An unusual case of giant jejunal diverticula presenting radiologically as toxic megacolon.

Jejunal diverticulosis is an uncommon entity of the gastrointestinal tract. It involves the presence of multiple diverticula (pouches) in the jejunal wall. Jejunal diverticulosis is not so common, and the epidemiology is ill defined, but usually, it is known to affect the elderly more. They are considered from a pathophysiological point of view as motility disorders, structural defects, or high intraluminal pressures, with the result of prolapse of the mucosa of the jejunum through weak points of the intestinal wall. It represents a rare entity with different clinical presentations, ranging from being asymptomatic to life-threatening complications such as obstruction, bleeding, or perforation. Treatment depends on the presentation and can be conservative or surgical management.

Unique multidisciplinary approach in a patient with small bowel obstruction and chronic mesenteric ischemia.

Management of small bowel obstruction (SBO) in patients with symptomatic chronic mesenteric ischemia is a phenomenon that has not been previously described in the literature. This is an index case report describing the utilization of a multidisciplinary approach in a patient that suffered from SBO from cecal perforation with history of chronic mesenteric ischemia attributed to superior mesenteric artery (SMA) and celiac trunk stenosis. The patient was a 70-year-old female with recent diagnosis of ischemic colitis and chronic mesenteric ischemia, found to have high-grade SBO with transition point in the right lower quadrant. Computerized tomography angiogram showed occluded SMA, and severe celiac artery stenosis. Interventional radiology revascularized the celiac trunk with stent placement prior to right hemicolectomy for management of her high-grade SBO. Prospective research should ascertain whether revascularization indeed leads to improved post-operative outcomes.

The Effect of Osseodensification on Ridge Expansion, Intraosseous Temperature, and Primary Implant Stability: A Pilot Study on Bovine Ribs.

Osseodensification is a novel technique based on nonsubtractive drilling to preserve and condense bone during osteotomy preparation. The aim of this ex vivo study was to compare osseodensification and conventional extraction drilling technique with regard to intraosseous temperatures, expansion of alveolar ridge width, and primary implant stability using different implant geometries: tapered and straight walled. A total of 45 implant sites were prepared in bovine ribs following osseodensification and conventional protocols. Changes in intraosseous temperatures were recorded at 3 depths using thermocouples, and ridge width was measured at 2 different depths before and after osseodensification preparations. The primary implant stability was measured using peak insertion torque and the implant stability quotient (ISQ) following placement of straight and tapered implants. A significant change in temperature was recorded during site preparation for all techniques tested but not at all depths. Osseodensification recorded higher mean temperatures (42.7°C) than conventional drilling, particularly at the midroot level. Statistically significant ridge expansion was observed at both the crestal and apical levels in the osseodensification group. The ISQ values were significantly higher only for tapered implants placed in osseodensification sites when compared with conventional drilling sites; however, there was no difference in the primary stability between tapered and straight implants within the osseodensification group. Within the limitations of the present pilot study, osseodensification was found to increase the primary stability of straight-walled implants without overheating the bone and significantly expanded the ridge width. However, further investigation is required to determine the clinical significance of the bone expansion created by this new technique.

Cutaneous eruptions from ibrutinib resembling epidermal growth factor receptor inhibitor-induced dermatologic adverse events.

BACKGROUND: Ibrutinib is an oral inhibitor of Bruton tyrosine kinase that is approved by the United States Food and Drug Administration for several lymphoproliferative disorders and chronic graft-versus-host disease. OBJECTIVE: To characterize cutaneous eruptions arising from ibrutinib and highlight overlap with epidermal growth factor receptor (EGFR) inhibitor-induced dermatologic adverse events. METHODS: Single-center retrospective cohort of patients referred to the Skin Toxicities Program for treatment of cutaneous eruptions while taking ibrutinib. RESULTS: Among 19 patients, cutaneous eruptions manifested as facial-predominant papulopustular eruptions, petechiae, or ecchymoses, photosensitivity, panniculitis, xerosis, and clinical staphylococcal overgrowth. Most patients were able to continue ibrutinib therapy with focused treatment of their cutaneous toxicities. LIMITATIONS: This study represents cases at a single tertiary care center and is limited to patients referred for toxicity. CONCLUSIONS: With the exception of petechiae, the cutaneous toxicities of ibrutinib overlap with those associated with selective EGFR inhibitors. We observed that these reactions can be successfully managed using approaches for EGFR inhibitor-induced cutaneous adverse events.

DiPODS: A Reagent for Site-Specific Bioconjugation via the Irreversible Rebridging of Disulfide Linkages.

Chemoselective reactions with thiols have long held promise for the site-specific bioconjugation of antibodies and antibody fragments. Yet bifunctional probes bearing monovalent maleimides-long the "gold standard" for thiol-based ligations-are hampered by two intrinsic issues: the in vivo instability of the maleimide-thiol bond and the need to permanently disrupt disulfide linkages in order to facilitate bioconjugation. Herein, we present the synthesis, characterization, and validation of DiPODS, a novel bioconjugation reagent containing a pair of oxadiazolyl methyl sulfone moieties capable of irreversibly forming covalent bonds with two thiolate groups while simultaneously rebridging disulfide linkages. The reagent was synthesized from commercially available starting materials in 8 steps, during which rotamers were encountered and investigated both experimentally and computationally. DiPODS is designed to be modular and can thus be conjugated to any payload through a pendant terminal primary amine (DiPODS-PEG4-NH2). Subsequently, the modification of a HER2-targeting Fab with a fluorescein-conjugated variant of DiPODS (DiPODS-PEG4-FITC) reinforced the site-specificity of the reagent, illustrated its ability to rebridge disulfide linkages, and produced an immunoconjugate with in vitro properties superior to those of an analogous construct created using traditional stochastic bioconjugation techniques. Ultimately, we believe that this work has particularly important implications for the synthesis of immunoconjugates, specifically for ensuring that the attachment of cargoes to immunoglobulins is robust, irreversible, and biologically and structurally benign.

Association of Hospital Discharge Against Medical Advice With Readmission and In-Hospital Mortality.

Importance: Hospital readmissions contribute to higher expenditures and may sometimes reflect suboptimal patient care. Individuals discharged against medical advice (AMA) are a vulnerable patient population and may have higher risk for readmission. Objectives: To determine odds of readmission and mortality for patients discharged AMA vs all others, to characterize patient and hospital-level factors associated with readmissions, and to quantify their overall cost burden. Design, Setting, and Participants: Nationally representative, all-payer cohort study using the 2014 National Readmissions Database. Eligible index admissions were nonobstetrical/newborn hospitalizations for patients 18 years and older discharged between January 2014 and November 2014. Admissions were excluded if there was a missing primary diagnosis, discharge disposition, length of stay, or if the patient died during that hospitalization. Data were analyzed between January 2018 and June 2018. Exposures: Discharge AMA and non-AMA discharge. Main Outcomes and Measures: Thirty-day all-cause readmission and in-hospital mortality rate. Results: There were 19.9 million weighted index admissions, of which 1.5% resulted in an AMA discharge. Within the AMA cohort, 85% were younger than 65 years, 63% were male, 55% had Medicaid or other (including uninsured) coverage, and 39% were in the lowest income quartile. Thirty-day all-cause readmission was 21.0% vs 11.9% for AMA vs non-AMA discharge (P < .001), and 30-day in-hospital mortality was 2.5% vs 5.6% (P < .001), respectively. Individuals discharged AMA were more likely to be readmitted to a different hospital compared with non-AMA patients (43.0% vs 23.9%; P < .001). Of all 30-day readmissions, 19.0% occurred within the first day after AMA discharge vs 6.1% for non-AMA patients (P < .001). On multivariable regression, AMA discharge was associated with a 2.01 (95% CI, 1.97-2.05) increased adjusted odds of readmission and a 0.80 (95% CI, 0.74-0.87) decreased adjusted odds of in-hospital mortality compared with non-AMA discharge. Nationwide readmissions after AMA discharge accounted for more than 400 000 inpatient hospitalization days at a total cost of $822 million in 2014. Conclusions and Relevance: Individuals discharged AMA have higher odds of 30-day readmission at significant cost to the health care system and lower in-hospital mortality rates compared with non-AMA patients. Patients discharged AMA are also more likely to be readmitted to different hospitals and to have earlier bounce-back readmissions, which may reflect dissatisfaction with their initial episode of care.

A phase II study of cabozantinib alone or in combination with trastuzumab in breast cancer patients with brain metastases.

PURPOSE: To analyze the efficacy and tolerability of cabozantinib-a small molecule inhibitor of MET and VEGFR2-alone or with trastuzumab in patients with breast cancer brain metastases (BCBM). METHODS: This single-arm phase II study enrolled patients with new or progressive measurable BCBM into 3 cohorts: Cohort 1 (HER2-positive), Cohort 2 (hormone receptor-positive/HER2-negative), and Cohort 3 (triple-negative). Patients received cabozantinib 60-mg daily on a 21-day cycle. Cohort 1 added trastuzumab every 3 weeks and had a primary objective of central nervous system (CNS) objective response rate (ORR) by RECIST 1.1. Secondary objectives for all cohorts were progression-free survival, overall survival, toxicity, and changes in vascular parameters and circulating biomarkers. Cohorts 2 and 3 also had CNS ORR as a secondary objective. RESULTS: Thirty-six BCBM patients enrolled (cohort 1, n = 21; cohort 2, n = 7; cohort 3, n = 8), with a median age of 50. Patients had a median of 3 prior lines for metastatic disease (range 1-9). Treatments prior to enrollment included craniotomy (n = 4), whole brain radiation (n = 24) and stereotactic radiosurgery (n = 11). CNS ORR was 5% in cohort 1, 14% in cohort 2, and 0% in cohort 3. Most common grade 3/4 adverse events included elevations in lipase (11%), AST (8%), ALT (6%), hyponatremia (8%), and hypertension (6%). Cabozantinib increased plasma concentrations of CA-IX, soluble (s)MET, PlGF, sTIE-2, VEGF, and VEGF-D, and decreased sVEGFR2 and TNF-α and total tumor blood volume. CONCLUSIONS: Cabozantinib had insufficient activity in heavily pretreated BCBM patients. Biomarker analysis showed that cabozantinib had antiangiogenic activity and increased tissue hypoxia. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT02260531.

Trends in Private Equity Acquisition of Dermatology Practices in the United States.

IMPORTANCE: Private equity (PE) firms invest in dermatology management groups (DMGs), which are physician practice management firms that operate multiple clinics and often acquire smaller, physician-owned practices. Consolidation of dermatology practices as a result of PE investment may be associated with changes in practice management in the United States. OBJECTIVE: To describe the scope of PE-backed dermatology practice acquisitions geographically over time. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study examined acquisitions of dermatology practices by PE-backed DMGs in the United States. Acquisition and investment data through May 31, 2018, were compiled using information from 5 financial databases. Transaction data were supplemented with publicly available information from 2 additional financial databases, 2 financial news outlets, and press releases from DMGs. All dermatology practices acquired by PE-backed DMGs were included. Acquisitions were verified to be dermatology practices that provided medical, surgical, and/or cosmetic clinical care. Private equity financing data were included when available. The addresses of clinics associated with acquired practices were mapped using spatial analytics software. MAIN OUTCOMES AND MEASURES: The number and location of PE practice acquisitions over time were measured based on the date of deal closure, the geographic footprint of each DMG's acquisition, and the financing of each DMG. RESULTS: Seventeen PE-backed DMGs acquired 184 practices between May 1, 2012, and May 22, 2018. These acquired practices accounted for an estimated 381 dermatology clinics as of mid-2018 (assessment period from May 1 to August 31). The total number of PE-owned dermatology clinics in the United States was substantially larger because these data did not reflect DMGs that opened new clinics (organic growth); acquisitions data represented only the ownership transfer of existing practices from physician to PE-backed DMG. Practice acquisitions increased each year, from 5 in 2012 to 59 in 2017. An additional 34 acquisitions took place from January 1 to May 31, 2018. The number of financing rounds to sustain transactions mirrored the aforementioned trends in practice acquisitions. Clinics associated with acquired practices spanned at least 30 states, with 138 of 381 clinics (36%) located in Texas and Florida. CONCLUSION AND RELEVANCE: The study findings suggest that PE firms have a financial stake in an increasing number of dermatology practices throughout the United States. Further research is needed to assess whether and how PE-backed ownership influences clinical decision-making, health care expenditures, and patient outcomes.

Analysis of Readmissions Following Hospitalization for Cellulitis in the United States.

Importance: Cellulitis commonly results in hospitalization. Limited data on the proportion of cellulitis admissions associated with readmission are available. Objective: To characterize the US national readmission rate associated with hospitalization for treatment of cellulitis. Design, Setting, and Participants: This retrospective cohort analysis of cellulitis admissions from the nationally representative 2014 Nationwide Readmissions Database calculated readmission rates for all cellulitis admissions and subsets of admissions. The multicenter population-based cohort included adult patients admitted for conditions other than obstetrical or newborn care. Data were collected from January 1 through November 30, 2014, and analyzed from February 1 through September 18, 2018. Bivariate logistic regression models were used to assess differences in readmission rates by patient characteristics. Costs were calculated for all readmissions after discharge from hospitalization for cellulitis (hereinafter referred to as cellulitis discharge) and by readmission diagnosis. Exposures: Admission with a primary diagnosis of cellulitis. Main Outcomes and Measures: Proportion of cellulitis admissions associated with nonelective readmission within 30 days, characteristics of patients readmitted after cellulitis discharge, and costs associated with cellulitis readmission. Results: A total of 447 080 (95% CI, 429 927-464 233) index admissions with a primary diagnosis of cellulitis (53.8% male [95% CI, 53.5%-54.2%]; mean [SD] age, 56.1 [18.9] years) were included. Overall 30-day all-cause nonelective readmission rate after cellulitis discharge was 9.8% (95% CI, 9.6%-10.0%). Among patients with cellulitis, age (odds ratio for 45-64 years, 0.78; 95% CI, 0.75-0.81; P = .001) and insurance status (odds ratio for Medicare, 2.45; 95% CI, 2.33-2.58; P < .001) were associated with increased readmission rates. The most common diagnosis of readmissions included skin and subcutaneous tissue infections. The total cost associated with nonelective readmissions attributed to skin and subcutaneous infections within 30 days of a cellulitis discharge during the study period was $114.4 million (95% CI, $106.8-$122.0 million). Conclusions and Relevance: Readmission after hospitalization for cellulitis is common and costly and may be preventable with improved diagnostics, therapeutics, and discharge care coordination.

Risk of Serious Infections Associated with Biologic Agents in Juvenile Idiopathic Arthritis: A Systematic Review and Meta-Analyses.

OBJECTIVE: To assess whether treatment with biologic response modifying agents during clinical trial study periods increases the risk of serious infections in children with juvenile idiopathic arthritis (JIA). STUDY DESIGN: A systematic literature review using Medline, Embase, Cochrane library, and the clinical trial registry was performed up to July 2017. Random effects meta-analyses were used to compare rates of serious infections in children with JIA given biologic agents compared with controls, and the pooled relative risk calculated. Subanalyses were performed for different biologic agent classes. RESULTS: In total, 19 trials accounting for 21 individual studies were included (11 for tumor necrosis factor-alpha inhibitors [n = 814 patients], 3 for interleukin-6 inhibitors [n = 318], 6 for interleukin-1 inhibitors [n = 353], and 1 for selective T-lymphocyte costimulation modulators [n = 122]). Patients (68% female) had a mean age of 10.8 years. Seventeen serious infections were reported among 810 children receiving biologic agents and 15 among 797 controls. The most frequent infections were bronchopulmonary and varicella. No statistically significant difference in risk of serious infections was found between children receiving biologic agents compared with control groups (pooled relative risk = 1.13; 95% CI [0.63, 2.03]) during the trial study periods. The risk remained nonsignificant when evaluating the different classes of biologic agents separately. However, the analyses were underpowered to detect differences in the risk of serious infections overall or differences between classes of biologic agents. CONCLUSIONS: In this systematic review and meta-analyses, serious infections were uncommon and not significantly increased among patients with JIA receiving biologic agents compared with controls. However, the analyses were underpowered and study periods were relatively short. Ongoing careful monitoring for serious infections remains necessary for all patients with JIA, and particularly those receiving biologic agents.

Clinicopathologic features correlated with paradoxical outcomes in stage IIC versus IIIA melanoma patients.

Under current AJCC staging criteria, stage IIC patients paradoxically have worse outcomes than IIIA patients despite the lack of nodal metastatic disease. This study sought to identify additional clinicopathologic characteristics correlated with worse patient outcomes. Retrospective chart review of stage IIC and IIIA melanoma patients were evaluated between 1995 and 2011 with clinical follow-up through 2015. Records were reviewed for demographics, clinical characteristics, and tumor pathology. Fisher's exact test and Wilcoxon's rank-sum test were used to assess group differences. Clinicopathologic features were evaluated relative to overall survival (OS), time to distant metastases, and local/regional recurrence. Overall, 128 patients were included (45 stage IIC and 83 stage IIIA) with a median follow-up time of 5.7 years. Compared with stage IIIA patients, stage IIC patients were older, and their melanomas were more likely to be nodular, amelanotic, thicker, have higher mitotic rate, tumor lymphocytic infiltrate, no radial growth phase, and less likely to have associated precursor lesions. Stage IIC patients had shorter OS and time to distant metastases; multivariate regression revealed that older age (>55 years) and mitotic rate (>5 mitoses/mm) were independent predictors of OS. Melanomas in stage IIC disease may be biologically distinct from those that are seen in stage IIIA. While sentinel node biopsies remain the standard-of-care, these results suggest that clinicians may want to assess the clinicopathologic characteristics described above to aggressively counsel, screen for distant disease, and consider adjuvant therapy, in particular for older patients and higher mitotic rates in thicker primary tumors, regardless of nodal status.

Trends in phototherapy utilization among Medicare beneficiaries in the United States, 2000 to 2015.

BACKGROUND: Phototherapy is a cost-effective treatment for many dermatoses, yet the emergence of alternative therapies such as biologics led many to think that phototherapy utilization was declining. OBJECTIVE: To characterize national, historical phototherapy utilization and costs among Medicare beneficiaries. METHODS: Longitudinal analysis of the Medicare Part B National Summary Data File from 2000 to 2015 for phototherapy billing codes. Geographic distribution of clinics and provider type obtained from the Medicare Provider Utilization and Payment Data for 2012 to 2015. RESULTS: The overall volume of phototherapy services billed to Medicare from 2000 to 2015 increased by 5% annually, from 334,670 to 692,093. Ultraviolet B therapy comprised 77% of phototherapy volume, utilization of psoralen plus ultraviolet A therapy declined by 9% annually, and excimer laser services grew by 29% annually. The number of phototherapy clinics is increasing but remains concentrated in only 11% of US counties. Between 2012 and 2015, dermatologists accounted for 92% of phototherapy volume. LIMITATIONS: Commercial payers and institutional claims (hospital-based physicians) are excluded. Clinical indications for phototherapy use are not reported in this database. CONCLUSION: Phototherapy utilization has grown, though the service mix has shifted toward ultraviolet B and laser excimer therapy and away from psoralen plus ultraviolet A therapy. Dermatologists manage most phototherapy. Uneven geographic distribution of phototherapy clinics limits access in nonurban areas, and further evaluation is needed to determine its impact on rural communities.

Association of Dermatologist Density With the Volume and Costs of Dermatology Procedures Among Medicare Beneficiaries.

Importance: The persistent shortage of dermatologists in the United States affects access to care and patient outcomes. Objective: To characterize the effect of geographic variations in dermatologist density on the provision of dermatology procedures within Medicare. Design, Setting, and Participants: This was a cross-sectional study using the 2013 Medicare Provider Utilization and Payment Database. Dermatology-related procedures were defined by the top 50 billing codes accounting for more than 95% of procedures billed by dermatologists. Billing codes corresponding to evaluation and monitoring visits and dermatopathology were excluded. Total costs were estimated from the Centers for Medicare & Medicaid Services physician fee schedule, based on the nonfacility national payment amount with no modifiers. Nationally representative administrative database that includes 100% of charges billed by noninstitutional clinicians covered under Medicare Part B. A total of 10 391 dermatologists practicing within the 50 states and Washington, DC, were included. The Medicare-eligible population was defined as all persons 65 years or older. Exposures: Density of dermatologists, categorized into first (5.3 per 100 000 persons ≥65 years) through fifth (54.8 per 100 000 persons ≥65 years) quintiles. Main Outcomes and Measures: Utilization of dermatology procedures (mean volume per 100 000 persons ≥65 years) and total cost (mean amount billed per person ≥65 years) by clinician type across quintiles of dermatologist density. Results: In 2013, dermatologists billed Medicare for 28 million procedures costing $2.21 billion. Mean billed amount by dermatologists per person 65 years or older was $15.87 in the lowest-density quintile vs $92.02 in the highest-density quintile. This trend suggests that each interval increase of 10 dermatologists per 100 000 persons 65 years or older is correlated with a $14.81 increase in Medicare spending on dermatology procedures (95% CI, 8.28-21.34; P = .005). Utilization of these procedures differed among clinician types, with dermatologists largely performing destruction of premalignant lesions and PCPs primarily doing injections. Conclusions and Relevance: There is evidence of supply-sensitive variation in the provision of dermatology procedures for the Medicare-eligible population; higher dermatologist density is correlated with increased utilization of dermatology procedures and subsequent billed charges to Medicare. Further research is needed to determine the effect of such variations on outcomes and whether incentives can better align dermatologists with areas of clinical need.

Phase II study of tivantinib (ARQ 197) in patients with metastatic triple-negative breast cancer.

BACKGROUND: MET expression and activation appear to be important for initiation and progression of triple-negative breast cancer. Tivantinib (ARQ 197) is an orally administered agent that targets MET, although recent preclinical data suggests the agent may have mechanisms of action that are independent of MET signaling. We conducted a phase 2 study of tivantinib monotherapy in patients with metastatic triple-negative breast cancer. METHODS: Patients with metastatic triple-negative breast cancer who had received 1 to 3 prior lines of chemotherapy in the metastatic setting were enrolled into this two-stage, single arm phase 2 study. Treatment consisted of twice daily oral dosing of tivantinib (360 mg po bid) during a 21-day cycle. Patients underwent restaging scans at 6 weeks, and then every 9 weeks. Tumor biomarkers that might predict response to tivantinib were explored. RESULTS: 22 patients were enrolled. The overall response rate was 5 % (95 % CI 0-25 %) and the 6-month progression-free survival (PFS) was 5 % (95 % CI 0-25 %), with one patient achieving a partial response (PR). Toxicity was minimal with only 5 grade ≥3 adverse events (one grade 3 anemia, one grade 3 fatigue, and 3 patients with grade 3/4 neutropenia). CONCLUSION: This study represents the first evaluation of tivantinib for the treatment of metastatic triple-negative breast cancer. These results suggest that single agent tivantinib is well tolerated, but did not meet prespecified statistical targets for efficacy.

Identification of core DNA elements that target somatic hypermutation.

Somatic hypermutation (SHM) diversifies the V region of Ig genes and underlies the process of affinity maturation, in which B lymphocytes producing high-affinity Abs are generated and selected. SHM is triggered in activated B cells by deamination of deoxycytosine residues mediated by activation-induced deaminase (AID). Whereas mistargeting of SHM and AID results in mutations and DNA damage in many non-Ig genes, they act preferentially at Ig loci. The mechanisms responsible for preferential targeting of SHM and AID activity to Ig loci are poorly understood. Using an assay involving an SHM reporter cassette inserted into the Ig L chain locus (IgL) of chicken DT40 B cells, we have identified a 1.9-kb DIVAC (diversification activator) element derived from chicken IgL that supports high levels of AID-dependent mutation activity. Systematic deletion analysis reveals that targeting activity is spread throughout much of the sequence and identifies two core regions that are particularly critical for function: a 200-bp region within the IgL enhancer, and a 350-bp 3' element. Chromatin immunoprecipitation experiments demonstrate that whereas DIVAC does not alter levels of several epigenetic marks in the mutation cassette, it does increase levels of serine-5 phosphorylated RNA polymerase II in the mutation target region, consistent with an effect on transcriptional elongation/pausing. We propose that multiple, dispersed DNA elements collaborate to recruit and activate the mutational machinery at Ig gene variable regions during SHM.