherapy with the anti-PD-1 antibody nivolumab in patients with at least two prior lines of therapy was associated with a response rate of 11.9% and a median duration of response of 17.9 months, leading to accelerated approval by the Food and Drug Administration (FDA) as third-line therapy for SCLC. Second-line checkpoint inhibitors have not performed well enough to change the standard of care, and maintenance immunotherapy has not shown significant benefit. However, the incorporation of concurrent immunotherapy in the first-line treatment of SCLC has improved outcomes. The addition of the anti-PD-L1 antibody atezolizumab to standard carboplatin plus etoposide led to an improvement in progression free survival (PFS) and overall survival, the first such improvement in over 30 years leading to the approval of atezolizumab as part of first-line therapy for advanced SCLC. While these landmark approvals offer promising novel treatment options for this recalcitrant disease, more work is needed to optimize their delivery and to build upon these important advances.

Blood-based tumor biomarkers in lung cancer for detection and treatment.

The therapeutic landscape of lung cancer has expanded significantly over the past decade. Advancements in molecularly targeted therapies, strategies to discover and treat resistance mutations, and development of personalized cancer treatments in the context of tumor heterogeneity and dynamic tumor biology have made it imperative to obtain tumor samples on several different occasions through the course of patient treatment. While this approach is critical to the delivery of optimal cancer treatment, it is fraught with a number of barriers including the need for invasive procedures with associated complications, access to limited amount of tissue, logistical delays in obtaining the biopsy, high healthcare cost, and in many cases inability to obtain tissue because of technically difficult location of the tumor. Given multiple limitations of obtaining tissue samples, the use of blood-based biomarkers ("liquid biopsies") may enable earlier diagnosis of cancer, lower costs by avoiding complex invasive procedures, tailoring molecular targeted treatments, improving patient convenience, and ultimately supplement clinical oncologic decision-making. In this paper, we review various blood-based biomarkers including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), tumor derived exosomes, tumor educated platelets (TEPs), and microRNA; and highlight current evidence for their use in detection and treatment of lung cancer.

The outcome of pediatric cadaveric renal transplantation in the UK and Eire.

An analysis of all pediatric cadaveric renal transplant recipients in the UK and Eire was undertaken to review the outcomes of pediatric cadaveric renal transplantation and to consider the implications for organ allocation procedures for pediatric recipients. Factors influencing the outcome of 1,252 pediatric cadaveric renal transplants in the UK and Eire in the 10-yr period from 1 January 1986 to 31 December 1995 were analyzed by Cox proportional hazards regression, including analysis of four distinct post-transplant epochs (0-3 months, 3-12 months, 12-36 months, and beyond 36 months). At the time of analysis (December 2000), 113 (11%) recipients had died and 47% of grafts had failed. In the multi-factorial modelling, the factors significantly affecting transplant outcome were cold ischaemia time, donor and recipient age and human leucocyte antigen (HLA) matching. Epoch analysis demonstrated that these factors operated at different times post-transplant. Cold ischaemia time had a strong influence on outcome at 3 months. A highly significant increased risk of graft failure was associated with donors under 5 yr of age. Young recipients had an increased risk of failure in the short term, but beyond 1 yr post-transplant there were few failures in young recipients while a steady rate of graft loss persisted in the older children. In terms of HLA matching, the worst outcome was observed for two HLA-DR mismatched grafts, while 000 and favorably matched kidneys (100, 010, 110 HLA-A, -B, -DR mismatches) survived longest. Hence, a policy of exchanging organs on the basis of HLA matching is justified for 000 mismatched and favorably matched kidneys. The poor outcome associated with very young donors should discourage pediatric units from transplanting kidneys from such young donors. The reasons for late losses in older recipients need investigation.