Sweet Syndrome, Not so Sweet during an Ulcerative Colitis Flare Especially When You Cannot Eat.

Sweet syndrome is a rare skin condition characterized by painful papules, nodules, or plaques with dense neutrophilic infiltrate in the upper dermis. It has been observed as idiopathic (classical), malignancy-associated, and drug-induced. The pathogenesis is not completely understood, but it is thought to involve hypersensitivity reactions to specific triggers. In some cases the etiology is unclear or may be multifactorial. We present a case of Sweet syndrome secondary to ulcerative colitis flare versus adalimumab re-induction.

Metastatic Castration-Resistant Prostate Cancer Remains Dependent on Oncogenic Drivers Found in Primary Tumors.

Metastatic prostate cancer is initially sensitive to androgen receptor inhibition, but eventually becomes castration-resistant prostate cancer (mCRPC). Early use of more intensive therapies targeting androgen receptor and other oncogenic drivers in treatment-naïve primary prostate cancer (PC) may be more effective than that in advanced mCRPC. However, analysis of primary tumors may not reveal targetable metastatic drivers that are subclonal in the primary tumor or acquired at metastatic sites. METHODS: PC samples spanning one patient's clinical course: diagnostic biopsies, pre- or post-enzalutamide metastatic biopsies, and rapid autopsy samples including a patient-derived xenograft (PDX) were analyzed by targeted exome sequencing followed by phylogenetic analysis. RESULTS: Left- and right-lobe primary PC tumors appeared to diverge, with the right acquiring additional shared mutations and striking differences in copy number alterations that later appeared in metastatic samples during the treatment course and at autopsy, whereas the left base tumor maintained a quiet copy number alteration landscape and partitioned into a dead-end node. RB1 loss, a common finding in advanced castration-resistant disease, was identified throughout mCRPC samples, but not in the primary tumor. Significantly, a truncal EGFR-activating mutation (R108K) was identified in the primary tumor and was also found to be maintained in the mCRPC samples and in a PDX model. Furthermore, the PDX model remained sensitive to the EGFR inhibitor erlotinib, despite the presence of both RB1 and BRCA2 losses. CONCLUSION: These findings indicate that truncal alterations identified in primary PC can drive advanced mCRPC, even in the presence of additional strong oncogenic drivers (ie, RB1 and BRCA2 loss), and suggest that earlier detection and targeting of these truncal alterations may be effective at halting disease progression.

Sex differences in soluble prorenin receptor in patients with type 2 diabetes.

BACKGROUND: The soluble prorenin receptor (sPRR), a member of the renin-angiotensin system (RAS), is elevated in plasma of patients with preeclampsia, hypertension, chronic kidney disease (CKD), and type 2 diabetes. Our goal was to examine the relationship between sPRR and RAS activation to define whether sexual dimorphisms in sPRR might explain sex disparities in renal outcomes in patients with type 2 diabetes. METHODS: Two hundred sixty-nine participants were included in the study (mean age, 48 ± 16 years; 42% men, 58% women), including 173 controls and 96 subjects with type 2 diabetes. In plasma and urine, we measured sPRR, plasma renin activity (PRA), and prorenin. In the urine, we also measured angiotensinogen along with other biomarkers of renal dysfunction. RESULTS: Plasma sPRR and PRA were significantly higher in women with type 2 diabetes compared to men. In these women, plasma sPRR was positively correlated with PRA, age, and body mass index (BMI). In contrast, in men the sPRR in urine but not in plasma positively correlated with eGFR in urine, but negatively correlated with urine renin activity, plasma glucose, age, and BMI. CONCLUSIONS: In patients with type 2 diabetes, sPRR contributes to RAS stimulation in a sex-dependent fashion. In diabetic women, increased plasma sPRR parallels the activation of systemic RAS; while in diabetic men, decreased sPRR in urine matches intrarenal RAS stimulation. sPRR might be a potential indicator of intrarenal RAS activation and renal dysfunction in men and women with type 2 diabetes.

Localized bullous pemphigoid after knee replacement surgery.

Bullous pemphigoid (BP) most commonly presents as widespread, itchy, tense blisters in older patients. Localized bullous pemphigoid is a less common form of BP that can be more difficult to diagnose because of its similarity to more common conditions such as allergic contact dermatitis or bullous cellulitis. Prompt recognition of localized BP is important so that appropriate treatment can be started. We present a 57-year-old woman who presented with pruritic tense bullae overlying the surgical scar from a knee replacement 6 months prior on her anterior right knee. This case illustrates the potential for localized BP to be triggered by surgical procedures.

Darier sign in a teenager with primary cutaneous marginal zone lymphoma.

Primary cutaneous marginal zone lymphoma (PCMZL) is a low-grade B-cell lymphoma that arises in the skin. An adolescent male presented with dermal nodules on the arms, legs, and back with a positive Darier sign, ultimately diagnosed as PCMZL. The nodules demonstrated a partial response to doxycycline in the setting of prior Lyme disease followed by a complete response to rituximab.

Automated Quantitative Measures of Terminal Duct Lobular Unit Involution and Breast Cancer Risk.

BACKGROUND: Manual qualitative and quantitative measures of terminal duct lobular unit (TDLU) involution were previously reported to be inversely associated with breast cancer risk. We developed and applied a deep learning method to yield quantitative measures of TDLU involution in normal breast tissue. We assessed the associations of these automated measures with breast cancer risk factors and risk. METHODS: We obtained eight quantitative measures from whole slide images from a benign breast disease (BBD) nested case-control study within the Nurses' Health Studies (287 breast cancer cases and 1,083 controls). Qualitative assessments of TDLU involution were available for 177 cases and 857 controls. The associations between risk factors and quantitative measures among controls were assessed using analysis of covariance adjusting for age. The relationship between each measure and risk was evaluated using unconditional logistic regression, adjusting for the matching factors, BBD subtypes, parity, and menopausal status. Qualitative measures and breast cancer risk were evaluated accounting for matching factors and BBD subtypes. RESULTS: Menopausal status and parity were significantly associated with all eight measures; select TDLU measures were associated with BBD histologic subtype, body mass index, and birth index (P < 0.05). No measure was correlated with body size at ages 5-10 years, age at menarche, age at first birth, or breastfeeding history (P > 0.05). Neither quantitative nor qualitative measures were associated with breast cancer risk. CONCLUSIONS: Among Nurses' Health Studies women diagnosed with BBD, TDLU involution is not a biomarker of subsequent breast cancer. IMPACT: TDLU involution may not impact breast cancer risk as previously thought.

Deep learning assessment of breast terminal duct lobular unit involution: Towards automated prediction of breast cancer risk.

Terminal duct lobular unit (TDLU) involution is the regression of milk-producing structures in the breast. Women with less TDLU involution are more likely to develop breast cancer. A major bottleneck in studying TDLU involution in large cohort studies is the need for labor-intensive manual assessment of TDLUs. We developed a computational pathology solution to automatically capture TDLU involution measures. Whole slide images (WSIs) of benign breast biopsies were obtained from the Nurses' Health Study. A set of 92 WSIs was annotated for acini, TDLUs and adipose tissue to train deep convolutional neural network (CNN) models for detection of acini, and segmentation of TDLUs and adipose tissue. These networks were integrated into a single computational method to capture TDLU involution measures including number of TDLUs per tissue area, median TDLU span and median number of acini per TDLU. We validated our method on 40 additional WSIs by comparing with manually acquired measures. Our CNN models detected acini with an F1 score of 0.73±0.07, and segmented TDLUs and adipose tissue with Dice scores of 0.84±0.13 and 0.87±0.04, respectively. The inter-observer ICC scores for manual assessments on 40 WSIs of number of TDLUs per tissue area, median TDLU span, and median acini count per TDLU were 0.71, 0.81 and 0.73, respectively. Intra-observer reliability was evaluated on 10/40 WSIs with ICC scores of >0.8. Inter-observer ICC scores between automated results and the mean of the two observers were: 0.80 for number of TDLUs per tissue area, 0.57 for median TDLU span, and 0.80 for median acini count per TDLU. TDLU involution measures evaluated by manual and automated assessment were inversely associated with age and menopausal status. We developed a computational pathology method to measure TDLU involution. This technology eliminates the labor-intensiveness and subjectivity of manual TDLU assessment, and can be applied to future breast cancer risk studies.

The Convergence of Vasculopathy and Vasculitis: Computer Mapping Analysis of 2 Renal Biopsies in a Patient with both Systemic Sclerosis and ANCA-Related Vasculitis.

Scleroderma vasculopathy and ANCA (antineutrophil cytoplasmic antibodies)-associated glomerulonephritis have rarely been reported to occur simultaneously in one patient. Herein, we report a patient who presented with a classic constellation of clinical and laboratory findings of systemic scleroderma and was subsequently found to be positive for p-ANCA. Two renal biopsies, performed 5 months apart, demonstrated typical changes of the two entities in both acute and "healed" phases, which were analyzed by computer mapping techniques. The two renal biopsies were serially sectioned and stained routinely, and with CD31 and CD34 as endothelial markers. The slides were digitized, aligned and analyzed. Each glomerular tuft was sequentially studied in terms of total area (µm2) and each biopsy was individually profiled. All arterial vessels were sequentially studied with whole vessel and luminal areas delineated and ratios calculated. The initial biopsy contained 32 glomeruli almost all with extensive fibrinoid necrosis and destruction of the capillary network. The arterial vessels (interlobular and arcuate) showed intimal edema with luminal occlusion. CD31/CD34 stains showed variable endothelial intactness but demonstrated the luminal size shifts. The second biopsy had 37 glomeruli that were either segmentally or globally sclerotic with no active changes. The vessels were now normally patent. Each glomerular tuft and arterial vessel in both biopsies was analyzed as a serial section histogram documenting these changes. These studies depict the rare occurrence of two entities together, the scleroderma kidney vasculopathy and the glomerulonephritis of ANCA-associated vasculitis syndrome both in an acute and healing phase, profiled by computer mapping techniques.

Renal medullary cyclooxygenase-2 and (pro)renin receptor expression during angiotensin II-dependent hypertension.

The (pro)renin receptor [(P)RR] upregulates cyclooxygenase-2 (COX-2) in inner medullary collecting duct (IMCD) cells through ERK1/2. Intrarenal COX-2 and (P)RR are upregulated during chronic ANG II infusion. However, the duration of COX-2 and (P)RR upregulation has not been determined. We hypothesized that during the early phase of ANG II-dependent hypertension, membrane-bound (P)RR and COX-2 are augmented in the renal medulla, serving to buffer the hypertensinogenic and vasoconstricting effects of ANG II. In Sprague-Dawley rats infused with ANG II (0.4 µg·min(-1)·kg(-1)), systolic blood pressure (BP) increased by day 7 (162 ± 5 vs. 114 ± 10 mmHg) and continued to increase by day 14 (198 ± 15 vs. 115 ± 13 mmHg). Membrane-bound (P)RR was augmented at day 3 coincident with phospho-ERK1/2 levels, COX-2 expression, and PGE2 in the renal medulla. In contrast, membrane-bound (P)RR was reduced and COX-2 protein levels were not different from controls by day 14. In cultured IMCD cells, ANG II increased secretion of the soluble (P)RR. In anesthetized rats, COX-2 inhibition decreased the glomerular filtration rate (GFR) and renal blood flow (RBF) during the early phase of ANG II infusion without altering BP. However, at 14 days of ANG II infusions, COX-2 inhibition decreased mean arterial BP (MABP), RBF, and GFR. Thus, during the early phase of ANG II-dependent hypertension, the increased (P)RR and COX-2 expression in the renal medulla may contribute to attenuate the vasoconstrictor effects of ANG II on renal hemodynamics. In contrast, at 14 days the reductions in RBF and GFR caused by COX-2 inhibition paralleled the reduced MABP, suggesting that vasoconstrictor COX-2 metabolites contribute to ANG II hypertension.

Angiotensin II-independent upregulation of cyclooxygenase-2 by activation of the (Pro)renin receptor in rat renal inner medullary cells.

During renin-angiotensin system activation, cyclooxygenase-2 (COX-2)-derived prostaglandins attenuate the pressor and antinatriuretic effects of angiotensin II (AngII) in the renal medulla. The (pro)renin receptor (PRR) is abundantly expressed in the collecting ducts (CD) and its expression is augmented by AngII. PRR overexpression upregulates COX-2 via mitogen-activated kinases/extracellular regulated kinases 1/2 in renal tissues; however, it is not clear whether this effect occurs independently or in concert with AngII type 1 receptor (AT1R) activation. We hypothesized that PRR activation stimulates COX-2 expression independently of AT(1)R in primary cultures of rat renal inner medullary cells. The use of different cell-specific immunomarkers (aquaporin-2 for principal cells, anion exchanger type 1 for intercalated type-A cells, and tenascin C for interstitial cells) and costaining for AT(1)R, COX-2, and PRR revealed that PRR and COX-2 were colocalized in intercalated and interstitial cells whereas principal cells did not express PRR or COX-2. In normal rat kidney sections, PRR and COX-2 were colocalized in intercalated and interstitial cells. In rat renal inner medullary cultured cells, treatment with AngII (100 nmol/L) increased COX-2 expression via AT(1)R. In addition, AngII and rat recombinant prorenin (100 nmol/L) treatments increased extracellular regulated kinases 1/2 phosphorylation, independently. Importantly, rat recombinant prorenin upregulated COX-2 expression in the presence of AT(1)R blockade. Inhibition of mitogen-activated kinases/extracellular regulated kinases 1/2 suppressed COX-2 upregulation mediated by either AngII or rat recombinant prorenin. Furthermore, PRR knockdown using PRR-short hairpin RNA blunted the rat recombinant prorenin-mediated upregulation of COX-2. These results indicate that COX-2 expression is upregulated by activation of either PRR or AT(1)R via mitogen-activated kinases/extracellular regulated kinases 1/2 in rat renal inner medullary cells.

Soluble form of the (pro)renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats.

Renin synthesis and secretion by principal cells of the collecting duct are enhanced in angiotensin (Ang) II-dependent hypertension. The presence of renin/(pro)renin and its receptor, the (pro)renin receptor ([P]RR), in the collecting duct may provide a pathway for Ang I generation with further conversion to Ang II. To assess whether (P)RR activation occurs during Ang II-dependent hypertension, we examined renal (P)RR levels and soluble (P)RR excretion in the urine of chronic Ang II-infused rats (80 ng/min; for 2 weeks; n=10) and sham-operated rats (n=10). Systolic blood pressure and Ang II levels in the plasma and kidney were increased whereas plasma renin activity was suppressed in Ang II-infused rats. Renal (P)RR transcripts were upregulated in the cortex and medulla of Ang II-infused rats. (P)RR immunoreactivity in collecting duct cells and the protein levels of the full-length form (37-kDa band) were significantly decreased in the medulla of Ang II-infused rats. The soluble (P)RR (28-kDa band) was detected in the renal medulla and urine samples of Ang II-infused rats, which also showed increases in urinary renin content. To determine whether the soluble (P)RR could stimulate Ang I formation, urine samples were incubated with recombinant human (pro)renin. Urine samples of Ang II-infused rats exhibited increased Ang I formation compared with sham-operated rats. Thus, in chronic Ang II-infused rats, the catalytic activity of the augmented renin produced in the collecting duct may be enhanced by the intraluminal soluble (P)RR and cell-surface located (P)RR, thus contributing to enhanced intratubular Ang II formation.