Mixed response to the first-line treatment of KRAS G12C inhibitor, sotorasib, in non-small cell lung cancer: A brief report.

Key Clinical Message: One Kirsten Ras (KRAS) G12C mutated non-small cell lung cancer (NSCLC) patient had improved poor performance status and obtained mixed response with the first-line KRAS-targeted treatment of sotorasib. After disease progression, partial response was achieved with chemotherapy plus immunotherapy. KRAS G12C mutated immunoenvironment in NSCLC may favor the immunotherapy. Abstract: KRAS is one of the most commonly mutated genes, which used to be untargetable. The phase II CodeBreak 100 trial revealed 6.8-month median progress-free survival (PFS) and 12.5-month overall survival (OS) in previously treated KRAS G12C-mutant NSCLC patients treated with KRAS inhibitor, sotorasib. The specimens of the brain, lymph node (LN), and blood from the patient were analyzed by next-generation sequencing. Hematoxylin and eosin staining and immunohistochemistry were performed for pathological characterization. Computed tomography (CT) and magnetic resonance imaging (MRI) scan were used for treatment response evaluation. The patient was diagnosed in a bad Eastern Cooperative Oncology Group performance status (ECOG-PS) with metastatic KRAS G12C-mutated lung adenocarcinoma who had achieved mixed response to sotorasib as the first-line treatment. Although 5-month PFS of the treatment with sotorasib was not surprising, the patient achieved significantly improved ECOG-PS score from 4 to 1. Subsequently, partial response (PR) was achieved with the treatment of pemetrexed plus pembrolizumab. This case highlights superior efficacy of first-line treatment with sotorasib for the advance untreated KRAS G12C-mutant patients. The high efficacy of the treatment with chemotherapy plus immunotherapy revealed that immunoenvironment of KRAS G12C-mutated patient may favor the immunotherapy.

An exosomal strategy for targeting cancer-associated fibroblasts mediated tumors desmoplastic microenvironments.

Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development.

A dual dynamically cross-linked hydrogel promotes rheumatoid arthritis repair through ROS initiative regulation and microenvironment modulation-independent triptolide release.

High oxidative stress and inflammatory cell infiltration are major causes of the persistent bone erosion and difficult tissue regeneration in rheumatoid arthritis (RA). Triptolide (TPL) has become a highly anticipated anti-rheumatic drug due to its excellent immunomodulatory and anti-inflammatory effects. However, the sudden drug accumulation caused by the binding of "stimulus-response" and "drug release" in a general smart delivery system is difficult to meet the shortcoming of extreme toxicity and the demand for long-term administration of TPL. Herein, we developed a dual dynamically cross-linked hydrogel (SPT@TPL), which demonstrated sensitive RA microenvironment regulation and microenvironment modulation-independent TPL release for 30 days. The abundant borate ester/tea polyphenol units in SPT@TPL possessed the capability to respond and regulate high reactive oxygen species (ROS) levels on-demand. Meanwhile, based on its dense dual crosslinked structure as well as the spontaneous healing behavior of numerous intermolecular hydrogen bonds formed after the breakage of borate ester, TPL could remain stable and slowly release under high ROS environments of RA, which dramatically reduced the risk of TPL exerting toxicity while maximized its long-term efficacy. Through the dual effects of ROS regulation and TPL sustained-release, SPT@TPL alleviated oxidative stress and reprogrammed macrophages into M2 phenotype, showing marked inhibition of inflammation and optimal regeneration of articular cartilage in RA rat model. In conclusion, this hydrogel platform with both microenvironment initiative regulation and TPL long-term sustained release provides a potential scheme for rheumatoid arthritis.

Survival paradox between stage IIB/C and stage IIIA colon cancer: is it time to revise the American Joint Committee on Cancer TNM system?

INTRODUCTION: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system. METHODS: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan-Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant. RESULTS: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001). CONCLUSION: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration.

H4K20me3, H3K4me2 and H3K9me2 mediate the effect of ER on prognosis in breast cancer.

Previous studies have indicated that histone methylations act as mediators in the relationship between oestrogen receptor (ER) and breast cancer prognosis, yet the mediating role has never been assessed. Therefore, we investigated seven histone methylations (H3K4me2, H3K4me3, H3K9me1, H3K9me2, H3K9me3, H3K27me3 and H4K20me3) to determine whether they mediate the prognostic impact of ER on breast cancer. Tissue microarrays were constructed from 1045 primary invasive breast tumours, and the expressions of histone methylations were examined by immunohistochemistry. Multifactorial logistic regression was used to analyse the associations between ER and histone methylations. Cox proportional hazard model was performed to assess the relationship between histone methylations and breast cancer prognosis. The mediation effects of histone methylations were evaluated by model-based causal mediation analysis. High expressions of H3K9me1, H3K9me2, H3K4me2, H3K27me3, H4K20me3 were associated with ER positivity, while high expression of H3K9me3 was associated ER negativity. Higher H3K9me2, H3K4me2 and H4K20me3 levels were associated with better prognosis. The association between ER and breast cancer prognosis was most strongly mediated by H4K20me3 (29.07% for OS; 22.42% for PFS), followed by H3K4me2 (11.5% for OS; 10.82% for PFS) and least by H3K9me2 (9.35% for OS; 7.34% for PFS). H4K20me3, H3K4me2 and H3K9me2 mediated the relationship between ER and breast cancer prognosis, which would help to further elucidate the impact of ER on breast cancer prognosis from an epigenetic perspective and provide new ideas for breast cancer treatment.

The relative risk of immune checkpoint inhibitor pneumonitis in advanced non-small- cell lung cancer: Meta-analyses of controlled clinical trials.

OBJECTIVE: Immune checkpoint inhibitor pneumonitis (CIP) is a prevalent form of immunotherapy-induced pulmonary toxicity, ranking among the leading causes of mortality associated with immune checkpoint inhibitors (ICIs). Despite its significance, the risk stratification of CIP in advanced non-small cell lung cancer (NSCLC) remains uncertain. In this study, we conducted a comprehensive analysis, comparing various factors such as histological types, treatment regimens, PD-L1 expression levels, and EGFR/ALK negativity in advanced NSCLC. Our investigation extends to evaluating the relative risk of developing CIP based on previous treatment history. This analysis aims to provide valuable insights for the identification of specific patient subgroups at higher risk, facilitating more effective risk management and precision therapy approaches. METHODS: PubMed, Embase, and Cochrane databases were systematically searched up to February 16, 2023. We conducted a screening of randomized controlled trials (RCTs) that compared ICI monotherapy or its combination with chemotherapy in advanced NSCLC. The trials were categorized based on histological type, treatment regimen, PD-L1 expression level, EGFR/ALK-negative status, and prior treatment history. Subsequently, the data were stratified into five subgroups, and the occurrences of all-grades (1-5) and high-grades (3-5) pneumonia events were extracted. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were then calculated for further analysis. RESULTS: Twenty-two RCTs, encompassing 13,725 patients with advanced NSCLC, were included in this analysis. Regardless of histology (OR = 2.47, 95% CI 1.41-4.33, P = 0.002; OR = 1.84, 95% CI 1.10-3.09, P = 0.02), treatment regimen (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.91, 95% CI 1.98-4.27, P < 0.00001), PD-L1 expression level (OR = 5.11, 95% CI 2.58-10.12, P < 0.00001; OR = 5.15, 95% CI 2.48-10.70, P < 0.0001), negative EGFR/ALK expression (OR = 4.32, 95% CI 2.22-8.41, P < 0.0001; OR = 3.6, 95% CI 1.56-8.28, P = 0.003), whether there is a history of treatment (OR = 3.27, 95% CI 2.00-5.35, P < 0.00001; OR = 2.74, 95% CI 1.75-4.29, P < 0.0001), ICI use was associated with a higher risk of all-grade (1-5) and high-grade (3-5) pneumonia compared to chemotherapy. Subgroup analysis revealed that the squamous group, the ICI vs. combination chemotherapy (CT) group, the PD-L1 > 50% group, and the previously untreated group had a higher risk of developing all-grade and grade 3-5 CIP (P < 0.05). CONCLUSIONS: In advanced NSCLC, ICI treatment was linked to an elevated risk of pneumonitis across all grades (1-5) as well as high-grade occurrences (3-5) compared to chemotherapy. Notably, individuals with squamous histology and high PD-L1 expression, along with those lacking a history of prior treatment, demonstrated a heightened susceptibility to developing immune-related pneumonitis of all grades (1-5) and high grades (3-5). These observations provide valuable insights for clinicians seeking to enhance the management of pulmonary toxicity associated with immunotherapy.

PPARG-mediated autophagy activation alleviates inflammation in rheumatoid arthritis.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease characterized by joint inflammation and bone damage, that not only restricts patient activity but also tends to be accompanied by a series of complications, seriously affecting patient prognosis. Peroxisome proliferator-activated receptor gamma (PPARG), a receptor that controls cellular metabolism, regulates the function of immune cells and stromal cells. Previous studies have shown that PPARG is closely related to the regulation of inflammation. However, the role of PPARG in regulating the pathological processes of RA is poorly understood. MATERIALS AND METHODS: PPARG expression was examined in the synovial tissues and peripheral blood mononuclear cells (PBMCs) from RA patients and the paw of collagen-induced arthritis (CIA) model rats. Molecular biology experiments were designed to examine the effect of PPARG and cannabidiol (CBD) on RAW264.7 cells and CIA rats. RESULTS: The results reveal that PPARG accelerates reactive oxygen species (ROS) clearance by promoting autophagy, thereby inhibiting ROS-mediated macrophage polarization and NLRP3 inflammasome activation. Notably, CBD may be a promising candidate for understanding the mechanism by which PPARG regulates autophagy-mediated inflammation. CONCLUSIONS: Taken together, these findings indicate that PPARG may have a role for distinguishing between RA patients and healthy control, and for distinguishing RA activity; moreover, PPARG could be a novel pharmacological target for alleviating RA through the mediation of autophagy. CBD can act as a PPARG agonist that alleviates the inflammatory progression of RA.

α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata.

Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4ß2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-ß-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.

Demographic and Clinical Factors Associated With Health-Related Quality-of-Life Profiles Among Prostate Cancer Survivors.

PURPOSE: Our purpose was to describe the prevalence and predictors of symptom and function clusters related to physical, emotional, and social components of general health-related quality of life (HRQOL) in a population-based sample of prostate cancer (PCa) survivors. METHODS: Participants (N = 1,162) completed a baseline survey at a median of 9 months after diagnosis to ascertain the co-occurrence of eight symptom and functional domains that are common across all cancers and not treatment-specific. We used latent profile analysis (LPA) to identify subgroup profiles of survivors with low, moderate, or high HRQOL levels. Multinomial logistic regression models were used to identify clinical and sociodemographic factors associated with survivors' membership in the low versus moderate or high HRQOL profile. RESULTS: The LPA identified 16% of survivors who were categorized in the low HRQOL profile at baseline, indicative of the highest symptom burden and lowest functioning. Factors related to survivors' membership in the low versus higher HRQOL profile groups included less than age 65 years at diagnosis, identifying as non-Hispanic Black race, not working, being a former versus never smoker, systemic therapy, less companionship, more comorbidities, lower health care financial well-being, or less spirituality. Several factors remained associated with remaining in the low versus higher HRQOL profiles on the follow-up survey (n = 699), including younger age, Black race, comorbidity, and lower financial and spiritual well-being. CONCLUSION: About one of six PCa survivors experienced elevated physical and psychosocial symptoms that were independent of local curative therapy, but with younger age, race, comorbidity, and lower financial and spiritual well-being as stable risk factors for poor HRQOL over time.

Ultrasound-guided erector spinae plane block for perioperative analgesia in patients undergoing laparoscopic nephrectomy surgery: A randomized controlled trial.

Study objective: Kidney neoplasms have a high incidence, and radical nephrectomy or partial nephrectomy are the main treatment options. Our study aims to investigate the use of ultrasound-guided erector spinae plane block for perioperative analgesia in patients undergoing laparoscopic nephrectomy surgery. Design: Prospective, randomized, double-blind. Setting: University hospital. Patients: Our study included 50 patients (ASA I-III) who underwent laparoscopic nephrectomy at the hospital of Second Affiliated Hospital of Army Medical University. Interventions: The patients were divided into two groups: the ESPB group and the control group. In the ESPB group, a mixture of 10 mL of 1% lidocaine, 10 mL of 0.7% ropivacaine, 0.5 µg/kg dexmedetomidine, and 5 mg of dexamethasone was administered. In the control group, 20 mL of 0.9% saline was administered. Measurements: The primary outcome measure was the total consumption of sufentanil during the intraoperative period. Secondary outcome measures included visual analogue scale (VAS) pain scores at rest and during coughing at 1 h, 6 h, 12 h, 24 h, and 48 h postoperatively, intraoperative consumption of remifentanil, frequency of rescue analgesic administration, consumption of rescue analgesia and incidence of postoperative nausea and vomiting within 48 h. Results: The ESPB group exhibited lower intraoperative consumption of sufentanil, lower consumption of rescue analgesia, as well as VAS scores at rest and during coughing within the first 24 h postoperatively, compared to the control group. However, no significant differences were observed in VAS scores at 48 h postoperatively, postoperative nausea and vomiting, or the need for postoperative rescue analgesia. Conclusions: Ultrasound-guided ESPB performed in patients who underwent laparoscopic nephrectomy demonstrated a substantial decrease in intraoperative opioid consumption, as well as lower VAS scores at rest and during coughing in the postoperative period.

Molecular features and clinical outcomes of EGFR-mutated, MET-amplified non-small-cell lung cancer after resistance to dual-targeted therapy.

Background: Some studies of dual-targeted therapy (DTT) targeting epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) have shown promising efficacy in non-small-cell lung cancer (NSCLC). Consequently, patient management following DTT resistance has gained significance. However, the underlying resistance mechanisms and clinical outcomes in these patients remain unclear. Objectives: This study aimed to delineate the molecular characteristics and survival outcomes of patients with NSCLC harboring EGFR mutations and acquired MET amplification after developing resistance to DTT. Design: We conducted a retrospective analysis of patients with NSCLC with EGFR mutations and acquired MET amplification who exhibited resistance to EGFR/MET DTT. Methods: Next-generation sequencing (NGS) was performed on patients with available tissue samples before and/or after the development of resistance to DTT. Stratified analyses were carried out based on data sources and subsequent salvage treatments. Univariate/multivariate Cox regression models and survival analyses were employed to explore potential independent prognostic factors. Results: The study included 77 NSCLC patients, with NGS conducted on 19 patients. We observed many resistance mechanisms, including EGFR-dependent pathways (4/19, 21.1%), MET-dependent pathways (2/19, 10.5%), EGFR/MET co-dependent pathways (2/19, 10.5%), and EGFR/MET-independent resistance mechanisms (11/19, 57.9%). Post-progression progression-free survival (pPFS) and post-progression overall survival (pOS) significantly varied among patients who received the best supportive care (BSC), targeted therapy, or chemotherapy (CT), with median pPFS of 1.5, 3.9, and 4.9 months, respectively (p = 0.003). Median pOS were 2.3, 7.7, and 9.2 months, respectively (p < 0.001). The number of treatment lines following DTT resistance and the Eastern Cooperative Oncology Group performance status emerged as the independent prognostic factors. Conclusion: This study revealed a heterogeneous landscape of resistance mechanisms to EGFR/MET DTT, with a similar prevalence of on- and off-target mechanisms. Targeted therapy or CT, as compared to BSC, exhibited the potential to improve survival outcomes for patients with advanced NSCLC following resistance to DTT.

Medicaid Expansion Increases Access for Rural and Impoverished Patients with Pancreatic Ductal Adenocarcinoma in Southern States.

INTRODUCTION: Medicaid expansion (ME) impacted patients when assessed at a national level. However, of the 32 states in which Medicaid expansion occurred, only 3 were Southern states. Whether results apply to Southern states that share similar geopolitical perspectives remains elusive. We aimed to assess the impact of ME on pancreatic ductal adenocarcinoma (PDAC) treatment in eight Southern states in the USA. PATIENTS AND METHODS: We identified uninsured or Medicaid patients (age 40-64 years) diagnosed with PDAC between 2011 and 2018 in Southern states from the North American Association of Central Cancer Registries-Cancer in North America (NAACCR-CiNA) research dataset. Medicaid-expanded states (MES; Louisiana, Kentucky, and Arkansas) were compared with non-MES (NMES; Tennessee, Alabama, Mississippi, Texas, and Oklahoma) using multivariate logistic regression. P < 0.05 was considered statistically significant. RESULTS: Among 3036 patients, MES significantly increased odds of Medicaid insurance by 36%, and increased proportions of insured Black patients by 3.7%, rural patients by 3.8%, and impoverished patients by 18.4%. After adjusting for age, race, rural-urban status, poverty status, and summary stage, the odds of receiving radiation therapy decreased by 26% for each year of expansion in expanded states (P = 0.01). Last, ME did not result in a significant difference between MES and NMES in diagnosing early stage disease (P = 0.98) nor in receipt of chemotherapy or surgery (P = 0.23 and P = 0.63, respectively). CONCLUSIONS: ME in Southern states increased insurance access to traditionally underserved groups. Interestingly, ME decreased the odds of receiving radiation therapy yearly and had no significant impact on receipt of chemotherapy or surgery.

[Research Progress of Pyroptosis in Leukemia: from Mechanism to Treatment --Review].

Pyroptosis is a programmed death mediated by activated caspase and Gasdermin family proteins, characterized by cell swelling, cytosolysis and release of inflammatory factors. Leukemia is a malignant disease characterized by abnormal differentiation and proliferation of hematopoietic stem cells, thus seriously threating human health. In recent years, it has been found that the transformation, proliferation, metastasis and treatment response of leukemia cells are closely related to pyrodeath. Pyroptosis provides a new perspective for the study of leukemia. This paper reviews the types and molecular mechanisms of pyroptosis, the role of pyroptosis in the occurrence and development of leukemia and the treatment of leukemia, so as to provide some references for further study of the relationship between pyroptosis and leukemia, in order to provide a new strategy for the treatment of leukemia.

Association of Major Adverse Financial Events and Later-Stage Cancer Diagnosis in the United States.

PURPOSE: This study assessed the prevalence of specific major adverse financial events (AFEs)-bankruptcies, liens, and evictions-before a cancer diagnosis and their association with later-stage cancer at diagnosis. METHODS: Patients age 20-69 years diagnosed with cancer during 2014-2015 were identified from the Seattle, Louisiana, and Georgia SEER population-based cancer registries. Registry data were linked with LexisNexis consumer data to identify patients with a history of court-documented AFEs before cancer diagnosis. The association of AFEs and later-stage cancer diagnoses (stages III/IV) was assessed using separate sex-specific multivariable logistic regression. RESULTS: Among 101,649 patients with cancer linked to LexisNexis data, 36,791 (36.2%) had a major AFE reported before diagnosis. The mean and median timing of the AFE closest to diagnosis were 93 and 77 months, respectively. AFEs were most common among non-Hispanic Black, unmarried, and low-income patients. Individuals with previous AFEs were more likely to be diagnosed with later-stage cancer than individuals with no AFE (males-odds ratio [OR], 1.09 [95% CI, 1.03 to 1.14]; P < .001; females-OR, 1.18 [95% CI, 1.13 to 1.24]; P < .0001) after adjusting for age, race, marital status, income, registry, and cancer type. Associations between AFEs prediagnosis and later-stage disease did not vary by AFE timing. CONCLUSION: One third of newly diagnosed patients with cancer had a major AFE before their diagnosis. Patients with AFEs were more likely to have later-stage diagnosis, even accounting for traditional measures of socioeconomic status that influence the stage at diagnosis. The prevalence of prediagnosis AFEs underscores financial vulnerability of patients with cancer before their diagnosis, before any subsequent financial burden associated with cancer treatment.

Path-BigBird: An AI-Driven Transformer Approach to Classification of Cancer Pathology Reports.

PURPOSE: Surgical pathology reports are critical for cancer diagnosis and management. To accurately extract information about tumor characteristics from pathology reports in near real time, we explore the impact of using domain-specific transformer models that understand cancer pathology reports. METHODS: We built a pathology transformer model, Path-BigBird, by using 2.7 million pathology reports from six SEER cancer registries. We then compare different variations of Path-BigBird with two less computationally intensive methods: Hierarchical Self-Attention Network (HiSAN) classification model and an off-the-shelf clinical transformer model (Clinical BigBird). We use five pathology information extraction tasks for evaluation: site, subsite, laterality, histology, and behavior. Model performance is evaluated by using macro and micro F1 scores. RESULTS: We found that Path-BigBird and Clinical BigBird outperformed the HiSAN in all tasks. Clinical BigBird performed better on the site and laterality tasks. Versions of the Path-BigBird model performed best on the two most difficult tasks: subsite (micro F1 score of 72.53, macro F1 score of 35.76) and histology (micro F1 score of 80.96, macro F1 score of 37.94). The largest performance gains over the HiSAN model were for histology, for which a Path-BigBird model increased the micro F1 score by 1.44 points and the macro F1 score by 3.55 points. Overall, the results suggest that a Path-BigBird model with a vocabulary derived from well-curated and deidentified data is the best-performing model. CONCLUSION: The Path-BigBird pathology transformer model improves automated information extraction from pathology reports. Although Path-BigBird outperforms Clinical BigBird and HiSAN, these less computationally expensive models still have utility when resources are constrained.

Plasma ddPCR for the detection of MET amplification in advanced NSCLC patients: a comparative real-world study.

Background: Mesenchymal-epithelial transition (MET) amplification is a crucial oncogenic driver and a resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) of non-small-cell lung cancer (NSCLC). Fluorescence in situ hybridization (FISH) is the gold standard for MET amplification detection. However, it is inapplicable when tissue samples are unavailable. Objective: This study assessed the performance of plasma droplet digital polymerase chain reaction (ddPCR) in MET amplification detection in NSCLC patients. Design and methods: A total of 87 NSCLC patients were enrolled, and 94 paired tissue and plasma samples were analyzed for the concordance between FISH and plasma ddPCR/tissue next-generation sequencing (NGS) in detecting MET amplification. In addition, the efficacy of patients with MET amplification using different detection methods who were treated with MET-TKIs was evaluated. Results: Plasma ddPCR showed substantial concordance with FISH (74.1% sensitivity, 92.5% specificity, and 87.2% accuracy with a kappa value of 0.68) and outperformed tissue NGS (kappa value of 0.64) in MET amplification detection. Combined plasma ddPCR and tissue NGS showed substantial concordance with FISH (92.3% sensitivity, 89.2% specificity, and an accuracy of 90.1% with a kappa value of 0.77). The efficacy is comparable in these NSCLC patients with MET amplification detected by FISH and plasma ddPCR who were treated with MET-TKIs. Conclusion: Plasma ddPCR is a potentially reliable method for detecting MET amplification in advanced NSCLC patients. Combined plasma ddPCR and tissue NGS might be an alternative or complementary method to MET amplification detection.

Functional Outcomes After Localized Prostate Cancer Treatment.

Importance: Adverse outcomes associated with treatments for localized prostate cancer remain unclear. Objective: To compare rates of adverse functional outcomes between specific treatments for localized prostate cancer. Design, Setting, and Participants: An observational cohort study using data from 5 US Surveillance, Epidemiology, and End Results Program registries. Participants were treated for localized prostate cancer between 2011 and 2012. At baseline, 1877 had favorable-prognosis prostate cancer (defined as cT1-cT2bN0M0, prostate-specific antigen level <20 ng/mL, and grade group 1-2) and 568 had unfavorable-prognosis prostate cancer (defined as cT2cN0M0, prostate-specific antigen level of 20-50 ng/mL, or grade group 3-5). Follow-up data were collected by questionnaire through February 1, 2022. Exposures: Radical prostatectomy (n = 1043), external beam radiotherapy (n = 359), brachytherapy (n = 96), or active surveillance (n = 379) for favorable-prognosis disease and radical prostatectomy (n = 362) or external beam radiotherapy with androgen deprivation therapy (n = 206) for unfavorable-prognosis disease. Main Outcomes and Measures: Outcomes were patient-reported sexual, urinary, bowel, and hormone function measured using the 26-item Expanded Prostate Cancer Index Composite (range, 0-100; 100 = best). Associations of specific therapies with each outcome were estimated and compared at 10 years after treatment, adjusting for corresponding baseline scores, and patient and tumor characteristics. Minimum clinically important differences were 10 to 12 for sexual function, 6 to 9 for urinary incontinence, 5 to 7 for urinary irritation, and 4 to 6 for bowel and hormone function. Results: A total of 2445 patients with localized prostate cancer (median age, 64 years; 14% Black, 8% Hispanic) were included and followed up for a median of 9.5 years. Among 1877 patients with favorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -12.1 [95% CI, -16.2 to -8.0]), but not worse sexual function (adjusted mean difference, -7.2 [95% CI, -12.3 to -2.0]), compared with active surveillance. Among 568 patients with unfavorable prognosis, radical prostatectomy was associated with worse urinary incontinence (adjusted mean difference, -26.6 [95% CI, -35.0 to -18.2]), but not worse sexual function (adjusted mean difference, -1.4 [95% CI, -11.1 to 8.3), compared with external beam radiotherapy with androgen deprivation therapy. Among patients with unfavorable prognosis, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel (adjusted mean difference, -4.9 [95% CI, -9.2 to -0.7]) and hormone (adjusted mean difference, -4.9 [95% CI, -9.5 to -0.3]) function compared with radical prostatectomy. Conclusions and Relevance: Among patients treated for localized prostate cancer, radical prostatectomy was associated with worse urinary incontinence but not worse sexual function at 10-year follow-up compared with radiotherapy or surveillance among people with more favorable prognosis and compared with radiotherapy for those with unfavorable prognosis. Among men with unfavorable-prognosis disease, external beam radiotherapy with androgen deprivation therapy was associated with worse bowel and hormone function at 10-year follow-up compared with radical prostatectomy.

Ultrasound-guided erector spinae plane block for perioperative analgesia in patients undergoing laparoscopic nephrectomies surgery: a randomized controlled trial.

BACKGROUND: Laparoscopic nephrectomy is a commonly utilized surgical approach for the management of renal cancer. Despite its widespread acceptance, postoperative pain management remains a significant challenge for many patients undergoing this procedure. Traditional pain management techniques, including opioid and nonsteroidal anti-inflammatory drug administration, may not provide adequate pain relief and may result in adverse effects. In recent years, erector spinae plane block (ESPB) has emerged as a promising regional anesthesia technique due to its simplicity, safety, and potential efficacy in reducing postoperative pain. ESPB has demonstrated effectiveness in reducing postoperative pain in various surgical procedures. However, the efficacy of ESPB in laparoscopic nephrectomy for renal cancer has not been extensively studied. As such, further investigation is necessary to determine the potential benefits of ESPB in this context. The addition of adjuvants such as dexmedetomidine and dexamethasone to nerve blocks has been shown to improve both the duration and quality of the block. Multiple studies have demonstrated the safety and efficacy of these adjuvants in reducing postoperative pain and opioid consumption and improving patient satisfaction. The use of dexmedetomidine and dexamethasone as adjuvants for nerve blocks represents a promising approach for enhancing regional anesthesia and analgesia. In light of these findings, we have incorporated dexmedetomidine and dexamethasone into our nerve block protocol. METHODS: This study is a randomized controlled trial conducted at a single center, with 50 participants being randomized in a 1:1 ratio to either the ESPB group or the control group. The trial aims to investigate the efficacy of ESPB in patients diagnosed with kidney cancer who are scheduled for laparoscopic nephrectomy. The primary outcome measure is the total consumption of intraoperative sufentanil. Secondary outcomes include the VAS score at rest and during coughing at 1 h, 6 h, 12 h, 24 h, and 48 h after surgery; total intraoperative remifentanil consumption; the number of times rescue analgesia is required; and the incidence of nausea and vomiting in the first 24 h after surgery. This study is registered for a duration of 1 year and is being conducted in China. DISCUSSION: The objective of our study is to evaluate the potential benefits of erector spinae plane block (ESPB) in patients undergoing laparoscopic nephrectomy, with a focus on the impact of dexmedetomidine and dexamethasone as adjuvants on the quality and duration of the block, as well as postoperative pain and opioid consumption. By investigating the effects of these adjuvants in the context of ESPB, we hope to contribute to the growing body of literature on the use of adjuvants in nerve blocks and provide further insight into the potential benefits of this approach for improving patient outcomes following laparoscopic nephrectomy. This trial was approved by the Ethics Committee of the Second Affiliated Hospital of Army Medical University. TRIAL REGISTRATION: China Clinical Trial Register ChiCTR2300068578 . Registered on 20 February 2023.

Adherence Rate to Alliance for Clinical Trials in Oncology Z0011 Trial Based on Breast Cancer Subtype.

BACKGROUND: The American College of Surgeons Oncology Group Z0011 (ACOSOG Z0011 or Z11) trial demonstrated no survival advantage with completion axillary lymph node dissection (ALND) for patients with T1-2 breast cancer, 1 to 2 positive SLNs who received adjuvant chemoradiation therapy. More than 70% of the cohort had estrogen receptor (ER)+ tumors. There is paucity of data on the adherence rate to Z11, as well as a dearth of data on the applicability of Z11 for the different subtypes. We conducted a large hospital-based study to evaluate the adherence rate to Z11 based on subtypes. STUDY DESIGN: The National Cancer Database was queried to evaluate 33,859 patients diagnosed with T1-2, N1, and M0 breast cancer treated with lumpectomy with negative margins, and adjuvant chemoradiation therapy between 2012 and 2018. Patients were classified into 3 groups: (1) ER+/HER2-, (2) ER-/HER2-, and (3) HER2+ regardless of ER status. The revised Scope of the Regional Lymph Node Surgery 2012 was used to classify patients into those who underwent an SLN or ALND. Differences in use of ALND by subtypes were compared. The Kaplan-Meier method and log-rank test were used to compare overall survival (OS). A p value of <0.05 was considered statistically significant. RESULTS: For ER+/human epidermal growth factor receptor 2 (HER2)-, ER-/HER2-, and HER2+ tumors, the rate of ALND was 43.6%, 50.2%, and 47.8%, respectively. The 5-year OS for SLN and ALND for the entire cohort was 94.0% and 93.1% (p = 0.0004); for ER+/HER2-, it was 95.4% and 94.7% (p = 0.04); for ER-/HER2-, it was 84.1% and 84.3% (p = 0.41); for HER2+, it was 94.2% and 93.2% (p = 0.20). Multivariable cox proportional hazard regression analysis demonstrated no significant survival differences between SLN and ALND (p = 0.776). CONCLUSIONS: Z11 is applicable for women with early N1 disease, regardless of subtypes. ALND did not confer a survival advantage over SLN. Despite this, up to 50% of patients who fit Z11 criteria continue to undergo ALND.

Deep learning uncertainty quantification for clinical text classification.

INTRODUCTION: Machine learning algorithms are expected to work side-by-side with humans in decision-making pipelines. Thus, the ability of classifiers to make reliable decisions is of paramount importance. Deep neural networks (DNNs) represent the state-of-the-art models to address real-world classification. Although the strength of activation in DNNs is often correlated with the network's confidence, in-depth analyses are needed to establish whether they are well calibrated. METHOD: In this paper, we demonstrate the use of DNN-based classification tools to benefit cancer registries by automating information extraction of disease at diagnosis and at surgery from electronic text pathology reports from the US National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) population-based cancer registries. In particular, we introduce multiple methods for selective classification to achieve a target level of accuracy on multiple classification tasks while minimizing the rejection amount-that is, the number of electronic pathology reports for which the model's predictions are unreliable. We evaluate the proposed methods by comparing our approach with the current in-house deep learning-based abstaining classifier. RESULTS: Overall, all the proposed selective classification methods effectively allow for achieving the targeted level of accuracy or higher in a trade-off analysis aimed to minimize the rejection rate. On in-distribution validation and holdout test data, with all the proposed methods, we achieve on all tasks the required target level of accuracy with a lower rejection rate than the deep abstaining classifier (DAC). Interpreting the results for the out-of-distribution test data is more complex; nevertheless, in this case as well, the rejection rate from the best among the proposed methods achieving 97% accuracy or higher is lower than the rejection rate based on the DAC. CONCLUSIONS: We show that although both approaches can flag those samples that should be manually reviewed and labeled by human annotators, the newly proposed methods retain a larger fraction and do so without retraining-thus offering a reduced computational cost compared with the in-house deep learning-based abstaining classifier.