Tissue response following implantation with the posterior dynamic distraction device (PDDD) in adolescent idiopathic scoliosis (AIS).

PURPOSE: The PDDD is a ratchet-based, unidirectional expandable rod to treat adolescent idiopathic scoliosis (AIS), primarily by correcting scoliotic deformity without full spinal fusion. We hypothesized that the device will be fully tolerated by the host and, if aseptic screw loosening occurs, it will be unrelated to wear particle formation. METHODS: This study comprised tissue samples from seven patients from a prospective study (NCT04296903) to assess the PDDD's safety and benefits, reoperated due to complications. Host response was assessed from histological slides (four levels/implant) in accordance with GLP and ISO10993-6:2016. The elementary chemical composition of wear particles present in tissue sections was quantified by energy dispersive X-ray spectroscopy (EDX). RESULTS: Host reaction was minor, characterized by low levels of diverse inflammatory cells, mild fibrosis, occasional small necrotic foci, neovascularization, hemorrhage, and, rarely, small bone fragments. Twenty-four of 28 tissue sections displayed varying degrees of wear particles (black discoloration), and most sections (17) were scored as 1 (< 25% of the sample). The discoloration observed corresponded to black-appearing, fine granular pigment. EDX analysis confirmed particles were composed of titanium, aluminum, and vanadium. Twenty-six of 28 samples were scored zero for necrosis and 2/28 were scored 1. Eleven samples were scored zero for fibrosis, 12 as 1, and five as 2. No aseptic screw loosening occurred. CONCLUSION: The PDDD induced minimal host reaction with little or no degeneration, inflammation or fibrosis. No changes present could be expected to promote device failure. The PDDD implant for treating AIS is well-tolerated and locally safe.

Functional neuronal circuits promote disease progression in cancer.

The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or normal tissues. We also demonstrate pharmacologic silencing of tumoral electrical activity. Tumors implanted in transgenic animals lacking nociceptor neurons show reduced electrical activity. These data suggest that intratumoral nerves remain functional at the tumor bed. Immunohistochemical staining demonstrates the presence of the neuropeptide, Substance P (SP), within the tumor space. We show that tumor cells express the SP receptor, NK1R, and that ligand/receptor engagement promotes cellular proliferation and migration. Our findings identify a mechanism whereby intratumoral nerves promote cancer progression.

Diffuse Ganglioneuromatosis of the Colon in a Patient with Neurofibromatosis 1.

Ganglioneuromas are rare, benign neurogenic tumors characterized by a proliferation of ganglion cells, nerve fibers, and support cells of the nervous system. They have been classified into three groups: solitary, polyposis, and diffuse. The diffuse type has several syndromic associations including multiple endocrine neoplasia syndrome type 2B and, less commonly, neurofibromatosis type 1. We report a case of diffuse ganglioneuromatosis in the colon of a 49-yearold male with a history of neurofibromatosis type 1. Gastrointestinal neoplasms associated with neurofibromatosis type 1 are reviewed.

An Incidental Finding of Paratesticular Malignant Mesothelioma During Operation for Hydrocelectomy.

Paratesticular malignant mesothelioma is a rare and potentially aggressive malignancy, accounting for approxi- mately 0.3-1.4 percent of all malignant mesotheliomas. The tumor presents as a painless scrotal mass associated with recurrent hydrocele. We report an incidental case of paratesticular malignant mesothelioma in a 73-year- old man that was found during an operation to remove a progressively enlarging, symptomatic hydrocele. During the procedure the surgeon noted multiple, irregular, extratesticular masses, and subsequently submitted a sam- ple for frozen section analysis. Frozen section assessment revealed a papillary-appearing, malignant tumor and the surgeon proceeded with a radical orchiectomy. Examination of the orchiectomy specimen revealed multiple, yellow-white, papillary, exophytic excrescences that tracked along the hydrocele and coursed up the tunica vagi- nalis of the spermatic cord. Microscopically, the tumor was composed of papillary fronds and nests of malignant cells with enlarged, hyperchromatic, pleomorphic nuclei. Pankeratin and calretinin immunohistochemical stains strongly highlighted the tumor cells, supporting the diagnosis of malignant mesothelioma. Suspicion of malignant mesothelioma as a differential diagnosis in the setting of enlarging hydrocele is imperative, as the care of the patient is dramatically altered to address the aggressive nature of the disease and the unfavorable outcome.

Cancer exosomes induce tumor innervation.

Patients with densely innervated tumors suffer with increased metastasis and decreased survival as compared to those with less innervated tumors. We hypothesize that in some tumors, nerves are acquired by a tumor-induced process, called axonogenesis. Here, we use PC12 cells as an in vitro neuronal model, human tumor samples and murine in vivo models to test this hypothesis. When appropriately stimulated, PC12 cells extend processes, called neurites. We show that patient tumors release vesicles, called exosomes, which induce PC12 neurite outgrowth. Using a cancer mouse model, we show that tumors compromised in exosome release are less innervated than controls. Moreover, in vivo pharmacological blockade of exosome release similarly attenuates tumor innervation. We characterize these nerves as sensory in nature and demonstrate that axonogenesis is potentiated by the exosome-packaged axonal guidance molecule, EphrinB1. These findings indicate that tumor released exosomes induce tumor innervation and exosomes containing EphrinB1 potentiate this activity.

Renal Angiomyolipoma With Incidental Oncocytoma: A Case Report and Review of Literature.

We present a 37-year-old female with a history of tuberous sclerosis. She developed flank pain, hypotension, and a sudden drop in hemoglobin levels which prompted a work-up. A computed tomography scan demonstrated enlarged heterogeneous kidneys and a large complex collection in the right kidney, likely hemorrhagic in nature. The findings were suspicious for bilateral angiomyolipomas with retroperitoneal hematoma. She was treated with bilateral transarterial embolization. She subsequently developed recurrent fever and was suspected of having emphysematous pyelonephritis, for which she underwent a right nephrectomy. The entire kidney was replaced by a tan bulging, lobular mass, with scattered tan-yellow nodules. Microscopic examination revealed an angiomyolipoma with an incidental oncocytoma. The association of renal angiomyolipoma and renal oncocytoma is rare and only 16 cases have been previously reported.

Gastric Zygomycosis in a Previously Healthy 56-Year-Old Male.

Zygomycosis refers to invasive fungal infections caused by fungi belonging to the phylum zygomycota. Infections generally occur in immunocompromised individuals. The following case is of a previously healthy 56 year-oldmale admitted to the hospital following a motor vehicle accident. During his hospitalization, there was a significant drop in hemoglobin with no obvious source of bleeding. This prompted the clinician to insert a nasogastric tube which returned at least 2 liters of black fluid and led to an upper gastrointestinal endoscopy. The endoscopy revealed numerous large crater-like gastric ulcers with adherent clot, up to 30 mm in greatest dimension. Biopsies of the ulcer margins revealed broad pauciseptate, ribbon-like, slightly refractile fungal forms, which were highlighted with periodic acid-Schiff (PAS) stain. A Gomori methanamine silver (GMS) stain was negative. These forms were suggestive of zygomycetes. A subsequent gastrectomy was performed, which revealed similar findings. The patient experienced severe trauma, which may have contributed to the progression of his condition; however, this is an unusual presentation as the patient was previously healthy, and he did not illustrate any conditions that might compromise his immunity. The severity and rarity of this condition makes this a very unique and intriguing case.

Metastatic Adenocarcinoma of the Prostate Diagnosed in a Colon Polyp: A Unique Clinicopathologic Scenario.

Adenocarcinoma of the prostate is the second most common cause of cancer-related deaths among males in the U.S. Metastatic disease commonly involves the bones, lymph nodes, lungs, liver, and brain. Rarely, colonic involvement is seen and it is generally due to direct extension to the rectum. It is exceedingly uncommon for distant metastasis to occur in the right colon and small bowel. We present a case of prostatic adenocarcinoma metastasizing to the appendiceal orifice in a 78-year-old male. Our patient had a history of adenocarcinoma of the prostate diagnosed four years prior to presentation. He also had a history of adenocarcinoma of the distal colon 30 years prior which resulted in a partial colectomy and permanent diverting colostomy. Prior to his presentation, follow-up colonoscopies failed to reveal disease progression or additional malignancy. During routine colonoscopy, he was found to have a 2.5 cm polyp near the appendiceal orifice. Histologically the polyp demonstrated colonic mucosa with an infiltration of the lamina propria by individual cells with abundant cytoplasm and round nuclei with prominent nucleoli. The neoplastic cells were strongly positive for PSA and negative for CK7, CK20, and CDX2 supporting a diagnosis of metastatic prostatic adenocarcinoma. Metastatic disease of extracolonic origin arising in a polyp is extremely uncommon, but metastases have been reported to involve breast, ovary, stomach, esophagus, and kidney. This case contributes to the scarce information available regarding metastatic spread of prostate cancer to the ascending colon and enlightens the community of pathologists, surgeons, gastroenterologists, and urologists about this unusual presentation of a common carcinoma.

Ovarian small cell carcinoma, hypercalcemic type exhibiting a response to high-dose chemotherapy.

A gravida 2, para 2 25-year-old woman three months post-partum presented to her primary physician with abdominal pain and bloating; a 20-cm complex cystic pelvic mass was identified by ultrasound. No ovarian masses were noted during ultrasound exam at the prior pregnancy, less than one year earlier. Her labs included hypercalcemia (11.8 mg/dL, normal less than 10.5) and an elevated CA 125 (160 U/mL, normal less than 35). An exploratory laparotomy revealed a 20-cm right ovarian mass. Frozen section was performed and a sex cord-stromal tumor was favored. Permanent sections of the specimen, however, revealed round, closely packed neoplastic cells with a high nuclear to cytoplasm ratio and high mitotic rate growing in a diffuse pattern with scattered follicle-like, ill-defined microcystic spaces. Immunohistochemical stains revealed the neoplasm to be focally positive for keratin and negative for inhibin. The final diagnosis rendered was small cell carcinoma of the ovary, hypercalcemic type. Further staging revealed para-aortic lymph node involvement (stage IIIC). Current literature suggests a very poor prognosis for these neoplasms despite aggressive therapy, with an overall survival rate of 10 percent. Rare response has been noted, however, with high-dose chemotherapy followed by autologous peripheral blood stem cell transplant. Our patient underwent a rigorous chemotherapeutic regimen followed by peripheral blood stem cell transplant, and as of August 2010, (17 months after initial diagnosis), the patient has had no recurrence.

The utility of PU.1 as an immunohistochemical marker for histiocytic and dendritic lesions of the skin.

PU.1 is a transcription factor restricted to the hematopoietic system. It is expressed in myeloid lineage and B lymphocytes but is absent in mature T cells and nonhematopoietic cells. Among myeloid lineage-derived cells, PU.1 is overexpressed in monocytes, histiocytes, and dendritic cells. We evaluated PU.1 expression in 78 cases of primary skin neoplasms, including 9 reticulohistiocytomas, 9 Langerhans cell histiocytoses, 7 juvenile xanthogranulomas, 9 fibrous papules, 8 dermatofibromas, 12 dermatofibrosarcoma protuberans, 9 Spitz nevi, and 15 malignant melanomas. Strong nuclear staining for PU.1 was seen in all cases of histiocyte and dendritic cell origin, including 9/9 reticulohistiocytomas, 9/9 Langerhans cell histiocytoses, and 7/7 juvenile xanthogranulomas. No staining for PU.1 was seen in any studied cases of fibrous papules, dermatofibrosarcoma protuberans, dermatofibromas, Spitz nevi, or malignant melanomas. This study indicates that PU.1 is a valuable immunohistochemical marker for identifying cutaneous histiocyte- and dendritic cell-derived lesions. PU.1 staining is easily interpreted due to the sharp nuclear staining as compared with the irregular and often variable cytoplasmic staining seen with CD68.

The significance of lymphovascular invasion in transurethral resection of bladder tumour and cystectomy specimens on the survival of patients with urothelial bladder cancer.

OBJECTIVE: To test the hypothesis that patients with bladder cancer who had evidence of lymphovascular invasion (LVI) in their transurethral resection of bladder tumour (TURBT) and radical cystectomy (RC) specimens would have a worse prognosis and higher likelihood of clinical understaging, and to assess the effect of LVI discovered at RC on subsequent disease-related mortality, as the prognostic significance of LVI in TURBT or RC specimens of patients treated for urothelial carcinoma of the bladder is not completely established. PATIENTS AND METHODS: We retrospectively reviewed the records of 163 patients with urothelial carcinoma of the bladder seen at our institution, and who had TURBT (69) or RC (94) between 1995 and 2005. We compared patients with LVI on TURBT and/or RC specimens to a group of controls who did not have LVI on TURBT (34) or RC (32). RESULTS: Patients with LVI present in their TURBT specimen had a shorter disease-specific survival than those without LVI, with a 5-year survival of 33.6% vs 62.9% (log-rank test P = 0.027; hazard ratio 2.21). LVI at TURBT varied with clinical stage (P = 0.049). Patients with LVI and who were clinical stage I or II had lower survival than those without LVI (P = 0.049; hazard ratio 2.68). LVI did not affect survival among those with clinical stage III or IV (P = 0.29). There was a trend for patients with LVI at TURBT to be clinically understaged compared to those without LVI (75% vs 46%) but the difference was not significant (P = 0.086). Patients with LVI detected in their RC specimen were significantly more likely to have cancer recurrence than were those with no evidence of LVI (48% vs 19%, P = 0.006). For the RC group there was also a significant difference in survival distribution between patients with evidence of LVI vs those without (5-year survival 45.5% vs 78.4%, P = 0.017). Those with LVI were significantly more likely to die from the disease than those without LVI (P = 0.017; hazard ratio 2.92). CONCLUSIONS: Our findings suggest that LVI is a histological feature that might be associated with a poorer prognosis in patients with urothelial carcinoma of the bladder. The presence of LVI in TURBT specimens predicts shorter survival for patients with stage I or II disease. The presence of LVI in RC specimens predicts recurrence of disease and shorter survival. Further studies are needed to determine whether this group of patients would benefit from early RC and/or perioperative chemotherapy to improve clinical outcomes.

Bone morphogenetic proteins in melanoma: angel or devil?

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-beta (TGF-beta) superfamily serving multiple functions in many cell and tissue types including proliferation, apoptosis, differentiation, chemotaxis, angiogenesis, and matrix production during embryogenic development as well as in adult life. Despite the tremendous progress in delineating functional derangements of BMP pathways in carcinogenesis during the last decade, the biological significance of BMPs in human melanoma has received very little attention. It is now clear that biological responses to BMPs are cell type-specific and divergent effects, i.e., both oncogenic and tumor suppressor activities, have been described. Thus, knowledge generated in one system may not translate directly to another. In this review, we summarize the current understanding of BMP signaling in various human cancers and discuss original data pertaining to cutaneous melanoma obtained in our laboratory.