Spindle epithelial tumor with thymus-like differentiation in fine needle aspiration of thyroid gland: Report of two cases.

Spindle epithelial tumor with thymus-like differentiation (SETTLE) is a rare, malignant tumor of the thyroid gland that typically affects young males and has a propensity for late metastasis. With fine needle aspiration (FNA) being a primary tool for diagnosis of thyroid lesions, there are rare reports of cytological features of SETTLE on FNA since its initial characterization 30 years ago . Here we report two cases of SETTLE, involving 9-year-old and 15-year-old male patients. Both patients underwent US-guided FNA with a subsequent resection confirming the diagnosis of SETTLE. In the first patient the thymic origin of the tumor was suspected on FNA, but the diagnosis of SETTLE was established only after resection. Five years later, this patient presented with an enlarged ipsilateral cervical lymph node. Needle biopsy confirmed it to be a metastatic tumor compatible with SETTLE. In the second patient the diagnosis of SETTLE was suggested on FNA. Cytology of the thyroid gland nodule on FNA from both patients showed loosely cohesive and single spindle-shaped epithelial cells associated with metachromatic stroma. The differential diagnosis of spindle cell lesions of the thyroid should include SETTLE based on characteristic morphological features, after more common entities of thyroid gland such as medullary carcinoma are excluded.

Human muscle stem cells are refractory to aging.

Age-related loss of muscle mass and strength is widely attributed to limitation in the capacity of muscle resident satellite cells to perform their myogenic function. This idea contains two notions that have not been comprehensively evaluated by experiment. First, it entails the idea that we damage and lose substantial amounts of muscle in the course of our normal daily activities. Second, it suggests that mechanisms of muscle repair are in some way exhausted, thus limiting muscle regeneration. A third potential option is that the aged environment becomes inimical to the conduct of muscle regeneration. In the present study, we used our established model of human muscle xenografting to test whether muscle samples taken from cadavers, of a range of ages, maintained their myogenic potential after being transplanted into immunodeficient mice. We find no measurable difference in regeneration across the range of ages investigated up to 78 years of age. Moreover, we report that satellite cells maintained their myogenic capacity even when muscles were grafted 11 days postmortem in our model. We conclude that the loss of muscle mass with increasing age is not attributable to any intrinsic loss of myogenicity and is most likely a reflection of progressive and detrimental changes in the muscle microenvironment such as to disfavor the myogenic function of these cells.

Clinically Unsuspected Injection Drug Abuse in Hospitalized Teens Diagnosed on Pathology.

Intravenous injection of medications intended for oral use can lead to pulmonary hypertension and death. Pathologic findings in the lung include embolization of foreign material, with the specific identification of excipients accomplished through special stains. Risk factors for this type of drug abuse include indwelling venous access and chronic medical problems. These risk factors, especially in adolescent and young adult patients, should prompt intravenous drug use as a possibility of lung disease/lesions. We describe 2 patients from a pediatric hospital with pulmonary pathology indicative of intravenous drug use, identified in autopsy and surgical pathology cases. Drug abuse was not clinically suspected in either patient until the time of pathologic exam, emphasizing a need for the pathologist to be able to recognize the associated histologic changes.

Characterizing placental stiffness using ultrasound shear-wave elastography in healthy and preeclamptic pregnancies.

PURPOSE: To measure the stiffness of the placenta in healthy and preeclamptic patients in the second and third trimesters of pregnancy using ultrasound shear-wave elastography (SWE). We also aimed to evaluate the effect of age, gestational age, gravidity, parity and body mass index (BMI) on placental stiffness and a possible correlation of stiffness with perinatal outcomes. METHODS: In a case-control study, we recruited a total of 47 singleton pregnancies in the second and third trimesters of which 24 were healthy and 23 were diagnosed with preeclampsia. In vivo placental stiffness was measured once at the time of recruitment for each patient. Pregnancies with posterior placentas, multiple gestation, gestational hypertension, chronic hypertension, diabetes, autoimmune disease, fetal growth restriction and congenital anomalies were excluded. RESULTS: The mean placental stiffness was significantly higher in preeclamptic pregnancies compared to controls in the third trimester (difference of means = 16.8; 95% CI (9.0, 24.5); P < 0.001). There were no significant differences in placental stiffness between the two groups in the second trimester or between the severe preeclampsia and preeclampsia without severe features groups (difference of means = 9.86; 95% CI (-5.95, 25.7); P ≥ 0.05). Peripheral regions of the placenta were significantly stiffer than central regions in the preeclamptic group (difference of means = 10.67; 95% CI (0.07, 21.27); P < 0.05), which was not observed in the control group (difference of means = 0.55; 95% CI (- 5.25, 6.35); P > 0.05). We did not identify a correlation of placental stiffness with gestational age, maternal age, gravidity or parity. However, there was a statistically significant correlation with BMI (P < 0.05). In addition, pregnancies with higher placental stiffness during the 2nd and 3rd trimesters had significantly reduced birth weight (2890 ± 176 vs. 2420 ± 219 g) and earlier GA (37.8 ± 0.84 vs. 34.3 ± 0.98 weeks) at delivery (P < 0.05). CONCLUSION: Compared to healthy pregnancies, placentas of preeclamptic pregnancies are stiffer and more heterogeneous. Placental stiffness is not affected by gestational age or the severity of preeclampsia but there is a correlation with higher BMI and poor perinatal outcomes.

High-Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

PURPOSE: Immunotherapy promises unprecedented benefits to patients with cancer. However, the majority of cancer types, including high-risk neuroblastoma, remain immunologically unresponsive. High-intensity focused ultrasound (HIFU) is a noninvasive technique that can mechanically fractionate tumors, transforming immunologically "cold" tumors into responsive "hot" tumors. EXPERIMENTAL DESIGN: We treated <2% of tumor volume in previously unresponsive, large, refractory murine neuroblastoma tumors with mechanical HIFU and assessed systemic immune response using flow cytometry, ELISA, and gene sequencing. In addition, we combined this treatment with αCTLA-4 and αPD-L1 to study its effect on the immune response and long-term survival. RESULTS: Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances antitumor response, improving survival from 0% to 62.5%. HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL2, IFNγ, and DAMPs, whereas immune regulators like CD4+Foxp3+, IL10, and VEGF-A are significantly reduced. HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4+, CD8α+, and CD8α+CD11c+ cells, CD11c+ in regional lymph nodes, and decrease in circulating IL10 compared with untreated group. We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared with tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, P < 0.0001). This combination treatment significantly also induces CD4+CD44+hiCD62L+low and CD8α+CD44+hiCD62L+low population and is adoptively transferable, imparting immunity, slowing subsequent de novo tumor engraftment. CONCLUSIONS: Mechanical fractionation of tumors using HIFU can effectively induce immune sensitization in a previously unresponsive murine neuroblastoma model and promises a novel yet efficacious immunoadjuvant modality to overcome therapeutic resistance.

Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system.

PURPOSE: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. METHODS AND MATERIALS: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 × 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. RESULTS: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. CONCLUSION: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system.

Quantification of Thyroid Cancer and Multinodular Goiter Risk in the DICER1 Syndrome: A Family-Based Cohort Study.

Context: The risk of thyroid cancer and multinodular goiter (MNG) in DICER1 syndrome, a rare tumor-predisposition disorder, is unknown. Objective: To quantify the risk of thyroid cancer and MNG in individuals with DICER1 syndrome. Design: Family-based cohort study. Setting: National Institutes of Health (NIH) Clinical Center (CC). Participants: The National Cancer Institute DICER1 syndrome cohort included 145 individuals with a DICER1 germline mutation and 135 family controls from 48 families. Interventions: Each individual completed a detailed medical history questionnaire. A subset underwent a 3-day evaluation at the NIH CC. Main Outcome Measures: The cumulative incidence of MNG (or thyroidectomy) was quantified using the complement of the Kaplan-Meier product limit estimator. We compared the observed number of thyroid cancers in the NCI DICER1 cohort with matched data from the Surveillance, Epidemiology, and End Results (SEER) Program. We performed germline and somatic (thyroid cancer, MNG) DICER1 sequencing. Results: By the age of 40 years, the cumulative incidence of MNG or thyroidectomy was 75% in women and 17% in men with DICER1 syndrome compared with 8% of control women (P < 0.001) and 0% of control men (P = 0.0096). During 3937 person-years of observation, individuals with DICER1 syndrome had a 16-fold increased risk of thyroid cancer (95% confidence interval, 4.3 to 41; P < 0.05) compared with the SEER rates. Of 19 MNG nodules and 3 thyroid cancers, 16 (84%) and 3 (100%), respectively, harbored germline and somatic pathogenic DICER1 mutations. Conclusions: We propose a model of thyroid carcinogenesis in DICER1 syndrome. Early-onset, familial, or male MNG should prompt consideration of the presence of DICER1 syndrome.

Boiling histotripsy lesion characterization on a clinical magnetic resonance imaging-guided high intensity focused ultrasound system.

PURPOSE: High intensity focused ultrasound (HIFU) is a non-invasive therapeutic technique that can thermally ablate tumors. Boiling histotripsy (BH) is a HIFU approach that can emulsify tissue in a few milliseconds. Lesion volume and temperature effects for different BH sonication parameters are currently not well characterized. In this work, lesion volume, temperature distribution, and area of lethal thermal dose were characterized for varying BH sonication parameters in tissue-mimicking phantoms (TMP) and demonstrated in ex vivo tissues. METHODS: The following BH sonication parameters were varied using a clinical MR-HIFU system (Sonalleve V2, Philips, Vantaa, Finland): acoustic power, number of cycles/pulse, total sonication time, and pulse repetition frequency (PRF). A 3×3×3 pattern was sonicated inside TMP's and ex vivo tissues. Post sonication, lesion volumes were quantified using 3D ultrasonography and temperature and thermal dose distributions were analyzed offline. Ex vivo tissues were sectioned and stained with H&E post sonication to assess tissue damage. RESULTS: Significant increase in lesion volume was observed while increasing the number of cycles/pulse and PRF. Other sonication parameters had no significant effect on lesion volume. Temperature full width at half maximum at the end of sonication increased significantly with all parameters except total sonication time. Positive correlation was also found between lethal thermal dose and lesion volume for all parameters except number of cycles/pulse. Gross pathology of ex vivo tissues post sonication displayed either completely or partially damaged tissue at the focal region. Surrounding tissues presented sharp boundaries, with little or no structural damage to adjacent critical structures such as bile duct and nerves. CONCLUSION: Our characterization of effects of HIFU sonication parameters on the resulting lesion demonstrates the ability to control lesion morphologic and thermal characteristics with a clinical MR-HIFU system in TMP's and ex vivo tissues. We demonstrate that this system can produce spatially precise lesions in both phantoms and ex vivo tissues. The results provide guidance on a preliminary set of BH sonication parameters for this system, with a potential to facilitate BH translation to the clinic.

Solution blow spun polymer: A novel preclinical surgical sealant for bowel anastomoses.

BACKGROUND: Solution blow spinning is a technique for depositing polymer fibers with promising potential use as a surgical sealant. This study assessed the feasibility and efficacy of solution blow spun polymer (BSP) for sealing bowel perforations in a mouse model of partial cecal transection. We then evaluated its use for reinforcing a surgical anastomosis in a preclinical piglet model. METHODS: Three commercially available surgical sealants (fibrin glue, polyethylene glycol (PEG) hydrogel, and cyanoacrylate) were compared to BSP in the ability to seal partially transected cecum in mice. For anastomosis feasibility testing in a piglet model, piglets were subjected to small bowel transection with sutured anastomosis reinforced with BSP application. Outcome measures included anastomotic burst pressure, anastomotic leak rate, 14-day survival, and complication rate. RESULTS: For the mouse model, the survival rates for the sealants were 30% for fibrin glue, 20% for PEG hydrogel, 78% for cyanoacrylate, and 67% for BSP. Three of 9 mice died after BSP administration because of perforation leak, failure to thrive with partial obstruction at the perforation site, and unknown causes. All other mice died of perforation leak. The mean burst pressure at 24h was significantly higher for BSP (81mm Hg) when compared to fibrin glue (6mm Hg, p=0.047) or PEG hydrogel (10mm Hg, p=0.047), and comparable to cyanoacrylate (64mm Hg, p=0.91). For piglets, 4 of 4 animals survived at 14days. Mean burst pressures at time of surgery were 37±5mm Hg for BSP and 11±9mm Hg for suture-only controls (p=0.09). CONCLUSIONS: Solution blow spinning may be an effective technique as an adjunct for sealing of gastrointestinal anastomosis. Further preclinical testing is warranted to better understand BSP properties and alternative surgical applications.

Inflammatory myofibroblastic tumor as a second neoplasm after Wilms tumor.

We report two survivors of Wilms tumor (WT) who developed inflammatory myofibroblastic tumor (IMT). The first patient had IMT in the mainstem bronchus 1 year after WT therapy that included vincristine, dactinomycin, doxorubicin (VDA) and whole lung radiation therapy (XRT). The second patient had IMT in the cecum 7 years after WT therapy consisting of VDA and abdominal XRT. The unlikely co-occurrence of WT and IMT suggests a genetic link between these tumors or that IMT can arise as a complication of cancer therapy. IMT should be considered in WT survivors who develop secondary tumors, especially at unusual sites.

DICER1 mutations in childhood cystic nephroma and its relationship to DICER1-renal sarcoma.

The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma.

Large occipital aneurysmal bone cyst causing obstructive hydrocephalus in a pediatric patient.

Aneurysmal bone cyst (ABC) is an uncommon benign, tumorlike lesion of bone that is usually located in the long bones and spine. On rare occasions, ABCs are found in the bones of the cranial vault and skull base, occasionally causing mass effect and cranial nerve findings. In this report the authors detail the case of a patient who presented with incidentally discovered hydrocephalus due to a large ABC of the occipital bone that produced mass effect and obstruction of CSF. The diagnosis, imaging findings, and surgical management of this interesting and rare case are discussed.

DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome.

Embryonal rhabdomyosarcoma (ERMS) is the most common childhood sarcoma and is a component of the familial pleuropulmonary blastoma (PPB)-predisposition syndrome. Using the PPB model, we hypothesized that DICER1 mutations would be found in familial and sporadic forms of ERMS. Blood samples from four children with familial PPB and ERMS, and 52 sporadic ERMS tumors were tested for DICER1 mutations. Germline DICER1 mutations were found in all four patients with familial PPB and 2 of 52 (3.8%) sporadic ERMS had somatic mutations. Our findings confirm the pathogenetic relationship between ERMS and PPB suggesting that ERMS may result from abnormal miRNA regulation.

Unexpected pathologies in pediatric parotid lesions: management paradigms revisited.

OBJECTIVES: To present case vignettes of unusual pediatric parotid pathologies and discuss management paradigms in the context of these lesions. STUDY DESIGN: Retrospective case series. SETTING: Free-standing, academic tertiary care pediatric hospital. METHODS: All patients over the past 18 months undergoing parotidectomy for a parotid mass were reviewed (N=5). RESULTS: Ages ranged from 17 months to 16 years. All presented with a remarkably similar clinical course, consisting of a persistent parotid mass for more than 3 months which was usually painless. Most (4/5 patients) had been treated with antibiotics prior to Otolaryngology consultation. Fine-needle aspiration (FNA) was performed on 3 patients and was diagnostic in one. Complete excision of the mass was performed in each child through a parotidectomy approach (3 total, 2 lateral lobe). The final pathology showed metastatic neuroblastoma (17 months old), undifferentiated primitive sarcoma (22 months old), mucoepidermoid carcinoma (11 years old), nodular fasciitis (12 years old), and hyperplastic lymph node (16 years old). The patient with neuroblastoma died from complications of bone marrow transplant. CONCLUSIONS: The differential diagnosis for a persistent pediatric parotid mass is expansive and differs from that found in the adult population. As this series highlights, in many cases, it is impossible to discern the pathology, or rule out malignancy, based upon the clinical course, imaging, or FNA results. Surgical excision remains the standard for management of these patients and is both diagnostic and therapeutic. Our anecdotal case series highlights the importance of having a low threshold for parotidectomy in these children.

Solid pseudopapillary tumor in a pancreatic rest of the jejunum.

Solid pseudopapillary tumors of the pancreas (SPTP) are very rare, and an SPTP arising in a pancreatic rest has been reported only 4 times previously and never in association with the jejunum. We report this unusual case of a 16 year old girl who presented with 4 days of intermittent, crampy abdominal pain and was found to have an SPTP arising in a pancreatic rest of the jejunum.