Faculty Bibliography

INTRODUCTION:This study was performed to determine the feasibility and safety of creating superficial histotripsy treatment in a live porcine thyroid model. METHODS:The porcine thymus comparable in size, shape and location to the human thyroid was used for this study. This model has been used for thyroid surgery studies due to the diminutive size of the porcine thyroid. Four female swine underwent a total of eight histotripsy treatments performed with a prototype therapy system (HistoSonics, Inc., Ann Arbor, MI). Two treatments were performed in each animal: a spherical 1.0 × 1.0 × 1.0 cm and ovoid 1.0 × 1.0 × 2.0 cm treatment zones. MRI immediately post-procedure was evaluated for histotripsy treatment zone size and imaging appearance, followed immediately by sacrifice. Tissue was then reviewed for percent cellular destruction and precision. RESULTS: > 0.05 vs. prescribed). MRI demonstrated well demarcated treatment zones and imaging findings consistent with cellular destruction. Histology demonstrated sharp transitions to normal tissue (mean 0.33 (+/- 0.13) cm), and high degrees of cellular destruction (mean 76% (+/- 12.5), range of 50-100%) in the treated tissue. Edema within the overlying muscle was seen in 2/8 treatments. CONCLUSION:Histotripsy is capable of safely creating precise histotripsy treatments within the superficial neck of a porcine thyroid model without evidence of considerable complications.

BACKGROUND:Previous human-scale porcine liver model studies of histotripsy have resulted in ablation zones elongated in the cranial-caudal (CC) dimension due to uninterrupted respiratory motion during the ablation procedure. PURPOSE/OBJECTIVE:The purpose of this study is to compensate for elongation of hepatic histotripsy ablation zones in the cranial-caudal (CC) dimension caused by respiratory motion by prescribing ellipsoid-shaped ablations. METHODS:Six female swine underwent 12 hepatic histotripsy ablations using a prototype clinical histotripsy system under general anesthesia. Each animal received two ablation zones prescribed as either an ellipsoid (2.5 cm (AP) × 2.5 cm (ML) × 1.7 cm (CC), prescribed volume = 5.8 cc) or a sphere (2.5 cm all dimensions, prescribed volume 8.2 cc). Ventilatory tidal volume was held constant at 400 cc for all ablations. Post-procedure MRI was followed by sacrifice and gross and microscopic histology. RESULTS:Ablations on MRI were slightly larger than prescribed in all dimensions. Ellipsoid plan ablations (2.8 × 3.0 × 3.1 cm, volume 13.2 cc, sphericity index 0.987) were closer to prescribed volume than spherical plan ablations (2.9 × 3.1 × 3.7 cm, volume 17.1 cc, sphericity index 0.953). Ellipsoid plan ablations were more spherical than sphere plan ablations, but the difference did not reach statistical significance (p = .0.06). Pathologic analysis confirmed complete necrosis within the center of each ablation zone with no widening of the zone of partial ablation on the superior and inferior as compared to the lateral borders (p = .0.22). CONCLUSION/CONCLUSIONS:Altering ablation zone prescription shape when performing hepatic histotripsy ablations can partially mitigate respiratory motion effects to achieve the desired ablation shape and volume.

The SMAD4 tumor suppressor gene product inhibits transforming growth factor-β-mediated signaling and is mutated in ~10% of colorectal carcinomas. The prognostic significance of SMAD4 mutations has been controversial. We studied the pathological and clinical characteristics of SMAD4-mutated intestinal adenocarcinomas using a retrospective case-control study design. Cases and controls were identified among 443 primary adenocarcinomas that had undergone next generation DNA sequencing (NGS) with the Ion AmpliSeq Cancer Hotspot Panel v2, which evaluates 50 cancer-related genes. Twenty-eight SMAD4-mutated (SMAD4m) patients were matched 1:2 with 56 consecutive SMAD4 wild-type (SMAD4wt) control patients from the same analysis stream. Compared with the SMAD4wt controls, the SMAD4m tumors were of higher stage (P = 0.026) and were more likely to feature mucinous differentiation (P = 0.0000), to occur in the setting of Crohn's disease (P = 0.0041), and to harbor concurrent RAS mutations (P = 0.0178). Tumor mucin content was significantly correlated with mutations involving the MH2 domain of the SMAD4 protein (P = 0.0338). Correspondence between mutation sites and morphology was demonstrated directly in a mixed adenocarcinoma and neuroendocrine tumor where SMAD4 mutations involving different protein domains were found in histologically disparate tumor regions despite both containing identical KRAS and TP53 mutations.

Upper gastrointestinal metastasis of endometrial carcinoma rarely occurs in the absence of locoregional disease and other distant metastases. We describe herein the unique case of an isolated gastric metastasis of a stage I endometrial adenocarcinoma. Because the metastatic tumor was initially misdiagnosed clinically and pathologically as a primary gastric carcinoma, we illustrate the histopathology and review the pertinent literature. A 42-year-old woman with Lynch syndrome underwent treatment of endometrial adenocarcinoma at an outside hospital comprising clinical and radiological staging including a positron emission tomography-computed tomography (PET-CT) scan followed by a total intra-abdominal hysterectomy, bilateral salpingoophorectomy and pelvic and paraaortic lymphadenectomy. The preoperative and pathology findings were consistent with a stage I tumor. Three months postoperatively, a PET-CT scan revealed a new 4.4 cm hypermetabolic lesion in the stomach. A biopsy of the lesion was interpreted pathologically as gastric adenocarcinoma with lymphoid stroma. Upon referral of the patient to our center for management, the biopsy was reviewed in consultation and the pathology materials from the hysterectomy procedure were retrieved for comparison. Based on the morphological and immunohistochemical similarities between the tumors the gastric tumor was diagnosed as metastatic endometrial adenocarcinoma. To our knowledge, this is the first documented case of an isolated gastric metastasis complicating stage I endometrial adenocarcinoma. Awareness of the potential for this occurrence and of the associated diagnostic pitfalls is crucial for accurate diagnosis and therapy.

Intestinal stricture, a major complication of Crohn's disease (CD), results from fibromuscular remodeling and expansion of the intestinal wall. The corresponding microanatomical alterations have not been fully described, hindering progress toward understanding their pathogenesis and devising appropriate treatments. We used tissue-specific staining and quantitative digital histomorphometry for this purpose. Serial histologic sections from 37 surgically resected ileal strictures and adjacent nonstrictured controls from patients with CD were evaluated after staining for smooth muscle actin, collagen (Sirius red), and collagen types I, III, and V. Overall mural thickening in strictures was increased 2.2 ± 0.2-fold compared with nonstrictured regions of the same specimens. The muscular layer most altered was the muscularis mucosae (MM). Compared with the internal and external layers of the muscularis propria, (MP) which were expanded 1.9 ± 0.2- and 1.3 ± 0.1-fold, respectively, the MM was expanded 17.7 ± 2.6-fold, reflecting the combined effects of architectural disarray, an 11.6 ± 1.4-fold increase smooth muscle content, and elaboration of pericellular type V collagen. In contrast, the architecture of the MP was preserved and pericellular collagen was virtually absent; rather, fibrosis in this layer was limited to expansion of the intramuscular septa by collagen types I and III. The muscular arteries and veins within the strictured submucosa frequently exhibited eccentric, luminally oriented adventitial mantles comprising hyperplastic myocytes and extracellular type V collagen. We conclude that the fibromuscular remodeling which results in CD-associated ileal strictures predominantly involves the MM and submucosal vasculature in a luminally polarized fashion and suggests that mucosal-based factors may contribute to stricture pathogenesis.

Background and aims/UNASSIGNED:Recently, smooth muscle hypertrophy has been suggested to be a contributor in small bowel lesions secondary to Crohn's disease (CD), in addition to inflammation and fibrosis. Here, we assess the value of magnetic resonance imaging (MRI) for the characterization of histopathologic tissue composition of small bowel CD, including inflammation, fibrosis and smooth muscle hypertrophy. Methods/UNASSIGNED:35 consecutive patients (M/F 17/18, mean age 33y) with ileal CD who underwent small bowel resection (for stricture in 27 patients) and a preoperative contrast-enhanced MRI exam within one month before surgery were retrospectively included. Image assessment included qualitative (pattern/degree of enhancement, presence of ulcerations/fistulas/abscesses) and quantitative parameters [wall thickness on T2/T1-weighted images (WI), enhancement ratios, apparent diffusion coefficient (ADC), Clermont and MaRIA scores]. MRI parameters were compared with histopathologic findings including active inflammation, collagen deposition and muscle hypertrophy using Chi-2/Fisher or Mann-Whitney tests, and univariate/multivariate logistic/linear regression analyses. Results/UNASSIGNED:Forty ileal segments were analyzed in 35 patients. Layered pattern at early-post-contrast phase was more prevalent (OR=8/p=0.015), ADC was significantly lower (OR=0.005/p=0.028) and MaRIA score was significantly higher (OR=1.125/p=0.013) in inflammation grades 2-3 compared to grade 1. Wall thickness on T2WI was significantly increased (OR=1.688/p=0.043), and fistulas (OR=14.5/p=0.017) were more prevalent in segments with disproportionately increased muscle hypertrophy vs. those with disproportionately increased fibrosis. MaRIA/Clermont scores, wall thickness on T1WI and T2WI and ADC were all significantly correlated with degree of muscular hypertrophy. Conclusion/UNASSIGNED:MRI predicts the degree of inflammation, and can distinguish prominent muscle hypertrophy from prominent fibrosis in ileal CD with reasonable accuracy (AUROC>0.7).

Transcription factor MEF2C regulates multiple genes linked to autism spectrum disorder (ASD), and human MEF2C haploinsufficiency results in ASD, intellectual disability, and epilepsy. However, molecular mechanisms underlying MEF2C haploinsufficiency syndrome remain poorly understood. Here we report that Mef2c ^+/-(Mef2c-het) mice exhibit behavioral deficits resembling those of human patients. Gene expression analyses on brains from these mice show changes in genes associated with neurogenesis, synapse formation, and neuronal cell death. Accordingly, Mef2c-het mice exhibit decreased neurogenesis, enhanced neuronal apoptosis, and an increased ratio of excitatory to inhibitory (E/I) neurotransmission. Importantly, neurobehavioral deficits, E/I imbalance, and histological damage are all ameliorated by treatment with NitroSynapsin, a new dual-action compound related to the FDA-approved drug memantine, representing an uncompetitive/fast off-rate antagonist of NMDA-type glutamate receptors. These results suggest that MEF2C haploinsufficiency leads to abnormal brain development, E/I imbalance, and neurobehavioral dysfunction, which may be mitigated by pharmacological intervention.

BACKGROUND:The purpose of this study was to determine the impact of revised ASCO/CAP 2013 HER2 guidelines on the clinical practice of pathologists and oncologists. MATERIALS AND METHODS:Retrospective analysis of 1739 patients with invasive breast carcinoma who underwent reflex HER2 (fluorescence in situ hybridization [FISH]) testing, using both 2007 and 2013 guidelines (2007-2014). RESULTS:by 2013 guidelines. Sixty-two of these 69 cases shifted from HER2 equivocal to positive due to change in FISH ratio cutoff from 2.2 to 2.0. Six cases had FISH ratio < 2.0 but immunohistochemistry (IHC) score 3+ in 10% to 30% of tumor cells. One case had FISH ratio of 2.0 and IHC score 3+ in 10% to 30% of tumor cells. FISH and IHC test results were discordant in 5% (95% CI, 4%-6%) of cases using 2013 guidelines. No increase in HER2 FISH equivocal cases was observed. Reflex FISH testing of all IHC 1+ cases at our institution additionally detected 58 patients (5%; 95% CI, 4%-6%) with HER2 amplification. CONCLUSIONS:cases, without introducing significant difference in discordance rate of the IHC and FISH assays. Inclusion of HER2 copy number criterion does not increase the number of FISH equivocal cases in our cohort. We recommend IHC 1+ cases should be offered reflex FISH testing because failure to test them will miss a small number (5%) of potentially treatable cases.