Uncommon Sociodemographic Factors Are Associated With Racial Disparities in Length of Stay Following Oncologic Elective Colectomy.

INTRODUCTION: Although outcome disparities by race have been identified in colorectal cancer, these patterns are challenging to explain using variables that are commonly available in databases. In a single institution serving a diverse community, length of stay (LOS) varies by race following elective oncologic colectomy. We investigated previously unexplored variables that may explain the relationship between race and LOS following elective resection of colorectal neoplasms. METHODS: Retrospective, single institution cohort study from January 2015 to December 2020 for adult patients undergoing elective colorectal cancer resections. Baseline demographic variables and intraoperative factors were analyzed for changes in LOS following elective colorectal resection. Additional retrospective chart review was carried out to determine household member composition and distance from home to hospital. Bivariate analysis was conducted to determine which variables should be included in multivariable analyses. All analyses were conducted using SAS Academic. RESULTS: Most patients (n = 383) were Asian (40%), Black (12%), or Hispanic (26%). Race and LOS were associated with age (P = 0.001 and P < 0.001 for race and LOS, respectively), American Society of Anesthesiologists class (P = 0.004 and P < 0.001), enhanced recovery after surgery protocols (P = 0.006 and P < 0.001), household members (P = 0.009 and P = 0.002), and discharge disposition (P = 0.049 and P < 0.001). In multivariable analysis, household members (P = 0.021) independently remained associated with LOS after controlling for race (P = 0.008) and discharge disposition (P < 0.001). CONCLUSIONS: Household member composition varies with LOS, suggesting that level of support at home may influence decisions regarding discharge disposition, which lead to differences in LOS.

SAGES guidelines for the use of laparoscopy during pregnancy.

BACKGROUND: When pregnant patients present with nonobstetric pathology, the physicians caring for them may be uncertain about the optimal management strategy. The aim of this guideline is to develop evidence-based recommendations for pregnant patients presenting with common surgical pathologies including appendicitis, biliary disease, and inflammatory bowel disease (IBD). METHODS: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Guidelines Committee convened a working group to address these issues. The group generated five key questions and completed a systematic review and meta-analysis of the literature. An expert panel then met to form evidence-based recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation approach. Expert opinion was utilized when the available evidence was deemed insufficient. RESULTS: The expert panel agreed on ten recommendations addressing the management of appendicitis, biliary disease, and IBD during pregnancy. CONCLUSIONS: Conditional recommendations were made in favor of appendectomy over nonoperative treatment of appendicitis, laparoscopic appendectomy over open appendectomy, and laparoscopic cholecystectomy over nonoperative treatment of biliary disease and acute cholecystitis specifically. Based on expert opinion, the panel also suggested either operative or nonoperative treatment of biliary diseases other than acute cholecystitis in the third trimester, endoscopic retrograde cholangiopancreatography rather than common bile duct exploration for symptomatic choledocholithiasis, applying the same criteria for emergent surgical intervention in pregnant and non-pregnant IBD patients, utilizing an open rather than minimally invasive approach for pregnant patients requiring emergent surgical treatment of IBD, and managing pregnant patients with active IBD flares in a multidisciplinary fashion at centers with IBD expertise.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Outcomes of a Colorectal Enhanced Recovery After Surgery Protocol Modified for a Diverse and Urban Community.

INTRODUCTION: Enhanced recovery after surgery (ERAS) colorectal programs have been shown to improve the length of stay (LOS) without increasing hospital resource utilization at academic centers worldwide. A multidisciplinary ERAS protocol that includes preoperative, intraoperative, and postoperative management guidelines was recently implemented at our urban, racially diverse, and academically affiliated community hospital. A delivery option was provided to reduce barriers to care. Given our unique patient population, the objective of our study was to determine if improvements in outcomes were reproducible in our hospital. METHODS: This is a retrospective study of patients undergoing elective colectomy at New York-Presbyterian Queens Hospital between January 1, 2015, and December 31, 2020. Patient outcomes were compared between surgeries performed under standard practice (all colectomies prior to April 2017) and those performed after the implementation of the ERAS protocol. Demographic and perioperative data were abstracted from a prospectively derived database used to submit data to the National Surgical Quality Improvement Program. Additional data were obtained from chart review. RESULTS: Six hundred five elective colectomies were performed by 12 surgeons (range 1-228 cases) during the study period. Of these, 22 were performed open (41% followed ERAS), 467 were performed laparoscopically (57% followed ERAS), and 116 were performed robotically (74% followed ERAS). The average patient age was 64 y. Of which, 55% were male; 34% were Asian, 27% were non-Hispanic Caucasian, 27% were Hispanic, and 11% were Black or African American (all P-values > 0.05 for ERAS versus non-ERAS). Average duration of procedure was longer in the ERAS group (262 min versus 243 min, P = 0.04), although when stratified by procedure type, this relationship held true only for laparoscopic procedures. Hospital LOS was significantly shorter in the ERAS group (4.3 versus 5.4 d, P < 0.001) and this relationship held true for procedures performed both laparoscopically (4.2 versus 5.3 d, P = 0.01) and robotically (4.1 versus 5.1 d, P = 0.04). Of the ERAS group, patients who opted for delivery of ERAS components (n = 205) had the shortest LOS when compared to patients who picked up components (n = 91) or opted out of ERAS (n = 309) (4.1 versus 4.4 versus 5.2 d, P = 0.003). No significant differences were found for 30-d mortality, 30-d readmission, wound infection, or other postoperative complications (all P-values > 0.05). CONCLUSIONS: Implementation of an ERAS protocol in an urban, diverse, academically affiliated community hospital is associated with reductions in LOS for colectomies performed both laparoscopically and robotically. Facilitating ERAS compliance with a delivery option was also associated with improvements in hospital LOS. Preoperative nutrition supplementation was not associated with outcomes. No differences in mortality, readmission rates, or rates of postoperative complications were found.

Operative Management of Acute Appendicitis Was Safe During the COVID-19 Pandemic Shutdown.

INTRODUCTION: In the spring of 2020, New York City was one of the first epicenters of the COVID outbreak. In this study, we evaluate the incidence and treatment of appendicitis in two New York City community hospitals during the COVID pandemic. METHODS: This retrospective study focused on the incidence and outcome of acute appendicitis in the adult population (>18 y old) during peak-COVID periods (March 16, 2020,-June 15, 2020) compared to pre-COVID and post-COVID periods. We compared the number of patients who underwent operative versus nonoperative management, patient demographics, length of stay (LOS), complications, and readmission rates within these time periods. Data are presented as mean ± standard deviation (analysis of variance). RESULTS: From January 1, 2020 to December 31, 2020, 393 patients presented with acute appendicitis and 321 (81.7%) were treated operatively, compared to 441 total and 366 treated operatively (83%) in 2019 (P = 0.88). During the COVID outbreak, fewer patients presented with appendicitis (mean 6.9 ± 1 pre-COVID case/week, 4.4 ± 2.4 peak-COVID cases/week and 7.6 ± 0.65 post-COVID cases/week, P = 0.018) with no significant difference in the pre-COVID and post-COVID period. There was no difference in LOS between the pre-, peak-, and post-COVID periods with a median of 1 for all the three, (interquartile range (IQR): 0.8-2, 0.6-2, 0.6-2, respectively, P = 0.43). Additionally, there was no difference in 30-day readmission rates (4.2%, 0%, 3.9%, P = 0.99) and postoperative complications (4.2%, 0%, 2.9%, P = 0.98). CONCLUSIONS: During peak-COVID, there was a significant reduction in the number of patients who presented with acute appendicitis without a post rebound increase in presentation. Those who presented during peak-COVID were able to undergo operative management safely, without affecting LOS or postoperative complications.

Multi-society consensus conference and guideline on the treatment of gastroesophageal reflux disease (GERD).

BACKGROUND: Gastroesophageal reflux disease (GERD) is one of the most common diseases in North America and globally. The aim of this guideline is to provide evidence-based recommendations regarding the most utilized and available endoscopic and surgical treatments for GERD. METHODS: Systematic literature reviews were conducted for 4 key questions regarding the surgical and endoscopic treatments for GERD in adults: preoperative evaluation, endoscopic vs surgical or medical treatment, complete vs partial fundoplication, and treatment for obesity (body mass index [BMI] ≥ 35 kg/m2) and concomitant GERD. Evidence-based recommendations were formulated using the GRADE methodology by subject experts. Recommendations for future research were also proposed. RESULTS: The consensus provided 13 recommendations. Through the development of these evidence-based recommendations, an algorithm was proposed for aid in the treatment of GERD. Patients with typical symptoms should undergo upper endoscopy, manometry, and pH-testing; additional testing may be required for patients with atypical or extra-esophageal symptoms. Patients with normal or abnormal findings on manometry should consider undergoing partial fundoplication. Magnetic sphincter augmentation or fundoplication are appropriate surgical procedures for adults with GERD. For patients who wish to avoid surgery, the Stretta procedure and transoral incisionless fundoplication (TIF 2.0) were found to have better outcomes than proton pump inhibitors alone. Patients with concomitant obesity were recommended to undergo either gastric bypass or fundoplication, although patients with severe comorbid disease or BMI > 50 should undergo Roux-en-Y gastric bypass for the additional benefits that follow weight loss. CONCLUSION: Using the recommendations an algorithm was developed by this panel, so that physicians may better counsel their patients with GERD. There are certain patient factors that have been excluded from included studies/trials, and so these recommendations should not replace surgeon-patient decision making. Engaging in the identified research areas may improve future care for GERD patients.

Osteoimmunology in Periodontitis and Orthodontic Tooth Movement.

PURPOSE OF REVIEW: To review the role of the immune cells and their interaction with cells found in gingiva, periodontal ligament, and bone that leads to net bone loss in periodontitis or bone remodeling in orthodontic tooth movement. RECENT FINDINGS: Periodontal disease is one of the most common oral diseases causing inflammation in the soft and hard tissues of the periodontium and is initiated by bacteria that induce a host response. Although the innate and adaptive immune response function cooperatively to prevent bacterial dissemination, they also play a major role in gingival inflammation and destruction of the connective tissue, periodontal ligament, and alveolar bone characteristic of periodontitis. The inflammatory response is triggered by bacteria or their products that bind to pattern recognition receptors that induce transcription factor activity to stimulate cytokine and chemokine expression. Epithelial, fibroblast/stromal, and resident leukocytes play a key role in initiating the host response and contribute to periodontal disease. Single-cell RNA-seq (scRNA-seq) experiments have added new insight into the roles of various cell types in the response to bacterial challenge. This response is modified by systemic conditions such as diabetes and smoking. In contrast to periodontitis, orthodontic tooth movement (OTM) is a sterile inflammatory response induced by mechanical force. Orthodontic force application stimulates acute inflammatory responses in the periodontal ligament and alveolar bone stimulated by cytokines and chemokines that produce bone resorption on the compression side. On the tension side, orthodontic forces induce the production of osteogenic factors, stimulating new bone formation. A number of different cell types, cytokines, and signaling/pathways are involved in this complex process. Inflammatory and mechanical force-induced bone remodeling involves bone resorption and bone formation. The interaction of leukocytes with host stromal cells and osteoblastic cells plays a key role in both initiating the inflammatory events as well as inducing a cellular cascade that results in remodeling in orthodontic tooth movement or in tissue destruction in periodontitis.

SAGES 2022 guidelines regarding the use of laparoscopy in the era of COVID-19.

BACKGROUND: SARS-CoV-2 has changed global healthcare since the pandemic began in 2020. The safety of minimally invasive surgery (MIS) utilizing insufflation from the standpoint of safety to the operating room personnel is currently being explored. The aims of this guideline are to examine the existing evidence to provide guidance regarding MIS for the patient with, or suspecting of having, the SARS-CoV-2 as well as the healthcare team involved. METHODS: Systematic literature reviews were conducted for 2 key questions (KQ) regarding the safety of MIS in the setting of COVID-19 pandemic. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis criteria. Evidence-based recommendations were formulated using a narrative synthesis of the literature by subject experts. Recommendations for future research were also proposed. RESULTS: In KQ1, a total of 1361 articles were reviewed, with 2 articles meeting inclusion. In KQ2, a total of 977 articles were reviewed, with 4 articles met inclusions criteria, of which 2 studies reported on the SARS-CoV2 virus specifically. Despite many publications in the field, very little well-controlled and unbiased data exist to inform the recommendations. Of that which is available, it shows that both laparoscopic and open operations in Covid-positive patients had similar rates of OR staff positivity rates; however, patients who underwent laparoscopic procedures had a lower perioperative mortality than open procedures. Also, SARS-CoV-2 particles have been detected in the surgical plume at laparoscopy. CONCLUSION: With demonstrated equivalence of operating room staff exposure, and noninferiority of laparoscopic access with respect to mortality, either laparoscopic or open approaches to abdominal operations may be used in patients with SARS-CoV-2. Measures should be employed for all laparoscopic or open cases to prevent exposure of operating room staff to the surgical plume, as virus can be present in this plume.

Research in Brief: Survey of hair care practices in various ethnic and racial pediatric populations.

Medicated shampoos are part of the standard care of seborrheic dermatitis (SD), yet hair-washing practices can vary in frequency, which could impact treatment effectiveness and therapeutic benefit. The goal of this study is to understand common hair-washing practices in pediatric patients, with focus on Black children with SD, through online survey. Patients identifying as Black or mixed race were more likely to use medicated washes weekly or less frequently than White patients (62.5% vs. 30.8%). It is important that clinicians understand Black- and mixed-race hair care practices to provide better clinical guidance on the usage of medicated shampoos, especially for the treatment of SD.

Review of the diagnosis and management of pediatric psychodermatologic conditions: Part I.

Pediatric psychodermatologic conditions encompass both primary dermatologic conditions with psychiatric comorbidities and primary psychiatric conditions with self-induced dermatologic manifestations. Detection, diagnosis, and management of primary psychiatric conditions with dermatologic manifestations are challenging due to patient-perceived stigma and lack of educational opportunities for dermatology providers. This two-part series highlights the most up-to-date evidence-based data and management techniques of some of the more common dermatoses of primary psychiatric conditions in children. Part I includes trichotillomania, skin-picking disorder, and onychophagia, and part II covers dermatitis artefacta, body dysmorphic disorder, and delusions of parasitosis by proxy, with special considerations for family dynamics.

A review of the diagnosis and management of pediatric psychodermatologic conditions: Part II.

Pediatric psychodermatologic conditions encompass both primary dermatologic conditions with psychiatric comorbidities and primary psychiatric conditions with self-induced dermatologic manifestations. Detection, diagnosis, and management of primary psychiatric conditions with dermatologic manifestations are challenging due to patient-perceived stigma and lack of educational opportunities for dermatology providers. This two-part series highlights the most up-to-date evidence-based data and management techniques of some of the more common dermatoses of primary psychiatric conditions in children. Part I includes trichotillomania, skin picking disorder, and onychophagia, and part II covers dermatitis artefacta, body dysmorphic disorder, and delusions of parasitosis by proxy, with special considerations for family dynamics.

National Cancer Institute support for targeted alpha-emitter therapy.

BACKGROUND: Radiopharmaceutical targeted therapy (RPT) has been studied for decades; however, recent clinical trials demonstrating efficacy have helped renewed interest in the modality. METHODS: This article reviews National Cancer Institute (NCI)'s support of RPT through communication via workshops and interest groups, through funding extramural programs in academia and small business, and through intramural research, including preclinical and clinical studies. RESULTS: NCI has co-organized workshops and organized interest groups on RPT and RPT dosimetry to encourage the community and facilitate rigorous preclinical and clinical studies. NCI has been supporting RPT research through various mechanisms. Research has been funded through peer-reviewed NCI Research and Program Grants (RPG) and NCI Small Business Innovation Research (SBIR) Development Center, which funds small business-initiated projects, some of which have led to clinical trials. The NCI Cancer Therapy Evaluation Program (CTEP)'s Radiopharmaceutical Development Initiative supports RPT in NCI-funded clinical trials, including Imaging and Radiation Oncology Core (IROC) expertise in imaging QA and dosimetry procedures. Preclinical targeted a-emitter therapy (TAT) research at the NCI's intramural program is ongoing, building on foundational work dating back to the 1980s. Ongoing "bench-to-bedside" efforts leverage the unique infrastructure of the National Institutes of Health's (NIH) Clinical Center. CONCLUSION: Given the great potential of RPT, our goal is to continue to encourage its development that will generate the high-quality evidence needed to bring this multidisciplinary treatment to patients.

Pregnant patients requiring appendectomy: comparison between open and laparoscopic approaches in NY State.

INTRODUCTION: Even though acute appendicitis is the most common general surgical condition encountered during pregnancy, the preferred approach to appendectomy in pregnant patients remains controversial. Current guidelines support laparoscopic appendectomy as the treatment of choice for pregnant women with appendicitis, regardless of trimester. However, recent published data suggests that the laparoscopic approach contributes to higher rates of fetal demise. Our study aims to compare laparoscopic and open appendectomy in pregnancy at a statewide population level. METHODS: ICD-9 codes were used to extract 1006 pregnant patients undergoing appendectomy between 2005 and 2014 from the NY Statewide Planning and Research Cooperative System (SPARCS) database. Surgical outcomes (any complications, 30-day readmission rate, length of stay (LOS)) and obstetrical outcomes (antepartum hemorrhage, preterm delivery, cesarean section, sepsis, chorioamnionitis) were compared between open and laparoscopic appendectomy. Multivariable generalized linear regression models were used to compare different outcomes between two surgical approaches after adjusting for possible confounders. RESULTS: The laparoscopic cohort (n = 547, 54.4%) had significantly shorter LOS than the open group (median ± IQR: 2.00 ± 2.00 days versus 3.00 ± 2.00 days, p value < 0.0001, ratio = 0.789, 95% CI 0.727-0.856). Patients with complicated appendicitis had longer LOS than those with simple appendicitis (p value < 0.0001, ratio = 1.660, 95% CI 1.501-1.835). Obstetrical outcomes (p value = 0.097, OR 1.254, 95% CI 0.961-1.638), 30-day non-delivery readmission (p value = 0.762, OR 1.117, 95% CI 0.538-2.319), and any complications (p value = 0.753, OR 0.924, 95% CI 0.564-1.517) were not statistically significant between the laparoscopic versus open appendectomy groups. Three cases of fetal demise occurred, all within the laparoscopic appendectomy group. CONCLUSIONS: The laparoscopic approach resulted in a shorter LOS. Although fetal demise only occurred in the laparoscopic group, these results were not significant (p value = 0.255). Our large population-based study further supports current guidelines that laparoscopic appendectomy may offer benefits over open surgery for pregnant patients in any trimester due to reduced time in the hospital and fetal and maternal outcomes comparable to open appendectomy.

Considering delay of cholecystectomy in the third trimester of pregnancy.

INTRODUCTION: Current guidelines support laparoscopic cholecystectomy as the treatment of choice for pregnant women with symptomatic gallbladder disease, regardless of the trimester. Early intervention has remained the standard of care, but recent evidence has challenged this practice in pregnant women. We sought to compare surgical and maternal-fetal outcomes of antepartum versus postpartum cholecystectomy in New York State. METHODS: Between 2005 and 2014, the New York Statewide Planning and Research Cooperative System (SPARCS) database was queried for patients who underwent cholecystectomy within 3 months before (antepartum cholecystectomy, APCCY: n = 82) and after (postpartum cholecystectomy, PPCCY: n = 5040) childbirth to approximate third-trimester operations. All patients who underwent cholecystectomy during pregnancy (n = 971) were extracted to evaluate inter-trimester differences. Subgroup analysis compared APCCY patients who were not hospitalized within 1 year before APCCY (n = 80) and PPCCY patients who were hospitalized within 1 year before childbirth (n = 29) for symptomatic biliary disease. Multivariable generalized linear regression models were used to characterize the association between timing of cholecystectomy and several primary outcomes: length of stay (LOS), 30-day non-pregnancy, non-delivery readmission (NPND), bile duct injury (BDI), composite maternal outcome (antepartum hemorrhage, preterm delivery, cesarean section), any complications, and fetal demise. RESULTS: Third-trimester APCCY women had longer LOS (Ratio: 1.44, 95% CI [1.26-1.66], p < 0.0001) and greater incidence of preterm delivery (OR 2.54, 95% CI [1.37-4.43], p = 0.0019). Cholecystectomy timing was not independently associated with differences in composite maternal outcome (p = 0.1480), BDI (p = 0.2578), 30-day NPND readmission (p = 0.7579), any complications (p = 0.2506), and fetal demise (2.44% versus 0.44%, p = 0.0545). Subgroup analysis revealed no differences in any of the seven outcomes. CONCLUSIONS: New York Statewide data suggest that although laparoscopic cholecystectomy is safe in pregnancy, delay of cholecystectomy should be discussed in the third trimester due to an increased risk for preterm delivery.

Cultural and biological factors in body dysmorphic disorder in East Asia.

Body dysmorphic disorder (BDD) can cause severe distress and impairment in many important areas of functioning. Although BDD has been well studied in Western populations, there is limited information on BDD in other cultures. In this review, we discuss the prevalence and presentation of BDD in East Asian countries and the significance of conducting further research in this particular group.

Innovations in translational research in dermatology: minimally invasive methods for biosample acquisition.

Translational research has improved patient care over the last decade. In dermatology, this research often requires human tissue for laboratory analysis. The skin biopsy remains the gold standard for tissue acquisition, but the procedure comes with a small risk of bleeding and infection. It also causes scarring and anxiety in certain populations. These risks and concerns may affect participation rates in translational studies, which can require multiple biopsies. Minimally invasive procedures may mitigate these risks and concerns. We queried the PubMed database for all minimally invasive technologies studied as of May 2021. Of the 53 articles reviewed, we identified 13 unique, minimally invasive methods for tissue biosample acquisition. Herein, we describe each sampling method, biosample type analyzed, disease target, molecular application, procedure, quantity of obtained biosample, purpose, and required equipment. We organize this information into a comprehensive chart. We then synthesize this information into another table that compares the pros and cons of each intervention. We found that tape stripping, suction blistering, hair plucking, microbiopsy, and microneedle patching provide a variety of useful biosample types for laboratory analysis. In translational research, these technologies have the potential to replace more invasive methods like the punch biopsy, likely improving participation in studies.

Off-label uses of TNF-a inhibitors and IL-12/23 inhibitors in dermatology.

TNF-a inhibitors, which include adalimumab, infliximab, etanercept, certolizumab, and golimumab, and IL-12/23 inhibitor, ustekinumab, have been widely used as a U.S. Food and Drug Administration (FDA) approved for the treatment of psoriasis. Outside of psoriasis, high levels of TNF-a had also been found in several skin diseases including hidradenitis suppurativa. IL-12 and IL-23 play important role in the pathogenesis of SLE, alopecia areata, and vitiligo. This paper reviews the off-label uses of TNF-a inhibitors and IL-12/23 inhibitors in skin disorders.

Severe Hepatotoxicity of Mithramycin Therapy Caused by Altered Expression of Hepatocellular Bile Transporters.

Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; P < 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter α/ß) in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P < 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity (P < 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P < 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a novel mechanism of drug-induced hepatotoxicity in which mithramycin not only alters farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibits bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies.

CD38 knockout suppresses tumorigenesis in mice and clonogenic growth of human lung cancer cells.

The ectodomain of the plasma membrane ectoenzyme CD38 functions as both an NAD glycohydrolase and an ADP-ribosyl cyclase by catalyzing, respectively, the conversion of NAD to nicotinamide and ADP-ribose or cyclic ADP-ribose. CD38 is attracting particular attention in cancer therapy. An anti-CD38 monoclonal antibody (daratumumab) was approved for treatment of patients with multiple myeloma. However, the role of CD38 in non-hematological malignancies has not been explored. Previously, we reported that ADP-ribose-acceptor hydrolase (ARH)-1 deficiency in mice was associated with tumor development. In the present study, we found that in wild-type and ARH1-deficient mice deletion of the CD38 gene reduced tumor formation. Significant reductions in tumor number were observed in lymphomas, adenocarcinomas and hemangio/histolytic sarcomas. Consistent with a role for CD38 in tumorigenesis, CRISPR/Cas9-based knockout of CD38 in A549 human adenocarcinoma cells inhibited anchorage-independent cell growth, cell invasion and xenograft growth in nude mice. CD38 mRNA and protein expression were evaluated in human lung cancer cell lines and in human lung cancer specimens. CD38 overexpression in tumor cells was identified in 11 of 27 patient samples. In addition, some human lung cancer cell lines had dramatically higher CD38 mRNA and protein expression than normal cells. Consistent with these observations, search of the Oncomine database showed that some human lung adenocarcinomas had higher CD38 mRNA levels compared to normal lung tissues. In total, our data are consistent with the conclusion that CD38 plays a role in murine and human lung tumorigenesis and that anti-CD38 treatment may have therapeutic potential in lung cancer.