Response-adapted, time-limited venetoclax, umbralisib, and ublituximab for relapsed/refractory chronic lymphocytic leukemia.

ABSTRACT: Many patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Owing to the synergistic antitumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment. We conducted a phase 1/2 clinical trial to determine the safety and efficacy of venetoclax in combination with umbralisib and the anti-CD20 monoclonal antibody, ublituximab, (U2-VeN) in patients with relapsed/refractory CLL (N = 46) and Richter transformation (N = 5). After 12 cycles, treatment was stopped for patients with CLL who achieved undetectable minimal residual disease (uMRD). Adverse events of special interest included diarrhea in 50% of patients (11% grade 3/4), and aspartate aminotransferase and/or alanine aminotransferase elevation in 15 patients (33%), with 3 (7%) grade 3/4. There were no cases of tumor lysis syndrome related to venetoclax, with outpatient initiation in 96% of patients. The intent-to-treat overall response rate for CLL was 98% with best response of 100% in evaluable patients (42% complete responses). The end-of-treatment rate of uMRD at 10-4 in bone marrow was 77% (30/39), including a 71% uMRD rate among 14 patients refractory to prior BTK inhibitor. Time-limited venetoclax and U2 is safe and highly effective combination therapy for patients with relapsed/refractory CLL including those who have been previously treated with covalent BTK inhibitors. This trial was registered on www.clinicaltrials.gov as #NCT03379051.

A Novel Approach to Locating Community Clinics to Promote Health Care Accessibility and Reduce Health Disparities in Baltimore, Maryland.

Baltimore, Maryland's entrenched racial residential segregation renders the city's world-class medical facilities and services inaccessible to many Black residents living in its most divested neighborhoods. Arguing the need for post-pandemic health care facilities to address health inequities as a practice of care-giving, this article describes a project funded by the National Institutes of Health (NIH) to define a novel, transdisciplinary methodology for identifying ideal vacant sites for conversion into community clinics in Baltimore's most vulnerable neighborhoods. Positioning architecture as a social determinant of health, this paper suggests ethical and methodological reorientations toward a compassionate approach to clinic design and placement.

Identifying Optimal Locations for Potential Temporary Community Clinics During Public Health Emergencies.

OBJECTIVES: This article argues that community healthcare clinics managed by dedicated medical professionals who are familiar with the special needs of the local community may serve as effective alternatives to centralized hospitals and medical facilities, which may be disconnected from these local communities. BACKGROUND: The literature indicates that socioeconomic factors that affect an individual's ability to seek medical help when needed can cause vulnerability to public health emergencies. These factors include belonging to lower income populations, being African American, being dependent due to age (below 18 or above 65) or disability, being an immigrant, English-language ability, access to transportation means, and the strength of an individual's social network. METHOD: This study aims at developing a multifaceted methodology to identify optimal locations for deployment of temporary healthcare clinics to address health disparity issues among socially vulnerable populations, especially during pandemics and public health crises. This case study looks at the Health Enterprise Zone (HEZ) in Baltimore and ranks Census tracts based on their vulnerability, using two novel health vulnerability indices and considering their locations. RESULTS: Using the proposed methodology, the optimal tracts within the HEZ are identified as potential locations for deploying temporary healthcare clinics. CONCLUSION: The analysis of vulnerabilities to public health emergencies based on socioeconomic factors can assist in identifying potential locations for setting up temporary healthcare clinics with the goal of assisting socially vulnerable populations during outbreaks and pandemics.

How to do it: Splenic flexure mobilisation via medial trans-mesocolic approach.

Complete splenic flexure mobilization is a critical step in left-sided colorectal resections. Surgeons use three approaches-anterior, medial, and lateral-to divide peritoneal ligaments connecting the left colon. The decision to perform mobilization varies, with minimal impact on post-operative outcomes but longer surgery times and rare complications. Pancreatic injury risk is low, though other structures, like arteries and the duodenum, may be at risk. Our video outlines the medial trans-mesocolic approach, with the patient positioned in lithotomy. We expose the duodenal-jejunal flexure, ligate the inferior mesenteric vein, and perform medial to lateral dissection, completing splenic flexure mobilization. This video vignette outlines how to perform this technique for left sided colorectal resections.

Melbourne colorectal collaboration: a multicentre review of the impact of COVID-19 on colorectal cancer in Melbourne, Australia.

BACKGROUND: As coronavirus (COVID-19) cases continue to rise, healthcare workers have been working overtime to ensure that all patients receive care in a timely manner. Our study aims to identify the impact and outcomes of COVID-19 on colorectal cancers presentations across the five major colorectal units in Melbourne, Australia. METHODS: This is a retrospective study from a prospectively collected database from the binational colorectal cancer audit (BCCA) registry, as well as inpatient records. All patients with colorectal cancer between Pre-COVID-19 period (1 July 2018-2030 June 2019) and COVID-19 period (1 July 2020-2030 June 2021) were compared. Benign pathology and other cancer types were excluded. RESULTS: A total of 1609 patients were included in the study (700 Pre-COVID-19 period, 906 COVID-19 period). During COVID-19 period, there was a higher proportion of emergency surgery (28.1% vs. 19.8%; P < 0.001), a higher nodal (P = 0.024) and metastatic stage (P = 0.018) at presentation, but no increase in the rate of return to operating theatres (P = 0.240), inpatient death (P = 0.019) or 30-day readmission (P = 0.000). There was also no difference in the post-operative surgical complications (P = 0.118). Utility of neoadjuvant therapy did not increase during the pandemic (P = 0.613). CONCLUSION: The heightened measures in the healthcare system ensured CRC patients still received their surgery in a timely fashion. With the current rise in the new strain of COVID-19 (Omicron), we have to continue to come up with new strategies to provide timely access to CRC care.

The financial burden of complications following rectal resection: A cohort study.

To investigate the costs associated with postoperative complications following rectal resection.Rectal resection is a major surgical procedure that carries a significant risk of complications. The occurrence of complications following surgery has both health and financial consequences. There are very few studies that examine the incidence and severity of complications and their financial implications following rectal resection.We identified 381 consecutive patients who underwent a rectal resection within a major university hospital. Patients were included using the International Classification of Diseases (ICD) codes. Complications in the postoperative period were reported using the validated Clavien-Dindo classification system. Both the number and severity of complications were recorded. Activity-based costing methodology was used to report financial outcomes. Preoperative results were also recorded and assessed.A 76.9% [95% CI: 68.3:86.2] of patients experienced one or more complications. Patients who had a complication had a median total cost of $22,567 [IQR 16,607:33,641]. Patients who did not have a complication had a median total cost of $15,882 [IQR 12,971:19,861]. The adjusted additional median cost for patients who had a complication was $5308 [95% CI: 2938:7678] (P < .001). Patients who experienced a complication tended to undergo an open procedure (P = .001), were emergent patients (P = .003), preoperatively had lower albumin levels (36 vs 38, P = .0003) and were anemic (P = .001).Complications following rectal resection are common and are associated with increased costs. Our study highlights the importance of evaluating and preventing complications in the postoperative period.

Quality indicators in colonoscopy: an evolving paradigm.

The year 1969 marked a revolution in the diagnosis of colorectal cancer (CRC). It is when Dr Wolff developed the colonoscope and quickly realized its potential in both diagnosis and treatment of colonic neoplasms. Over the past 50 years there has been exponential increase in utilization of colonoscopy with over 1 million colonoscopies performed annually throughout Australasia. Endoscopic removal of pre-malignant lesions has been proven to reduce the incidence and mortality of colorectal. Although timing and frequency of surveillance colonoscopy plays a crucial role in risk reduction of CRC, this is dependent upon the findings of the index colonoscopy. The goal of screening colonoscopy is to detect CRC and identify and remove pre-malignant neoplasms that risk progression to CRC. With increasing uptake of bowel screening throughout Australasia, there is increasing pressure to ensure all endoscopists and endoscopy units perform at a universal high-quality. All too often high demand and constant delays compromise colonoscopy quality. Without clear and concise quality indicators with transparent measurement and audit, these flaws can quickly jeopardize screening goals and patient outcomes. This review aims to explore six key quality indicators and explore the evidence behind the current recommended standards. These key indicators include; rate of adequate bowel preparation, caecal intubation rate, adenoma detection rate, withdrawal time, complication rates and surveillance intervals.

Lhx9 Is Required for the Development of Retinal Nitric Oxide-Synthesizing Amacrine Cell Subtype.

Amacrine cells are the most diverse group of retinal neurons. Various subtypes of amacrine interneurons mediate a vast majority of image forming and non-image forming visual functions. The transcriptional regulation governing the development of individual amacrine cell subtypes is not well understood. One such amacrine cell subtype comprises neuronal nitric oxide synthase (nNOS/bNOS/NOS1)-expressing amacrine cells (NOACs) that regulate the release of nitric oxide (NO), a neurotransmitter with physiological and clinical implications in the retina. We have identified the LIM-homeodomain transcription factor LHX9 to be necessary for the genesis of NOACs. During retinal development, NOACs express Lhx9, and Lhx9-null retinas lack NOACs. Lhx9-null retinas also display aberrations in dendritic stratification at the inner plexiform layer. Our cell lineage-tracing studies show that Lhx9-expressing cells give rise to both the GAD65 and GAD67 expressing sub-populations of GABAergic amacrine cells. As development proceeds, Lhx9 is downregulated in the GAD65 sub-population of GABAergic cells and is largely restricted to the GAD67 sub-population of amacrine cells that NOACs are a part of. Taken together, we have uncovered Lhx9 as a new molecular marker that defines a subset of amacrine cells and show that it is necessary for the development of the NOAC subtype of amacrine cells.

A Derivation and Validation Study of an Early Blood Transfusion Needs Score for Severe Trauma Patients.

BACKGROUND: There is no existing adequate blood transfusion needs determination tool that Emergency Medical Services (EMS) personnel can use for prehospital blood transfusion initiation. In this study, a simple and pragmatic prehospital blood transfusion needs scoring system was derived and validated. METHODS: Local trauma registry data were reviewed retrospectively from 2004 through 2013. Patients were randomly assigned to derivation and validation cohorts. Multivariate logistic regression was used to identify the independent approachable risks associated with early blood transfusion needs in the derivation cohort in which a scoring system was derived. Sensitivity, specificity, and area under the receiver operational characteristic (AUC) were calculated and compared using both the derivation and validation data. RESULTS: A total of 24,303 patients were included with 12,151 patients in the derivation and 12,152 patients in the validation cohorts. Age, penetrating injury, heart rate, systolic blood pressure, and Glasgow coma scale (GCS) were risks predictive of early blood transfusion needs. An early blood transfusion needs score was derived. A score > 5 indicated risk of early blood transfusion need with a sensitivity of 83% and a specificity of 80%. A sensitivity of 82% and a specificity of 80% were also found in the validation study and their AUC showed no statistically significant difference (AUC of the derivation = 0.87 versus AUC of the validation = 0.86, P > 0.05). CONCLUSIONS: An early blood transfusion scoring system was derived and internally validated to predict severe trauma patients requiring blood transfusion during prehospital or initial emergency department resuscitation.

Generation and characterization of Lhx9-GFPCreER(T2) knock-in mouse line.

LHX9 is a LIM-homeodomain transcription factor essential for the development of gonads, spinal cord interneurons, and thalamic neurons to name a few. We recently reported the expression of LHX9 in retinal amacrine cells during development. In this study, we generated an Lhx9-GFPCreER(T) (2) (GCE) knock-in mouse line by knocking-in a GCE cassette at the Lhx9 locus, thus inactivating endogenous Lhx9. Lhx9(GCE) (/+) mice were viable, fertile, and displayed no overt phenotypical characteristics. Lhx9(GCE) (/) (GCE) mice were all phenotypically female, smaller in size, viable, but infertile. The specificity and efficacy of the Lhx9-GCE mouse line was verified by crossing it to a Rosa26-tdTomato reporter mouse line, which reveals the Cre recombinase activities in retinal amacrine cells, developing limbs, testis, hippocampal neurons, thalamic neurons, and cerebellar neurons. Taken together, the Lhx9-GCE mouse line could serve as a beneficial tool for lineage tracing and gene manipulation experiments. genesis

Expression of LIM-homeodomain transcription factors in the developing and mature mouse retina.

LIM-homeodomain (LIM-HD) transcription factors have been extensively studied for their role in the development of the central nervous system. Their function is key to several developmental events like cell proliferation, differentiation and subtype specification. However, their roles in retinal neurogenesis remain largely unknown. Here we report a detailed expression study of LIM-HD transcription factors LHX9 and LHX2, LHX3 and LHX4, and LHX6 in the developing and mature mouse retina using immunohistochemistry and in situ hybridization techniques. We show that LHX9 is expressed during the early stages of development in the retinal ganglion cell layer and the inner nuclear layer. We also show that LHX9 is expressed in a subset of amacrine cells in the adult retina. LHX2 is known to be expressed in retinal progenitor cells during development and in Müller glial cells and a subset of amacrine cells in the adult retina. We found that the LHX2 subset of amacrine cells is not cholinergic and that a very few of LHX2 amacrine cells express calretinin. LHX3 and LHX4 are expressed in a subset of bipolar cells in the adult retina. LHX6 is expressed in cells in the ganglion cell layer and the neuroblast layer starting at embryonic stage 13.5 (E13.5) and continues to be expressed in cells in the ganglion cell layer and inner nuclear layer, postnatally, suggesting its likely expression in amacrine cells or a subset thereof. Taken together, our comprehensive assay of expression patterns of LIM-HD transcription factors during mouse retinal development will help further studies elucidating their biological functions in the differentiation of retinal cell subtypes.

Second primary colorectal cancer in the era of prevalent screening and imaging.

BACKGROUND: Oncology literature is increasingly recognizing prevalence of second primary cancers including several longitudinal studies showing an increased risk of colorectal cancer following a prostate cancer diagnosis. A retrospective study was conducted to examine the relationship between prior prostate cancer diagnoses and subsequent colorectal cancer diagnoses. METHODS: A multi-centre prospective colorectal cancer registry was queried for patients with a prior history of prostate, breast or lung cancer. Characteristics of these patients were compared to patients with colorectal cancer and no prior cancer history. RESULTS: Of 4660 cases of colorectal cancer diagnosed between 1998 and 2011, 2665 (57.2%) were male, median age was 68 years. For patients with a history of prostate cancer (n = 111), breast cancer (n = 61) and lung cancer (n = 23), the great majority of subsequent colorectal cancer diagnoses occurred in the initial 2 to 4 years after the first cancer diagnosis. This was accompanied by an increased rate of asymptomatic colorectal cancer at presentation, due to both screen detected and incidental cancer diagnoses. There was no clear relationship between any prostate cancer treatment and subsequent colorectal cancer risk, location or timing. DISCUSSION: In the modern era, there is an increased rate of colorectal cancer diagnosis in years shortly following another common cancer history. This is consistently seen across different primary tumour streams including prostate, breast and lung cancers and in part contributed by screen detected and incidental colorectal cancer diagnoses. Future studies should consider this potential confounding factor when asserting an increased rate of colorectal cancer as a second primary cancer.

Pretreatment transcriptional profiling for predicting response to neoadjuvant chemoradiotherapy in rectal adenocarcinoma.

PURPOSE: Patients presenting with locally advanced rectal cancer currently receive preoperative radiotherapy with or without chemotherapy. Although pathologic complete response is achieved for approximately 10% to 30% of patients, a proportion of patients derive no benefit from this therapy while being exposed to toxic side effects of treatment. Therefore, there is a strong need to identify patients who are unlikely to benefit from neoadjuvant therapy to help direct them toward alternate and ultimately more successful treatment options. EXPERIMENTAL DESIGN: In this study, we obtained expression profiles from pretreatment biopsies for 51 rectal cancer patients. All patients underwent preoperative chemoradiotherapy, followed by resection of the tumor 6 to 8 weeks posttreatment. Gene expression and response to treatment were correlated, and a supervised learning algorithm was used to generate an original predictive classifier and validate previously published classifiers. RESULTS: Novel predictive classifiers based on Mandard's tumor regression grade, metabolic response, TNM (tumor node metastasis) downstaging, and normal tissue expression profiles were generated. Because there were only 7 patients who had minimal treatment response (>80% residual tumor), expression profiles were used to predict good tumor response and outcome. These classifiers peaked at 82% sensitivity and 89% specificity; however, classifiers with the highest sensitivity had poor specificity, and vice versa. Validation of predictive classifiers from previously published reports was attempted using this cohort; however, sensitivity and specificity ranged from 21% to 70%. CONCLUSIONS: These results show that the clinical utility of microarrays in predictive medicine is not yet within reach for rectal cancer and alternatives to microarrays should be considered for predictive studies in rectal adenocarcinoma.