Citations

OBJECTIVE Management of locally invasive colorectal carcinoma at any stage currently involves surgical excision followed by chemoradiotherapy; however, the prognosis is poor, with a 5-year overall survival (OS) of only 5%. Failure to achieve gross-total resection is associated with poorer OS, and patients with residual tumor postresection (R1 or R2 resection) have a median OS of 7 months compared with 23 months in those who undergo resection with negative margins (R0 resection). For tumors that have invaded the sacrum, sacrectomy becomes necessary to achieve R0 resection. The objective of this study was to provide a descriptive multicenter account of resection for locally invasive colorectal carcinoma with sacral invasion, focusing on the association of tumor morphometry with surgical planning and perioperative outcomes. METHODS Demographic, comorbidity, clinical, tumor-specific, operative characteristic, and outcome data were collected on all patients who underwent resection of colorectal carcinoma with concurrent sacral resection between January 2005 and May 2022. Patients were grouped into those having undergone surgery for purely palliative intent, or those with resection with attempt at local control and dichotomized into level of osteotomy (either proximal or distal to the S2–3 level). RESULTS Twenty-two patients (median age 50.5 [IQR 43.3–60.0] years, 54.5% female) underwent sacrectomy for colorectal carcinoma. Operative records indicated intent for local control in 14 patients and palliative in the remaining 8 patients. Palliative surgical intent was based primarily on the presence of distant metastases. There was no significant difference in median local progression-free survival between patients undergoing osteotomy proximal to the S2–3 level and those undergoing osteotomy distal to the S2–3 level. CONCLUSIONS En bloc resection is believed to offer the best local control in patients with locally invasive colorectal carcinoma. The present descriptive series highlights outcomes of en bloc resection with partial or full sacrectomy in patients with tumors showing local extension into the sacrum. Complications are common, most often in the form of wound dehiscence or infection, and many patients require placement in a rehabilitation or intermediate-care facility upon discharge. However, for those with stage III (locally aggressive) disease, median OS exceeds 16 years, suggesting that such aggressive management with en bloc resection may be warranted in properly selected patients.

Abstract Among 64 patients with Erdheim-Chester disease treated with a BRAF inhibitor (median follow-up 4 years), we found high response rates (85%) but frequent discontinuations (61%), primarily because of adverse events. Additionally, patients experienced poor health-related quality of life and high symptom burden.

Identifying the mechanisms of ventilator/ventilation-induced lung injury requires an understanding of the pulmonary physiology involved in the mechanical properties of the lung along with the involvement of the inflammatory cascade. Accurately measuring parameters that represent physiologic lung stress and lung strain at the bedside can be clinically challenging. Although surrogates for lung stress and strain have been proposed, such as plateau pressure and driving pressure, these values only represent a static variable in the ventilator breath. It has been proposed that a single variable could be used as a unifying parameter to identify a threshold for the safe application of mechanical ventilation. The concept of “mechanical power” applies an energy load transfer designation to the ventilator settings and output of tidal volume, airway pressures, and flow. However, there is a potential disconnect between the use of “absolute” mechanical power and the variability of body weight throughout a mixed medical population. Using ideal body weight as an influential factor to express mechanical power can potentially allow for a more accurate depiction of energy applied to the lungs and a potentially reliable injurious mechanical ventilation threshold indicator.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a devastating cancer with an increasing incidence and extremely dismal prognosis. Discovery and mechanistic understanding of the genetic and epigenetic drivers of PDAC is therefore of critical importance. Here, we uncover serine protease inhibitor Kazal type 1 (SPINK1) as a putative determinant of clinical progression and demonstrate that it can have a non-canonical function as a regulator of epigenomic states of PDAC cells and associated extensive changes in gene expression. We show that SPINK1 expression, which varies in PDAC, is associated with key aggressive phenotypic cancer states and is correlated with the expression of stemness markers both in vitro and in patient samples. Mechanistically, our results strongly suggest that SPINK1 acts through a new signaling axis, by interacting with COL18A1 in the Golgi apparatus, promoting endostatin release and eventually inducing extensive histone H3 modifications. These results reveal a new function of SPINK1 in PDAC and suggest a potential therapeutic route to combat PDAC aggressiveness by targeting the SPINK1-COL18A1-endostatin signaling.

Abstract Temporal lobe epilepsy is a common neurological disease characterized by recurrent seizures that often originate within limbic networks involving amygdala and hippocampus. The limbic network is involved in crucial physiologic functions involving memory, emotion and sleep. Temporal lobe epilepsy is frequently drug-resistant, and people often experience comorbidities related to memory, mood and sleep. Deep brain stimulation targeting the anterior nucleus of the thalamus (ANT-DBS) is an established therapy for temporal lobe epilepsy. However, the optimal stimulation parameters and their impact on memory, mood and sleep comorbidities remain unclear. We used an investigational brain sensing-stimulation implanted device to accurately track seizures, interictal epileptiform spikes (IES), and memory, mood and sleep comorbidities in five ambulatory subjects. Wireless streaming of limbic network local field potentials (LFPs) and subject behaviour were captured on a mobile device integrated with a cloud environment. Automated algorithms applied to the continuous LFPs were used to accurately cataloged seizures, IES and sleep-wake brain state. Memory and mood assessments were remotely administered to densely sample cognitive and behavioural response during ANT-DBS in ambulatory subjects living in their natural home environment. We evaluated the effect of continuous low-frequency and duty cycle high-frequency ANT-DBS on epileptiform activity and memory, mood and sleep comorbidities. Both low-frequency and high-frequency ANT-DBS paradigms reduced seizures. However, continuous low-frequency ANT-DBS showed greater reductions in IES, electrographic seizures and better sleep and memory outcomes. These results highlight the potential of synchronized brain sensing and dense behavioural tracking during ANT-DBS for optimizing neuromodulation therapy. While studies with larger patient numbers are needed to validate the benefits of low-frequency ANT-DBS, these findings are potentially translatable to individuals currently implanted with ANT-DBS systems.

Abstract Purpose: Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer. Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors. Patients and Methods: We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic triple-negative breast cancer with ≤3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL −1. Results: The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response >12 months and ongoing even after stopping treatment (5.4–69.0 months). Patients with PD-L1–positive tumors (modified proportion score ≥10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1–negative tumors. Consistent with preclinical studies, four of six patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells after starting binimetinib. Conclusions: Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

The trial-to-implant ratio for spinal cord stimulation (SCS) has long served as a cornerstone metric for optimizing patient selection and cost containment. Historically, screening trials played a pivotal role in identifying non-responders, thereby minimizing unnecessary permanent implantations. The utility of the trial paradigm is supported by Medicare data from 2009, which reported a trial-to-implant ratio of 42.5%. However, advancements in SCS technology have significantly transformed the neuromodulation landscape and have been associated with higher rates of trial success. By 2018, the Medicare data showed trial-to-implant ratios exceeding 63%, with randomized clinical trials from 2020 to 2021 reporting ratios exceeding 80%–90%. These significant increases in trial-to-implant ratios suggest that only a minority of SCS candidates do not undergo a subsequent permanent device implantation. As such, re-evaluation of the trial-to-implant paradigm, from the perspective of practicing pain physicians in the USA, in light of evolving clinical practices and economic pressures, is warranted. This discourse explores the benefits and limitations of the trial-to-implant ratio, emphasizing its role as a safeguard against overutilization and a tool for standardizing clinical practices but weighed against its shortcomings including a lack of alignment with long-term outcomes, underscore the need for alternative metrics that include per capita trial utilization and explant-to-implant ratios. European responses to similar questions have resulted in utilizing validated symptom screening tools and direct-to-implant pathways in lieu of a screening trial altogether as potential strategies to optimize SCS utilization while maintaining cost-effectiveness. As healthcare systems adapt to advancements in neuromodulation, a balanced perspective on trial-to-implant ratios and complementary metrics is essential to ensure equitable access, sustainable outcomes and evidence-based care for the future of SCS therapy.

BACKGROUND: Within the US, there has been an overall increase in cost of malpractice insurance for surgeons and decrease in federal reimbursement for surgical work. This study aimed to analyze state-to-state variability to understand differences in costs relative to reimbursement for surgeons and temporal trends. STUDY DESIGN: This study uses publicly available data to conduct a cross-sectional evaluation of surgeon medical malpractice premium rates and surgical reimbursement between 2013 and 2023. Surgeon reimbursement was represented in terms of the unit reimbursement rate for laparoscopic cholecystectomy (LC). The ratio of surgeon reimbursement to malpractice cost was calculated and considered as the number of LCs required in each state to cover the cost of malpractice insurance. RESULTS: Inflation-adjusted reimbursement for LC decreased in all states with a mean decrease of 24%. Although there was an overall decrease in inflation-adjusted medical malpractice premium cost, some states experienced an increase of up to 22% (Rhode Island), whereas other states experienced a decrease in cost of 62% (Oregon). For the year 2023, there was significant variability in the number of LCs needed to afford malpractice insurance premiums across states, ranging from 21 (Minnesota) to 163 (Illinois). Rhode Island experienced the greatest increase in change from 2013 to 2023 (63%), whereas Oregon experienced the greatest decrease (50%). CONCLUSIONS: This study finds significant variation in Medicare-based surgeon compensation relative to malpractice insurance costs across the US. This discrepancy highlights the challenges faced by surgical practices due to inconsistent insurance cost and decreases in reimbursement rates.

Abstract The TopBP1-ATR axis is critical for maintaining genomic stability during DNA replication stress, yet the precise regulation of TopBP1 in replication stress responses remains poorly understood. In this study, we identified PHD and Ring Finger Domains 1 (PHRF1) as an important ATR activator through its interaction with TopBP1. Our analysis revealed a correlation between PHRF1 and genomic stability in cancer patients. Mechanistically, PHRF1 is recruited to DNA lesions in a manner dependent on its PHD domain and histone methylation. Subsequently, PHRF1 mono-ubiquitinates TopBP1 at lysine 73, which enhances the TopBP1-ATR interaction and activates ATR. Depletion of PHRF1 disrupts ATR activation and sensitizes cells to replication stress-inducing agents. Furthermore, conditional knockout of Phrf1 in mice leads to early lethality and impaired ATR-Chk1 axis signaling. Collectively, our findings establish PHRF1 as a novel E3 ligase for TopBP1, coordinating the replication stress response by enhancing TopBP1-ATR signaling.