When Talking Heads Stop Making Sense

My paper examines the role of mental illness in Beckett's Waiting For Godot, and how linguistic coherence creates othering

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P &lt; .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.</p

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P &lt; .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.</p

Marker discovery and associations with β-carotene content in Indian dairy cattle and buffalo breeds

Vitamin A is essential for human health, but current intake levels in many developing countries such as India are too low due to malnutrition. According to the World Health Organization, an estimated 250 million preschool children are vitamin A deficient globally. This number excludes pregnant women and nursing mothers, who are particularly vulnerable. Efforts to improve access to vitamin A are key because supplementation can reduce mortality rates in young children in developing countries by around 23%. Three key genes, BCMO1, BCO2, and SCARB1, have been shown to be associated with the amount of beta-carotene (BC) in milk. Whole-genome sequencing reads from the coordinates of these 3 genes in 202 non-Indian cattle (141 Bos taurus, 61 Bos indicus) and 35 non-Indian buffalo (Bubalus bubalis) animals from several breeds were collected from data repositories. The number of SNP detected in the coding regions of these 3 genes ranged from 16 to 26 in the 3 species, with 5 overlapping SNP between B. taurus arid B. indicus. All these SNP together with 2 SNP in the upstream part of the gene but already present in dbSNP (https://www.ncbi.nim mih.gov/projects/SNP/) were used to build a custom Sequenom array. Blood for DNA and milk samples for BC were obtained from 2,291 Indian cows of 5 different breeds (Gir, Holstein cross, Jersey Cross, Tharparkar, and Sahiwal) and 2,242 Indian buffaloes (Jafarabadi, Murrali, Pandharpuri, arid Surti breeds). The DNA was extracted and genotyped with the Sequenom array. For each individual breed and the combined breeds, SNP with an association that had a P-value &lt;0.3 in the first round of linear analysis were included in a second step of regression analyses to determine allele substitution effects to increase the content of BC in milk. Additionally, an F-test for all SNP within gene was performed with the objective of determining if overall the gene had a significant effect on the content of BC in milk. The analyses were repeated using a Bayesian approach to compare and validate the previous frequentist results. Multiple significant SNP were found using both methodologies with allele substitution effects ranging from 6.21 (3.13) to 9.10 (5.43) mu g of BC per 100 mL of milk. Total gene effects exceeded the mean BC value for all breeds with both analysis approaches. The custom panel designed for genes related to BC production demonstrated applicability in genotyping of cattle and buffalo in India and may be used for cattle or buffalo from other developing countries. Moreover, the recommendation of selection for significant specific alleles of some gene markers provides a route to effectively increase the BC content in milk in the Indian cattle and buffalo populations