Survival After Induction Chemotherapy and Chemoradiation Versus Chemoradiation and Adjuvant Chemotherapy for Locally Advanced Rectal Cancer.

BACKGROUND: Total neoadjuvant therapy (TNT) improves tumor response in locally advanced rectal cancer (LARC) patients compared to neoadjuvant chemoradiotherapy alone. The effect of TNT on patient survival has not been fully investigated. MATERIALS AND METHODS: This was a retrospective case series of patients with LARC at a comprehensive cancer center. Three hundred and eleven patients received chemoradiotherapy (chemoRT) as the sole neoadjuvant treatment and planned adjuvant chemotherapy, and 313 received TNT (induction fluorouracil and oxaliplatin-based chemotherapy followed by chemoradiotherapy in the neoadjuvant setting). These patients then underwent total mesorectal excision or were entered in a watch-and-wait protocol. The proportion of patients with complete response (CR) after neoadjuvant therapy (defined as pathological CR or clinical CR sustained for 2 years) was compared by the χ2 test. Disease-free survival (DFS), local recurrence-free survival, distant metastasis-free survival, and overall survival were assessed by Kaplan-Meier analysis and log-rank test. Cox regression models were used to further evaluate DFS. RESULTS: The rate of CR was 20% for chemoRT and 27% for TNT (P=.05). DFS, local recurrence-free survival, metastasis-free survival, and overall survival were no different. Disease-free survival was not associated with the type of neoadjuvant treatment (hazard ratio [HR] 1.3; 95% confidence interval [CI] 0.93-1.80; P = .12). CONCLUSIONS: Although TNT does not prolong survival than neoadjuvant chemoradiotherapy plus intended postoperative chemotherapy, the higher response rate associated with TNT may create opportunities to preserve the rectum in more patients with LARC.

Consolidation mFOLFOX6 Chemotherapy After Chemoradiotherapy Improves Survival in Patients With Locally Advanced Rectal Cancer: Final Results of a Multicenter Phase II Trial.

BACKGROUND: Adding modified FOLFOX6 (folinic acid, fluorouracil, and oxaliplatin) after chemoradiotherapy and lengthening the chemoradiotherapy-to-surgery interval is associated with an increase in the proportion of rectal cancer patients with a pathological complete response. OBJECTIVE: The purpose of this study was to analyze disease-free and overall survival. DESIGN: This was a nonrandomized phase II trial. SETTINGS: The study was conducted at multiple institutions. PATIENTS: Four sequential study groups with stage II or III rectal cancer were included. INTERVENTION: All of the patients received 50 Gy of radiation with concurrent continuous infusion of fluorouracil for 5 weeks. Patients in each group received 0, 2, 4, or 6 cycles of modified FOLFOX6 after chemoradiation and before total mesorectal excision. Patients were recommended to receive adjuvant chemotherapy after surgery to complete a total of 8 cycles of modified FOLFOX6. MAIN OUTCOME MEASURES: The trial was powered to detect differences in pathological complete response, which was reported previously. Disease-free and overall survival are the main outcomes for the current study. RESULTS: Of 259 patients, 211 had a complete follow-up. Median follow-up was 59 months (range, 9-125 mo). The mean number of total chemotherapy cycles differed among the 4 groups (p = 0.002), because one third of patients in the group assigned to no preoperative FOLFOX did not receive any adjuvant chemotherapy. Disease-free survival was significantly associated with study group, ypTNM stage, and pathological complete response (p = 0.004, <0.001, and 0.001). A secondary analysis including only patients who received ≥1 cycle of FOLFOX still showed differences in survival between study groups (p = 0.03). LIMITATIONS: The trial was not randomized and was not powered to show differences in survival. Survival data were not available for 19% of the patients. CONCLUSIONS: Adding modified FOLFOX6 after chemoradiotherapy and before total mesorectal excision increases compliance with systemic chemotherapy and disease-free survival in patients with locally advanced rectal cancer. Neoadjuvant consolidation chemotherapy may have benefits beyond increasing pathological complete response rates. See Video Abstract at http://links.lww.com/DCR/A739.

The global impact of COVID-19 on tuberculosis: A thematic scoping review, 2020-2023.

BACKGROUND: This thematic scoping review of publications sought to understand the global impact of COVID-19 on tuberculosis (TB), interpret the scope of resonating themes, and offer policy recommendations to stimulate TB recovery and future pandemic preparedness. DATA SOURCES: Publications were captured from three search engines, PubMed, EBSCO, and Google Scholar, and applicable websites written in English from January 1, 2020, to April 30, 2023. STUDY SELECTION: Our scoping review was limited to publications detailing the impact of COVID-19 on TB. Original research, reviews, letters, and editorials describing the deleterious and harmful--yet sometimes positive--impact of COVID-19 (sole exposure) on TB (sole outcome) were included. The objective was to methodically categorize the impacts into themes through a comprehensive review of selected studies to provide significant health policy guidance. DATA EXTRACTION: Two authors independently screened citations and full texts, while the third arbitrated when consensus was not met. All three performed data extraction. DATA SYNTHESIS/RESULTS: Of 1,755 screened publications, 176 (10%) covering 39 countries over 41 months met the inclusion criteria. By independently using a data extraction instrument, the three authors identified ten principal themes from each publication. These themes were later finalized through a consensus decision. The themes encompassed TB's care cascade, patient-centered care, psychosocial issues, and health services: 1) case-finding and notification (n = 45; 26%); 2) diagnosis and laboratory systems (n = 19; 10.7%) 3) prevention, treatment, and care (n = 22; 12.2%); 4) telemedicine/telehealth (n = 12; 6.8%); 5) social determinants of health (n = 14; 8%); 6) airborne infection prevention and control (n = 8; 4.6%); 7) health system strengthening (n = 22; 13%); 8) mental health (n = 13; 7.4%); 9) stigma (n = 11; 6.3%); and 10) health education (n = 10; 5.7%). LIMITATIONS: Heterogeneity of publications within themes. CONCLUSIONS: We identified ten globally generalizable themes of COVID-19's impact on TB. The impact and lessons learned from the themed analysis propelled us to draft public health policy recommendations to direct evidence-informed guidance that strengthens comprehensive global responses, recovery for TB, and future airborne pandemic preparedness.

Human T cells upregulate CD69 after coculture with xenogeneic genetically-modified pig mesenchymal stromal cells.

Mesenchymal stromal cells (MSC) obtained from α1,3-galactosyltransferase gene knock-out pigs transgenic for the human complement-regulatory protein CD46 (GTKO/CD46 pMSC) suppress in vitro human anti-pig cellular responses as efficiently as allogeneic human MSC. We investigated the immunoregulatory effects of GTKO/CD46 pMSC on human CD4(+) and CD8(+) T cell proliferation in response to pig aortic endothelial cells (pAEC). pMSC efficiently suppressed T cell proliferation, which was associated with downregulation of granzyme B expression. No induction of CD4(+)CD25(+)Foxp3(hi) regulatory T cells or T cell apoptosis was documented. In correlation with T cell proliferation, CD25 expression was upregulated on T cells in response to pAEC but not to pMSC. In contrast, CD69 expression was upregulated on T cells in response to both pMSC and pAEC, which was associated with a significant increase in the phosphorylation of STAT5. GTKO/CD46 pMSC possibly regulate human T cell responses through modulation of CD69 expression and STAT5 signaling.

Mass casualties in Tahrir Square at the climax of the Egyptian uprising: evidence of an emerging pattern of regime's organized escalating violence during 10 hours on the night of January 28, 2011.

OBJECTIVE: Documentation of the management of mass casualties in Tahrir Square. BACKGROUND: We documented the sequences of our medical response to mass casualties in Tahrir Square between January 28, 2011, and February 4, 2011, at "Kasr El-Ainy" Cairo University Hospital, the largest hospital in the Middle East and the tertiary referral center for all hospitals in Egypt that happened to be the closest to Tahrir Square. METHODS: At the peak of Tahrir Square demonstrations, injured protesters received first aid in a makeshift clinic inside Tahrir Square, manned by volunteer doctors and nurses, before they were evacuated to the Cairo University Hospital Surgical Casualty Department. General surgeons, orthopedic surgeons, anesthesiologists, and critical care nurses from multidisciplinary teams hastily triaged and treated the incoming casualties. Thousands of casualties were seen at the peak of the uprising. This article provides a detailed review of mass casualties seen between January 28, 2011, and February 4, 2011. RESULTS: Of 3012 casualties, 453 were triaged as "immediate care" patients. On arrival, 339 of 453 patients (74.8%) needed surgical intervention within 6 hours of arrival whereas 74 of 453 patients (16.3%) were managed conservatively. Forty of 453 (8.8%) of patients did not survive their injuries. Most of the inpatients (302/453, 66.6%) were admitted within 10 hours on January 28, 2011, during which evidence of a pattern of regime's organized escalating violence emerged. CONCLUSIONS: We describe the pattern of injuries and our management of Tahrir Square mass casualties. We believe that forming multidisciplinary teams of surgeons, anesthesiologists, and nurses was the key to our effective management of such a huge event.

A SMAD4-modulated gene profile predicts disease-free survival in stage II and III colorectal cancer.

BACKGROUND: Colorectal cancer is the second-leading cause of cancer-related mortality in the United States and a leading cause of cancer-related mortality worldwide. Loss of SMAD4, a critical tumor suppressor and the central node of the transforming growth factor-beta superfamily, is associated with worse outcomes for colorectal cancer patients; however, it is unknown whether an RNA-based profile associated with SMAD4 expression could be used to better identify high-risk colorectal cancer patients. AIM: Identify a gene expression-based SMAD4-modulated profile and test its association with patient outcome. METHODS AND RESULTS: Using a discovery dataset of 250 colorectal cancer patients, we analyzed expression of BMP/Wnt target genes for association with SMAD4 expression. Promoters of the BMP/Wnt genes were interrogated for SMAD-binding elements. Fifteen genes were implicated and three tested for modulation by SMAD4 in patient-derived colorectal cancer tumoroids. Expression of the 15 genes was used for unsupervised hierarchical clustering of a training dataset and two resulting clusters modeled in a centroid model. This model was applied to an independent validation dataset of stage II and III patients. Disease-free survival was analyzed by the Kaplan-Meier method. In vitro analysis of three genes identified in the SMAD4-modulated profile (JAG1, TCF7, and MYC) revealed modulation by SMAD4 consistent with the trend observed in the profile. In the training dataset (n = 553), the profile was not associated with outcome. However, among stage II and III patients (n = 461), distinct clusters were identified by unsupervised hierarchical clustering that were associated with disease-free survival (p = .02, log-rank test). The main model was applied to a validation dataset of stage II/III CRC patients (n = 257) which confirmed the association of clustering with disease-free survival (p = .013, log-rank test). CONCLUSIONS: A SMAD4-modulated gene expression profile identified high-risk stage II and III colorectal cancer patients, can predict disease-free survival, and has prognostic potential for stage II and III colorectal cancer patients.

KRAS Mutants Upregulate Integrin ß4 to Promote Invasion and Metastasis in Colorectal Cancer.

KRAS mutation in colorectal cancer is associated with aggressive tumor behavior through increased invasiveness and higher rates of lung metastases, but the biological mechanisms behind these features are not fully understood. In this study, we show that KRAS-mutant colorectal cancer upregulates integrin α6ß4 through ERK/MEK signaling. Knocking-out integrin ß4 (ITGB4) specifically depleted the expression of integrin α6ß4 and this resulted in a reduction in the invasion and migration ability of the cancer cells. We also observed a reduction in the number and area of lung metastatic foci in mice that were injected with ITGB4 knockout KRAS-mutant colorectal cancer cells compared with the mice injected with ITGB4 wild-type KRAS-mutant colorectal cancer cells, while no difference was observed in liver metastases. Inhibiting integrin α6ß4 in KRAS-mutant colorectal cancer could be a potential therapeutic target to diminish the KRAS-invasive phenotype and associated pulmonary metastasis rate. IMPLICATIONS: Knocking-out ITGB4, which is overexpressed in KRAS-mutant colorectal cancer and promotes tumor aggressiveness, diminishes local invasiveness and rates of pulmonary metastasis.

Genomic and transcriptomic determinants of response to neoadjuvant therapy in rectal cancer.

The incidence of rectal cancer is increasing in patients younger than 50 years. Locally advanced rectal cancer is still treated with neoadjuvant radiation, chemotherapy and surgery, but recent evidence suggests that patients with a complete response can avoid surgery permanently. To define correlates of response to neoadjuvant therapy, we analyzed genomic and transcriptomic profiles of 738 untreated rectal cancers. APC mutations were less frequent in the lower than in the middle and upper rectum, which could explain the more aggressive behavior of distal tumors. No somatic alterations had significant associations with response to neoadjuvant therapy in a treatment-agnostic manner, but KRAS mutations were associated with faster relapse in patients treated with neoadjuvant chemoradiation followed by consolidative chemotherapy. Overexpression of IGF2 and L1CAM was associated with decreased response to neoadjuvant therapy. RNA-sequencing estimates of immune infiltration identified a subset of microsatellite-stable immune hot tumors with increased response and prolonged disease-free survival.

KRAS mutant rectal cancer cells interact with surrounding fibroblasts to deplete the extracellular matrix.

Somatic mutations in the KRAS oncogene are associated with poor outcomes in locally advanced rectal cancer but the underlying biologic mechanisms are not fully understood. We profiled mRNA in 76 locally advanced rectal adenocarcinomas from patients that were enrolled in a prospective clinical trial and investigated differences in gene expression between KRAS mutant (KRAS-mt) and KRAS-wild-type (KRAS-wt) patients. We found that KRAS-mt tumors display lower expression of genes related to the tumor stroma and remodeling of the extracellular matrix. We validated our findings using samples from The Cancer Genome Atlas (TCGA) and also by performing immunohistochemistry (IHC) and immunofluorescence (IF) in orthogonal cohorts. Using in vitro and in vivo models, we show that oncogenic KRAS signaling within the epithelial cancer cells modulates the activity of the surrounding fibroblasts in the tumor microenvironment.

Pharmacists as a Source of Advice on Medication Use for Athletes.

Background: The World Anti-Doping Agency (WADA) specifies substances that competitive sportspersons are not allowed to take. Some of these substances are contained in common medicines used in everyday medical practice and could be used by athletes by accident. Objectives: This study aimed to explore pharmacists' knowledge and confidence in guiding athletes about the use of medicines in professional sport. Methods: Registered pharmacists in Australia were invited to participate in an online survey. The survey had five domains and aimed to identify pharmacists' demographic information, interest in sport, familiarity with WADA guidelines, knowledge on prohibited drug classes, and their opinion about the role of pharmacists in educating athletes on medication use. Descriptive statistics were provided and where appropriate, Chi-square, Mann-Whitney and independent t-test were used to identify potential associations and difference between means. Results: One hundred and thirty-five pharmacists (response rate of 10.6%) completed the survey, with the majority indicating that they were not confident in advising athletes on medication use. Although most respondents believed that pharmacists have a role in the education of athletes to help avoid unintentional doping, only about a quarter indicated that they had sufficient knowledge to advise athletes. About one-half of the respondents could provide fully correct answers when asked to identify the WADA status of some commonly used drugs. Conclusions: The results of the survey indicate that upskilling is required to enable pharmacists in Australia to provide accurate medication advice to professional athletes.

Radiogenomics of rectal adenocarcinoma in the era of precision medicine: A pilot study of associations between qualitative and quantitative MRI imaging features and genetic mutations.

OBJECTIVE: To investigate associations between genetic mutations and qualitative as well as quantitative features on MRI in rectal adenocarcinoma at primary staging. METHODS: In this retrospective study, patients with rectal adenocarcinoma, genome sequencing, and pretreatment rectal MRI were included. Statistical analysis was performed to evaluate associations between qualitative features obtained from subjective evaluation of rectal MRI and gene mutations as well as between quantitative textural features and gene mutations. For the qualitative evaluation, Fisher's Exact test was used to analyze categorical associations and Wilcoxon Rank Sum test was used for continuous clinical variables. For the quantitative evaluation, we performed manual segmentation of T2-weighted images for radiomics-based quantitative image analysis. Thirty-four texture features consisting of first order intensity histogram-based features (n = 4), second order Haralick textures (n = 5), and Gabor-edge based Haralick textures were computed at two different orientations. Consensus clustering was performed with 34 computed texture features using the K-means algorithm with Euclidean distance between the texture features. The clusters resulting from the algorithm were then used to enumerate the prevalence of gene mutations in those clusters. RESULTS: In 65 patients, 45 genes were mutated in more than 3/65 patients (5%) and were included in the statistical analysis. Regarding qualitative imaging features, on univariate analysis, tumor location was significantly associated with APC (p = 0.032) and RASA1 mutation (p = 0.032); CRM status was significantly associated with ATM mutation (p = 0.021); and lymph node metastasis was significantly associated with BRCA2 (p = 0.046) mutation. However, these associations were not significant after adjusting for multiple comparisons. Regarding quantitative imaging features, Cluster C1 had tumors with higher mean Gabor edge intensity compared with cluster C2 (θ = 0°, p = 0.018; θ = 45°, p = 0.047; θ = 90°, p = 0.037; cluster C3 (θ = 0°, p = 0.18; θ = 45°, p = 0.1; θ = 90°, p = 0.052), and cluster C4 (θ = 0°, p = 0.016; θ = 45°, p = 0.033; θ = 90°, p = 0.014) suggesting that the cluster C1 had tumors with more distinct edges or heterogeneous appearance compared with other clusters. CONCLUSIONS: Although this preliminary study showed promising associations between quantitative features and genetic mutations, it did not show any correlation between qualitative features and genetic mutations. Further studies with larger sample size are warranted to validate our preliminary data.

SMAD4 Loss in Colorectal Cancer Patients Correlates with Recurrence, Loss of Immune Infiltrate, and Chemoresistance.

PURPOSE: SMAD4 has shown promise in identifying patients with colorectal cancer at high risk of recurrence or death.Experimental Design: A discovery cohort and independent validation cohort were classified by SMAD4 status. SMAD4 status and immune infiltrate measurements were tested for association with recurrence-free survival (RFS). Patient-derived xenografts from SMAD4-deficient and SMAD4-retained tumors were used to examine chemoresistance. RESULTS: The discovery cohort consisted of 364 patients with stage I-IV colorectal cancer. Median age at diagnosis was 53 years. The cohort consisted of 61% left-sided tumors and 62% stage II/III patients. Median follow-up was 5.4 years (interquartile range, 2.3-8.2). SMAD4 loss, noted in 13% of tumors, was associated with higher tumor and nodal stage, adjuvant therapy use, fewer tumor-infiltrating lymphocytes (TIL), and lower peritumoral lymphocyte aggregate (PLA) scores (all P < 0.04). SMAD4 loss was associated with worse RFS (P = 0.02). When stratified by SMAD4 and immune infiltrate status, patients with SMAD4 loss and low TIL or PLA had worse RFS (P = 0.002 and P = 0.006, respectively). Among patients receiving 5-fluorouracil (5-FU)-based systemic chemotherapy, those with SMAD4 loss had a median RFS of 3.8 years compared with 13 years for patients with SMAD4 retained. In xenografted mice, the SMAD4-lost tumors displayed resistance to 5-FU. An independent cohort replicated our findings, in particular, the association of SMAD4 loss with decreased immune infiltrate, as well as worse disease-specific survival. CONCLUSIONS: Our data show SMAD4 loss correlates with worse clinical outcome, resistance to chemotherapy, and decreased immune infiltrate, supporting its use as a prognostic marker in patients with colorectal cancer.

A rectal cancer organoid platform to study individual responses to chemoradiation.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients' tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.

Avulsion fracture of the coracoid process in a patient with chronic anterior shoulder instability treated with the Latarjet procedure: a case report.

INTRODUCTION: Shoulder dislocations can cause acute and chronic instabilities that need to be addressed in order to restore joint functioning. The transfer of the coracoid process has become a feasible surgical procedure in patients with shoulder instability. Several concomitant injuries after recurrent dislocations have been described. CASE PRESENTATION: A 32-year-old German man presented to our department with a history of recurrent shoulder dislocations. He was diagnosed with an avulsion fracture of the coracoid process and dislocation of an osseous piece with attachment to the conjoined tendons during the surgical transfer of the coracoid process. Therefore, we performed an open Latarjet procedure and reattached the bony piece with the conjoined tendons to the glenoid rim. Three months after the operation the patient presented with a satisfying range of motion and without instabilities or pain. He was able to return to his job. CONCLUSIONS: Patients suffering from anterior shoulder dislocation might develop accompanying lesions after numerous dislocations that are not present upon first visit. Different techniques for the reconstruction of the glenoid rim and the restoration of shoulder joint stability have been described in the literature. We opted for a coracoid transfer and achieved an optimal reconstruction, as shown on the postoperative computed tomography scan. An avulsion fracture of the coracoid process with dislocation of the conjoined tendons can not only be found in patients suffering a direct trauma as pointed out in the literature, but also in patients with anterior shoulder instability with recurrent anterior shoulder dislocation.

The clinical impact of continuing to prescribe antiretroviral therapy in patients with advanced AIDS who manifest no virologic or immunologic benefit.

INTRODUCTION: Despite the efficacy and tolerability of modern antiretroviral therapy (ART), many patients with advanced AIDS prescribed these regimens do not achieve viral suppression or immune reconstitution as a result of poor adherence, drug resistance, or both. The clinical outcomes of continued ART prescription for such patients have not been well characterized. METHODS: We examined the causes and predictors of all-cause mortality, AIDS-defining conditions, and serious non-AIDS-defining events among a cohort of participants in a clinical trial of pre-emptive therapy for CMV disease. We focused on participants who, despite ART had failed to achieve virologic suppression and substantive immune reconstitution. RESULTS: 233 ART-receiving participants entered with a median baseline CD4+ T cell count of 30/mm(3) and plasma HIV RNA of 5 log10 copies/mL. During a median 96 weeks of follow-up, 24.0% died (a mortality rate of 10.7/100 patient-years); 27.5% reported a new AIDS-defining condition, and 22.3% a new serious non-AIDS event. Of the deaths, 42.8% were due to an AIDS-defining condition, 44.6% were due to a non-AIDS-defining condition, and 12.5% were of unknown etiology. Decreased risk of mortality was associated with baseline CD4+ T cell count ≥25/mm(3) and lower baseline HIV RNA. CONCLUSIONS: Among patients with advanced AIDS prescribed modern ART who achieve neither virologic suppression nor immune reconstitution, crude mortality percentages appear to be lower than reported in cohorts of patients studied a decade earlier. Also, in contrast to the era before modern ART became available, nearly half of the deaths in our modern-era study were caused by serious non-AIDS-defining events. Even among the most advanced AIDS patients who were not obtaining apparent immunologic and virologic benefit from ART, continued prescription of these medications appears to alter the natural history of AIDS--improving survival and shifting the causes of death from AIDS- to non-AIDS-defining conditions.