Initial Safety and Feasibility Results From a Phase 1, Diagnose-and-Treat Trial of Neoadjuvant Intratumoral Cisplatin for Stage IV NSCLC.

Neoadjuvant intratumoral cisplatin has the potential to generate substantial cytotoxicity and immune priming within the tumor environment, while minimizing systemic, off-target, adverse events. We initiated a phase 1A, 3+3 dose-ranging study of neoadjuvant, intratumoral cisplatin, delivered through endobronchial ultrasound bronchoscopy, in the same procedure as the initial diagnosis. There were no dose-limiting toxicity identified at the 20mg level.

The evolution of performing a kidney biopsy: a single center experience comparing native and transplant kidney biopsies performed by interventional radiologists and nephrologists.

BACKGROUND: Kidney biopsy is the most vital tool guiding a nephrologist in diagnosis and treatment of kidney disease. Over the last few years, we have seen an increasing number of kidney biopsies being performed by interventional radiologists. The goal of our study was to compare the adequacy and complication rates between kidney biopsies performed by interventional radiology versus nephrology.  METHODS : We performed a single center retrospective analysis of a total of all kidney biopsies performed at our Institution between 2015 and 2021. All biopsies were performed using real-time ultrasound. Patients were monitored for four hours post biopsy and repeat ultrasound or hemoglobin checks were done if clinically indicated. The entire cohort was divided into two groups (Interventional radiology (IR) vs nephrology) based on who performed the biopsy. Baseline characteristics, comorbidities, blood counts, blood pressure, adequacy of the biopsy specimen and complication rates were recorded. Multivariable logistic regression was used to compare complication rates (microscopic hematuria, gross hematuria and need for blood transfusion combined) between these two groups, controlling for covariates of interest. ANCOVA (analysis of variance, controlling for covariates) was used to compare differences in biopsy adequacy (number of glomeruli per biopsy procedure) between the groups. RESULTS: 446 kidney biopsies were performed in the study period (229 native and 147 transplant kidney biopsies) of which 324 were performed by IR and 122 by nephrologist. There was a significantly greater number of core samples obtained by IR (mean = 3.59, std.dev. = 1.49) compared to nephrology (mean = 2.47, std.dev = 0.79), p < 0.0001. IR used 18-gauge biopsy needles while nephrologist exclusively used 16-gauge needles. IR used moderate sedation (95.99%) or general anesthesia (1.85%) for the procedures more often than nephrology, which used them only in 0.82% and 0.82% of cases respectively (p < 0.0001). Trainees (residents or fellows) participated in the biopsy procedures more often in nephrology compared to IR (97.4% versus 69.04%, p < 0.0001). The most frequent complication identified was microscopic hematuria which occurred in 6.8% of biopsies. For native biopsies only, there was no significant difference in likelihood of complication between groups, after adjustment for covariates of interest (OR = 1.01, C.I. = (0.42, 2.41), p = 0.99). For native biopsies only, there was no significant difference in mean number of glomeruli obtained per biopsy procedure between groups, after adjustment for covariates of interest (F(1,251) = 0.40, p = 0.53). CONCLUSION: Our results suggest that there is no significant difference in the adequacy or complication rates between kidney biopsies performed by IR or nephrology. This conclusion may indicate that kidney biopsies can be performed safely with adequate results either by IR or nephrologists depending on each institution's resources and expertise.

Anatomy of a Cyberattack: Part 1: Managing an Anatomic Pathology Laboratory During 25 Days of Downtime.

OBJECTIVES: Our institution was affected by a multi-institution, systemwide cyberattack that led to a complete shutdown of major patient care, operational, and communication systems. The attack affected our electronic health record (EHR) system, including all department-specific modules, the laboratory information system (LIS), pharmacy, scheduling, billing and coding, imaging software, internet access, and payroll. Downtime for the EHR lasted 25 days, while other systems were nonfunctional for more than 40 days, causing disruptions to patient care and significantly affecting our laboratories. As more institutions transition to network EHR systems, laboratories are increasingly vulnerable to cyberattack. This article focuses on the approaches we developed in the anatomic pathology (AP) laboratory to continue operations, consequences of the prolonged downtime, and strategies for the future. METHODS: Our AP laboratory developed manual processes for surgical and cytopathology processing, redeployed staff, and used resources within the department and of nearby facilities to regain and maintain operations. RESULTS: During the downtime, our AP laboratory processed 1,362 surgical pathology and consult cases as well as 299 cytology specimens and outsourced 1,308 surgical pathology and 1,250 cytology cases. CONCLUSIONS: Our laboratory successfully transitioned to downtime processes during a 25-day complete network outage. The crisis allowed for innovative approaches in managing resources.

Anatomy of a Cyberattack: Part 4: Quality Assurance and Error Reduction, Billing and Compliance, Transition to Uptime.

OBJECTIVES: Our institution was the victim of a cyberattack that necessitated use of manual laboratory systems for more than 25 days. These manual processes had to be created not only to enable us to process our case volume without bottlenecks but also to maintain patient safety and allow for billing. METHODS: Our laboratory needed to create a safe reporting process to ensure ongoing patient safety and error reduction during the downtime. Additionally, we needed to ensure the ability to bill for performed tests in some areas of the lab and maintain compliance with regulatory policies. RESULTS: Amendment rates in our system were higher than before the attack, but no patient harm was observed. Intraoperative assessments declined, but high-acuity cases continued with a discrepancy rate comparable with the normal state. Many hours and resources (human and otherwise) were necessary to reconcile the work done to bill for services, but we were able to capture revenue through careful planning. CONCLUSIONS: This article records the challenges we faced and the successes we achieved in maintaining compliance and a low error rate in the face of manual processes, the steps necessary to bring the cases into the newly restored electronic health record, and how we billed for the services we rendered.

Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.

Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.

Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis with Kidney Involvement in a Patient with AL Amyloidosis.

Antineutrophil cytoplasmic autoantibody (ANCA) vasculitis has occasionally been associated with other systemic glomerulonephritis, such as anti-glomerular basement membrane disease. Here, we report the first clinical case of ANCA-associated crescentic glomerulonephritis with AL amyloidosis. An 81-years-old gentleman presented to the hospital with acute kidney injury (serum creatinine 4.7 mg/dL) on a background of chronic kidney disease and volume overload. Autoimmune serology was remarkable for p-ANCA and myeloperoxidase positivity. A renal biopsy confirmed pauci-immune glomerulonephritis and lambda light-chain amyloid deposition (confirmed on liquid chromatography and tandem mass spectrometry). The patient was initially managed with rituximab and subsequently transitioned to bortezomib-based chemotherapy but died due to decompensated heart failure. This case report promotes greater awareness of the unusual presentation of amyloidosis and guides future research and treatment.

First European Haplotype of Echinococcus multilocularis Identified in the United States: An Emerging Disease?

BACKGROUND: Echinococcus multilocularis is one of the most severe and lethal parasitic diseases of humans, most often reported in Europe and Asia. Only 1 previous case has been documented in the contiguous United States from Minnesota in 1977. European haplotypes have been identified in carnivores and domestic dogs as well as recently in patients in western and central Canada. METHODS: We used immunohistochemical testing with the monoclonal antibody Em2G11 and a species-specific enzyme-linked immunosorbent assay affinity-purified antigen Em2, as well as COX1 gene sequencing. RESULTS: Using pathology, immunohistochemical staining, specific immunodiagnostic testing, and COX1 gene sequencing, we were able to definitively identify E. multilocularis as the causative agent of our patient's liver and lung lesions, which clustered most closely with the European haplotype. CONCLUSIONS: We have identified the first case of a European haplotype E. multilocularis in the United States and the first case of this parasitic infection east of the Mississippi River. Given the identification of this haplotype in Canada, this appears to be an emerging infectious disease in North America.

Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice.

OBJECTIVES: Recent investigations in humans and mouse models with lupus have revealed evidence of mitochondrial dysfunction and production of mitochondrial reactive oxygen species (mROS) in T cells and neutrophils. This can provoke numerous cellular changes including oxidation of nucleic acids, proteins, lipids and even induction of cell death. We have previously observed that in T cells from patients with lupus, the increased mROS is capable of provoking oligomerisation of mitochondrial antiviral stimulator (MAVS) and production of type I interferon (IFN-I). mROS in SLE neutrophils also promotes the formation of neutrophil extracellular traps (NETs), which are increased in lupus and implicated in renal damage. As a result, in addition to traditional immunosuppression, more comprehensive treatments for lupus may also include non-immune therapy, such as antioxidants. METHODS: Lupus-prone MRL-lpr mice were treated from weaning for 11 weeks with the mitochondria-targeted antioxidant, MitoQ (200 µM) in drinking water. Mice were then assessed for ROS production in neutrophils, NET formation, MAVS oligomerisation, serum IFN-I, autoantibody production and renal function. RESULTS: MitoQ-treated mice manifested reduced neutrophil ROS and NET formation, decreased MAVS oligomerisation and serum IFN-I, and reduced immune complex formation in kidneys, despite no change in serum autoantibody . CONCLUSIONS: These findings reveal the potential utility of targeting mROS in addition to traditional immunosuppressive therapy for lupus.

Unique Multidisciplinary Training Practices in Cytopathology: Simulation Training in Ultrasound-Guided Fine Needle Aspiration of the Thyroid.

The training of ultrasound-guided fine needle aspiration in pathology residency and fellowship programs can be a challenging task with variable outcomes, particularly when there is a lack of a standardized approach. In 2014, the Department of Pathology and Laboratory Medicine in collaboration with the Endocrine Division of the Department of Medicine at the University of Vermont Medical Center implemented simulation training for the incoming cytopathology and endocrinology fellows prior to fellows interacting with patients at the clinic in order to provide a structured approach to learning the technical components of ultrasound-guided fine needle aspiration. In 2018, a second simulation session was added to focus on communication, providing fellows an opportunity to further develop the communication skills that enhance patient connection, empathy, and trust. The combined simulation experience has provided the fellows an ideal learning environment to enhance their understanding of the technical aspects of ultrasound-guided fine needle aspiration as well as the necessary components of communication prior to having to perform the procedure on actual patients. This results in a biopsy clinic that runs more efficiently with improved patient satisfaction and trainee confidence when addressing patient concerns. This collaborative training experience also addresses many of the important aspects surrounding the Accreditation Council for Graduate Medical Education competencies in patient safety, procedure, communication, professionalism, and team-based systems. We report the details of these simulation sessions, how they are structured, key stakeholders involved, and means for communicating feedback to our learners with an emphasis on the importance and value of utilizing standardized patients.

Carboplatin and Pembrolizumab Chemoimmunotherapy Achieves Remission in Recurrent, Metastatic Sebaceous Carcinoma.

A 72-year-old Caucasian woman who had recurrent sebaceous carcinoma of the right orbit with bilateral cervical lymph node involvement 24 months after orbital exenteration was treated with carboplatin (area under the curve of 5) and pembrolizumab (2 mg/kg) for 6 cycles, followed by maintenance pembrolizumab. She obtained a complete pathological remission and remains free of local, regional, and systemic disease at 15 months.

Transition to Subspecialty Sign-Out at an Academic Institution and Its Advantages.

Many pathology departments are introducing subspecialty sign-out in surgical pathology. In 2014, the University of Vermont Medical Center transitioned from general sign-out to partial subspecialty sign-out to include gastrointestinal and breast/cervix subspecialty benches; other specimens remained on general benches. Our experiences with the transition are described, including attending pathologist, trainee, support staff, and clinician satisfaction. A survey was e-mailed to all University of Vermont Medical Center anatomic pathology attendings, pathology trainees, pathologist assistants and grossing technicians, and clinicians who send surgical pathology specimens, immediately before and 1 year after transitioning to partial subspecialty sign-out. Quality assurance metrics were obtained for the 18 months prior to and following the transition. Gastrointestinal and breast/cervix attendings were more satisfied with partial subspecialty sign-out compared to those on the general benches. Overall, trainees were more satisfied with general sign-out because of the rotation schedule but preferred partial subspecialty sign-out due to improved teaching and more focused learning while on subspecialty benches. Clinicians remained very satisfied with our department and our reports; no differences were observed. Turnaround time was unchanged. After switching to partial subspecialty sign-out, there were significantly fewer discrepancies following multidisciplinary conference review for gastrointestinal and breast/cervix cases but remained the same for general cases. Fewer formal internal consults were performed after transitioning to partial subspecialty sign-out across all areas, but more notable for gastrointestinal and breast/cervix cases. Our data show improved quality assurance metrics and trainee education in a subspecialty sign-out setting compared to general sign-out setting.

Metachronous Involvement, Diagnostic Imprecision of Serum Immunoglobulin G4 Levels, and Discordance Between Clinical and Radiological Findings in Immunoglobulin G4-Related Pachymeningitis: A Longitudinal Case Report.

Immunoglobulin G4-related disease is an increasingly recognized, idiopathic systemic disorder that might be associated with elevated serum IgG4 level and tissue infiltration by IgG4-positive plasma cells. We describe the clinical features and biopsy findings in a patient who presented with features suggestive of pachymeningitis and multiple cranial neuropathies. Meningeal biopsy and other laboratory studies established the diagnosis of IgG4-related hypertrophic pachymeningitis. Despite treatment with corticosteroids and mycophenolate mofetil, the patient exhibited a fluctuating progressive course, which stabilized with rituximab, although the radiological findings persisted over 2½ years of follow-up. Our case highlights many important evolving concepts in the disorder, including unusual pathologic features, lack of correlation between serum IgG4 levels and the clinical course, and posttreatment clinicoradiological discordance. We provide potential explanations for this discrepancy, highlight the validity of novel cerebrospinal fluid studies and progressive systemic involvement despite use of immune-suppressive treatments, and emphasize the usefulness of rituximab as a disease-stabilizing agent.

Paraproteinemic keratopathy in monoclonal gammopathy of undetermined significance treated with primary keratoprosthesis: Case report, histopathologic findings, and world literature review.

RATIONALE: We report a case of paraproteinemic keratopathy associated with monoclonal gammopathy of undetermined significance, treated with keratoprosthesis as a primary penetrating procedure. Histopathological findings and a world literature review are presented. PATIENT CONCERNS: A 74 year old female recently diagnosed with monoclonal gammopathy undetermined significance presented with progressive blurry vision bilaterally. DIAGNOSES: Examination revealed corneal opacities consistent with paraproteinemic keratopathy. INTERVENTIONS: Corneal transplantation with the Boston Type I keratoprosthesis was performed on the right and, a year later, on the left. OUTCOMES: Visual outcomes were good. Histopathological staining of host corneal buttons were consistent with monoclonality, and electron microscopy revealed fibrillar extracellular aggregates within intervening normal stroma. LESSONS: Corneal deposits may be the only manifestation of monoclonal gammopathy of undetermined significance in patients who are otherwise systemically asymptomatic. Ophthalmologists who encounter corneal opacities may order the appropriate diagnostic studies to determine the presence of occult systemic disease. Risk of graft failure after penetrating keratoplasty from recurring opacities is high, so keratoprosthesis as a primary penetrating procedure may afford superior long-term outcomes. Host corneal buttons retrieved from penetrating keratoplasty or corneal biopsy may be sent for histopathological examination to confirm the diagnosis.

Reversal of Gastric Bypass Resolves Hyperoxaluria and Improves Oxalate Nephropathy Secondary to Roux-en-Y Gastric Bypass.

Hyperoxaluria after Roux-en-Y gastric bypass (RYGB) increases the risk for kidney injury. Medical therapies for hyperoxaluria have limited efficacy. A 65-year-old female was evaluated for acute kidney injury [AKI, serum creatinine (Cr) 2.1 mg/dl, baseline Cr 1.0 mg/dl]. She did not have any urinary or gastrointestinal symptoms or exposure to nephrotoxic agents. Sixteen months prior to this evaluation, she underwent RYGB for morbid obesity. Her examination was unremarkable for hypertension or edema and there was no protein or blood on urine dipstick. Kidney biopsy revealed acute tubulointerstitial nephritis with oxalate crystals in tubules. The concurrent finding of severe hyperoxaluria (urine oxalate 150 mg/day) confirmed the diagnosis of oxalate nephropathy. Despite medical management of hyperoxaluria, her AKI worsened. Laparoscopic reversal of RYGB was performed and within 1 month, her hyperoxaluria resolved (urine oxalate 20 mg/day) and AKI improved (Cr 1.7 mg/dl). Surgical reversal of RYGB may be considered in patients with oxalate nephropathy at high risk of progression who fail medical therapy. Physicians need to be aware of the possibility of oxalate nephropathy after RYGB and promptly treat the hyperoxaluria to halt further kidney damage.

Primary vaginal mucinous adenocarcinoma of intestinal type, associated with intestinal metaplasia of Skene ducts in a diethylstilbestrol-exposed woman.

OBJECTIVES: Primary mucinous vaginal adenocarcinoma of intestinal type is an extremely rare malignancy of uncertain histogenesis, which makes for a diagnostic challenge. We report a case and describe the histopathologic features and the unusual immunoprofile of this rare entity. METHODS: We report a case of vaginal mucinous adenocarcinoma of intestinal type in a diethylstilbestrol-exposed woman in which intestinal metaplasia of the Skene duct was found at the time of recurrence. RESULTS: As the histogenesis of primary vaginal intestinaltype adenocarcinomas remains uncertain, the finding of Skene duct metaplasia in association with invasive adenocarcinoma lends support to the origin of vaginal mucinous adenocarcinomas of intestinal type to be metaplasia, at least in some cases. Such an origin accounts for the unusual immunohistochemical profile, which raises concern for a metastatic adenocarcinoma of gastrointestinal origin. CONCLUSIONS: Recognition of this rare entity is important, particularly to avoid the pitfall of misdiagnosing metastatic disease.

High dose intracoronary N-acetylcysteine in a porcine model of ST-elevation myocardial infarction.

We sought to evaluate the safety and efficacy of N-acetylcysteine (NAC) on ischemia and reperfusion in a pig model focusing on cardio-renal protection. High doses of NAC may provide protection from contrast induced nephropathy (CIN). NAC has also been demonstrated to reduce myocardial infarction size and improve left ventricular function after ischemia in both humans and animals studies. In this study we tested the safety and cardiorenal protective efficacy of intracoronary NAC delivered in the radiographic contrast agent in a pig model that simulates the catheter based reperfusion therapy of ST elevation myocardial infarctions. 27 pigs underwent 45 min of ischemia after surgical ligation of distal left descending coronary artery. With coronary reperfusion the animals received at total of 200 mL of the contrast agent Iopamidol with and without NAC to mimic radiographic contrast use during invasive reperfusion therapy. At 24 h the following endpoints were compared: LV function (MRI, echocardiography), myocardial injury (infarct size, area-at-risk, troponin, creatinine kinase) and CIN (creatinine, BUN and renal histology). The effects of NAC on platelet reactivity were also evaluated. Intracoronary administration of NAC administered in the contrast agent is safe. NAC reduces platelet reactivity and there was a trend towards a better cardiac function at 24 h. There was no significant difference in the size of the myocardial infarction. In this model of ischemia-reperfusion high dose NAC did not protect from CIN. High dose intracoronary NAC administered with the radiographic contrast is safe but does not provide significant cardio-renal protection.

HER-2/neu detection in fine-needle aspirates of breast cancer: fluorescence in situ hybridization and immunocytochemical analysis.

We evaluated HER-2 receptor status by immunocytochemical and immunohistochemical analyses and fluorescence in situ hybridization (FISH) in 51 fine-needle aspiration (FNA) specimens together with the corresponding formalin-fixed, paraffin-embedded (FFPE) tissue samples obtained from surgically resected breast cancers. Three fixation methods were compared: ethanol, formalin, and CytoLyt-ThinPrep (Cytyc, Boxborough, MA). HER-2 was overexpressed and amplified in 8 (16%) of 51 FFPE specimens. Of the 8 cases, gene amplification was observed in 8 FNA specimens (100%) and overexpression in 2 (25%) ethanol-, 4 (50%) CytoLyt-, and 5 (63%) formalin-fixed FNA specimens. Strong pairwise kappa association between FISH results performed on FNA specimens and FFPE tissue samples (ethanol fixation, kappa = 0.848; ThinPrep, kappa = 0.918) and moderate (ThinPrep, kappa = 0.692; formalin fixation, kappa = 0.667) to poor (ethanol, kappa = 0.300) pairwise kappa agreement between tissue immunohistochemical and FNA immunocytochemical results was demonstrated. We conclude that HER-2 protein expression on cytologic preparations was insufficiently reliable for clinical use, whereas HER-2 gene amplification determined by FISH demonstrated strong and consistent correlation with HER-2 status of FFPE tissue samples.