Initial Enucleation Research Articles

Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma.

Simple SummaryRelapse outside the eye of retinoblastoma (the most common eye cancer in children) is an uncommon event in developed countries, however it is the main cause of death in patients with retinoblastoma worldwide. The genomic features of this population are not known. We studied 23 cases from four countries and found a characteristic pattern in chromosomal copy number alterations that could help guide future clinical management of these patients.Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.

Unilateral retinoblastoma; natural history and an age-based protocol in 248 patients

ObjectivesWe aimed to study the clinical state and prognosis of patients with unilateral retinoblastoma who were being treated at a paediatric comprehensive cancer centre in a limited-resource country, to assess the different phases of treatment and the success of different, more complex real-life models.SubjectsIn this retrospective study, we created a snapshot of our retinoblastoma database for the period between 2007 and 2015. Patients whose data were included in the study were followed up until 2016. Out of a total of 744 screened patients, we included data of 248 patients who had been diagnosed with unilateral retinoblastoma.ResultsAs classified as per the International Retinoblastoma Classification, 1 patient presented with group A, 21 with group B, 39 with group C, 104 with group D and 83 with group E retinoblastoma. Chemotherapy was the initial line of treatment in 115 patients and enucleation in 133 others. Later, 141 patients (56.9%) required further management. Patients had a mean ocular survival time of 20.8 months. Nine patients developed extraocular disease at a later stage of management: five after upfront enucleation and four after neoadjuvant chemotherapy. Mean overall survival time stood at 90.2 months. Four and three deaths were recorded in groups D and E, respectively. A single patient died in the initial chemotherapy arm, while six passed away in the initial enucleation arm.ConclusionOur study highlights the importance of initial chemotherapy and close follow-up after enucleation of classes D and E affected eyes even in absence of germline mutations.

Clinical, Genomic, and Pharmacological Study of MYCN-Amplified RB1 Wild-Type Metastatic Retinoblastoma.

Simple SummaryWe present two cases of a subtype of retinoblastoma, a rare ocular tumor in children, presenting without the typical mutation in the RB1 gene but showing amplification of the transcription factor MYCN frequently reported in pediatric malignancies. Even though previous reports suggested that this tumor sybtype could present metastases, patients with metastatic disease were not reported. Our cases had metastasis to the orbit and lymph nodes and poor sensitivity to standard chemotherapy but no dissemination to the central nervous system, as described for patients with mutations in the RB1. We were able to grow the cells of one of our patients in vitro, perform comprehensive genomic analysis that showed previously not reported mutations and other chromosomal alterations. In an animal model, we could reproduce the clinical dissemination and we identified an innovative active drug combination that could help for the treatment of these children with poor prognosis.An uncommon subgroup of unilateral retinoblastomas with highly aggressive histological features, lacking aberrations in RB1 gene with high-level amplification of MYCN (MCYNRB1) has only been described as intra-ocular cases treated with initial enucleation. Here, we present a comprehensive clinical, genomic, and pharmacological analysis of two cases of MCYNRB1 with orbital and cervical lymph node involvement, but no central nervous system spread, rapidly progressing to fatal disease due to chemoresistance. Both patients showed in common MYCN high amplification and chromosome 16q and 17p loss. A somatic mutation in TP53, in homozygosis by LOH, and high chromosomal instability leading to aneuploidy was identified in the primary ocular tumor and sites of dissemination of one patient. High-throughput pharmacological screening was performed in a primary cell line derived from the lymph node dissemination of one case. This cell line showed resistance to broad spectrum chemotherapy consistent with the patient’s poor response but sensitivity to the synergistic effects of panobinostat–bortezomib and carboplatin–panobinostat associations. From these cells we established a cell line derived xenograft model that closely recapitulated the tumor dissemination pattern of the patient and served to evaluate whether triple chemotherapy significantly prolonged survival of the animals. We report novel genomic alterations in two cases of metastatic MCYNRB1 that may be associated with chemotherapy resistance and in vitro/in vivo models that serve as basis for tailoring therapy in these cases.

Label-free stimulated Raman scattering microscopy visualizes changes in intracellular morphology during human epidermal keratinocyte differentiation

Epidermal keratinocyte (KC) differentiation, which involves the process from proliferation to cell death for shedding the outermost layer of skin, is crucial for the barrier function of skin. Therefore, in dermatology, it is important to elucidate the epidermal KC differentiation process to evaluate the symptom level of diseases and skin conditions. Previous dermatological studies used staining or labelling techniques for this purpose, but they have technological limitations for revealing the entire process of epidermal KC differentiation, especially when applied to humans. Here, we demonstrate label-free visualization of three-dimensional (3D) intracellular morphological changes of ex vivo human epidermis during epidermal KC differentiation using stimulated Raman scattering (SRS) microscopy. Specifically, we observed changes in nuclei during the initial enucleation process in which the nucleus is digested prior to flattening. Furthermore, we found holes left behind by improperly digested nuclei in the stratum corneum, suggesting abnormal differentiation. Our findings indicate the great potential of SRS microscopy for discrimination of the degree of epidermal KC differentiation.

Conservative surgical treatments for nonsyndromic odontogenic keratocysts: a systematic review and meta-analysis.

This manuscript presents a systematic review of the clinicopathologic features and outcomes of conservative surgical treatments for nonsyndromic odontogenic keratocysts (OKCs) and assesses the recurrence rates through a meta-analysis, in order to indicate the best conservative approach. PRISMA guidelines for systematic reviews were followed, and the protocol was registered (PROSPERO/Nr.: CRD42017060964). An electronic search was conducted using the PubMed/MEDLINE, Science Direct, Web of Science, Scopus, and The Cochrane Library databases, and relevant articles were selected based on specific inclusion criteria. The PICOS criteria (Population: nonsyndromic patients of any age with OKC, with histopathological diagnosis and minimum follow-up of 12months; Intervention and Comparison: marsupialization or decompression with or without enucleation, and enucleation alone; Outcome: recurrence rates; Study design: clinical trials, controlled trials, retrospective studies, and case series containing at least 10 cases of OKC) were employed. A pooled odds ratio (OR) was computed through the Mantel-Haenszel test (M-H) with 95% confidence intervals (CI). One thousand nine hundred OKCs were analyzed; the age of the patients varied from 6 to 90years (mean of 38.6years); a male to female ratio of 1.57:1 was observed; 74.5% of the lesions occurred in the mandible; 75.7% of OKCs were unilocular; the association with impacted tooth was reported for 344 OKCs; and the mean follow-up was 60.1months. One thousand three hundred thirty-one OKCs were treated by conservative surgical treatments, and 261 cases (19.8%) presented recurrence. Nonetheless, minor total recurrence rates were observed after decompression followed by enucleation (11.9%) and marsupialization followed by enucleation (17.8%). In contrast, enucleation alone showed a total recurrence rate of 20.8%. The results suggest a significant superiority of success for OKC treatments that use decompression followed by enucleation, instead of an initial enucleation (M-H, OR = 0.48; 95% CI = 0.22 to 1.08; P = 0.0163). No consensus exists concerning the best management for OKCs. More aggressive treatments (ostectomy, resection, or use of adjunctive therapies like Carnoy's solution and liquid nitrogen) can have many disadvantages and risks. Therefore, it is necessary to identify the conservative approach for OKCs that results in a lower recurrence rate.

Recurrent pleomorphic adenoma: is treatment considerably delayed thus affecting surgical morbidity?

Objective: To examine the incidence of late presentation of patients with recurrent pleomorphic adenoma (RPA) of the parotid gland.Methods: This is a retrospective analysis of patients treated in our center. We examined patients demographics, disease characteristics, treatment, and outcome and as well as the time period length from the first discovery of a recurrent mass until seeking treatment at our clinic and its effect on morbidity.Results: A total of 30 patients were included. 26% underwent initial enucleation in other institutions. In eight patients (26%), the recurrence of the mass was second or higher. The patients average time period length until seeking treatment was 2.48 years, with 33% of patients showing a time period length of over three years. Multifocal tumor, tumor diameter larger than 2 cm and facial nerve involvement were found in 15 (50%),16 (53.3%) and seven (25%) patients respectively. Patient's delay of presentation by ≥3 years was associated with a tumor size of ≥2 cm (Relative Risk [RR] = 2, p = .02). Patient's delay of presentation by ≥2 years was also associated with a trend towards a higher rate of post-operative facial nerve palsy (RR = 3.37, p = .07, CI = 0.88–12.85).Conclusion: Most patients with RPA were presented late, thus affecting disease extent and surgical morbidity.

Pediatric malignant salivary gland tumors: 60 year follow up

ObjectiveTo evaluate the presentation, treatments and outcomes in pediatric patients with salivary gland malignancies. Study designRetrospective chart review (1950–2012), Prospective phone interview. MethodsPatients ≤18 years old with a salivary gland malignancy treated at our institution were identified. Patients were also contacted by phone for a follow up survey. ResultsFifty-six patients were identified. Tumor origin was 88% parotid (n = 49), 5% (n = 3) submandibular and 7% (n = 4) minor salivary glands. Time from onset of symptoms to diagnosis was over one year (mean = 14.4 years). Fifteen out of 52 patients with major gland malignancy had a locoregional recurrence and local recurrences were almost all after initial enucleation. Two of these patients died of disease (overall disease specific survival = 96%). Three out of 4 patients with minor gland malignancy had a local recurrence and two patients with high grade pathology developed metastases and died of their disease (overall survival = 50%). On long term follow up survey in 13 patients (25%), 100% reported normal facial movement and 54% described symptoms of Frey's syndrome, which is higher than other reported series in children. Recurrence was noted up to 45 years after initial treatment. ConclusionsThe majority of malignant pediatric salivary gland tumors are low grade and have excellent survival, especially if found at an early stage. Minor salivary gland malignancies, particularly high grade, have a worse prognosis. Long term mild Frey's syndrome can be expected in approximately half of patients. We advocate a need for long term follow up and increased awareness among providers to diagnose these patients earlier.

Enucleation and Limited Pancreatic Resection Provide Long-Term Cure for Insulinoma in Multiple Endocrine Neoplasia Type 1

Aim: To assess the characteristics and long-term outcome after surgery in patients with multiple endocrine neoplasia type 1 (MEN1)-associated insulinoma. Methods: Retrospective analysis of prospectively collected data of MEN1 patients with organic hyperinsulinism at a tertiary referral center. Results: Thirteen (17%) of 74 patients with MEN1 had organic hyperinsulinism. The median age at diagnosis was 27 (range 9-48) years. In 7 patients insulinoma was the first manifestation of the syndrome. All patients had at least one pancreatic neuroendocrine neoplasm (pNEN) upon imaging, including CT, MRI or endoscopic ultrasonography. Seven patients had solitary lesions upon imaging, 4 patients had one dominant tumor with coexisting multiple small pNENs, and 2 patients had multiple lesions without dominance. Eight patients had limited resections (1 segmental resection, 7 enucleations), 4 subtotal distal pancreatectomies, and 1 patient a partial duodenopancreatectomy. There was no postoperative mortality. Six patients experienced complications, including pancreatic fistula in 5 patients. Pathological examination revealed median three (range 1-14) macro-pNENs sized between 6 and 40 mm, and a total of 14 potentially benign insulinomas were detected in the 13 patients. After median follow-up of 156 months, only 1 patient developed recurrent hyperinsulinism after initial enucleation. Twelve patients developed new pNENs in the pancreatic remnant and 4 patients underwent reoperations (3 for metastatic ZES, 1 for recurrent hyperinsulinism). One of 5 patients with an initial extended pancreatic resection developed insulin-dependent diabetes mellitus. Conclusion: Enucleation and limited resection provide long-term cure for MEN1 insulinoma in patients with solitary or dominant tumors. Subtotal distal pancreatectomy should thus be preserved for patients with multiple pNENs without dominance given the risk of exocrine and endocrine pancreas insufficiency in the mostly young patients.

A novel modification of conventional laparoscopic myomectomy using manual assistance for multiple uterine myomas

To evaluate the efficacy and feasibility of finger-assisted laparoscopic myomectomy for multiple myomas. A total of 565 patients with symptomatic myomas underwent finger-assisted laparoscopic myomectomy between January 2006 and March 2011 to remove multiple myomas at our center. Laparoscopic myomectomy technique was modified, and involved the insertion of two fingers into the vagina to elevate the uterus, while one or two fingers of the other hand were inserted into the abdomen through a suprapubic 15-mm trocar port for palpation of small myomas, which did not distort the uterine contour. The mean (SD; range) patient age was 38.26 years (5.84; 25-48 years). The diameter of the largest myoma in each case was 6.13 cm (1.21; 4-15 cm). The total number of myomas enucleated in the initial enucleation was 2228. There were 597 additional myomas enucleated with finger-assisted guidance. The mean diameter of the additionally enucleated myomas was 1.1 cm (range, 0.2-2.5 cm), which was significantly smaller than those of the initially enucleated myomas (p=0.002). The mean operative time was 97.1 min (30.2; 35-180 min). The decrease in postoperative hemoglobin concentration was 1.6g/dL (0.7; 0.4-3.2g/dL). During the operation, no patients required a blood transfusion. Six patients developed postoperative fever. There was no occurrence of bowel or urinary tract injury. The mean postoperative hospital stay was 3.2 days (0.9; 2-6 d). All procedures were successfully completed without the need for laparotomy. Finger-assisted laparoscopic myomectomy is a feasible and safe approach in the surgical treatment of multiple myomas.

Some Clinical Findings at Presentation Can Predict High-risk Pathology Features in Unilateral Retinoblastoma

To identify clinical features at presentation to help in detecting patients with retinoblastoma and pathology risk factors (PRFs) preoperatively, and therefore selecting a high-risk population that could benefit from preoperative treatment. A retrospective analysis of a prospectively filled form of 182 consecutive patients with unilateral retinoblastoma treated with initial enucleation from 1988 to 2006. Univariate and multivariate analyses were carried out. Major choroidal invasion and postlaminar optic nerve and scleral extension were considered PRFs. Within this subgroup, a higher-risk cohort (microscopical residual disease caused by trans-scleral invasion or invasion to the resection margin of the optic nerve) was analyzed separately. One hundred sixty-four patients had completely resected and 18 had microscopical residual disease. Seventy three had at least 1 PRF (massive invasion to the choroid in 25, to the postlaminar optic nerve in 41, intrascleral in 10, to the resection margin of the optic nerve in 12, and trans-scleral in 6). Seventy-one patients had glaucoma and 19 had buphthalmia. Intraocular pressure, glaucoma, and buphthalmia correlated significantly with the occurrence of both PRF and microscopical residual disease in multivariate analysis. Buphthalmia was the most specific factor but the sensitivity was lower. Glaucoma and buphthalmia had a high negative predictive value. Patients presenting with glaucoma and/or buphthalmia have a significantly higher risk for the occurrence of PRF, including those resulting in microscopically residual disease.

Recurrent pleomorphic adenoma of the parotid gland

Background Surgery of recurrent pleomorphic adenoma presents an increased risk of facial nerve injury and a considerable re-recurrence rate. Methods A series of 33 patients with first recurrence of pleomorphic adenoma of the parotid gland was analyzed. The data were derived from medical records as well as from interviews and clinical examinations of all living patients. Histologic material of the initial and recurrent tumor were reviewed. Results Multifocal recurrence and carcinoma in pleomorphic adenoma were observed in 73% and 9% of patients, respectively. The incidence of permanent partial facial nerve injury after surgery was 23% in patients with initial enucleation and 14% in those with initial superficial parotidectomy (including 1 patient with facial nerve resection and 1 patient with a partial facial paresis before recurrence surgery). A subsequent recurrence occurred in 6 patients, all with initial enucleation after a mean time interval of 9 years. Conclusions The preservation of the facial nerve was possible in all but 1 patient treated for the first recurrence with a relatively low rate of permanent partial facial paresis because of the use of the operating microscope and facial nerve monitor. To evaluate the re-recurrence rate, a follow-up of at least 10 years is necessary.

Recurrent calcifying odontogenic cyst involving the maxillary sinus

The calcifying odontogenic cyst is an uncommon lesion that occurs in both jaws, however involvement of the maxillary sinus is rare. The accepted mode of treatment is enucleation with curettage since it is generally believed that recurrence following such treatment is extremely rare. Of the reported cases of recurrent calcifying odontogenic cysts, none have involved the maxillary sinus. This report is of a large recurrent calcifying odontogenic cyst involving the maxillary sinus, eroding the orbital floor as well as anterior and medial walls of the maxillary sinus and displacing an impacted upper canine into the nasal cavity, in a 45-year-old male patient, 8 years after the initial enucleation.

Experience with chemoreduction and focal therapy for intraocular retinoblastoma in a developing country

Chemoreduction is used for the treatment of retinoblastoma in industrialized nations; however, there are fewer data from developing countries. Before the implementation of this program, radiotherapy was used in almost all preserved eyes. Retrospective evaluation from 1995 to 2001 at the Hospital Garrahan (Argentina). Carboplatin 18.7 mg/kg/day 1 and vincristine (0.05 mg/kg/day 1) were offered to patients with Reese-Ellsworth (RE) groups I-III and all unilateral cases. Etoposide (3.3 mg/kg/day 1 and 2) was added for groups IV and V. The number of cycles was tailored according to response. Fifty-eight patients (78 eyes) were evaluated (39 bilateral, 19 unilateral). With a median follow-up of 47 months, 40 patients had unilateral enucleation, 14 were not enucleated, and 4 had bilateral enucleation. Nineteen patients had unilateral initial enucleation. Eye preservation at 5 years was: RE groups I-III (n = 24 eyes), 0.9 (SE: 0.095) IV-V (n = 54), 0.45 (SE 0.07). Patients received a median of four cycles of chemotherapy. Acute toxicity was mild. External beam radiotherapy was avoided in 41% of eyes with groups I-III. Etoposide was avoided in 24 patients. Two patients died of metastasis. No secondary malignancy occurred. Compared to our previous experience, eye preservation was better and even though less radiotherapy was used, it was prescribed more often than currently recommended in eyes with less advanced disease because of limited availability of sophisticated local therapy.

Tubulopapillary hidradenoma-like tumor of the mandible: Clinicopathologic and immunohistochemical features

Tubulopapillary hidradenoma is a benign sweat gland tumor that appears as a well-defined, superficially located dermal nodule. It combines ductal as well as apocrine and eccrine glandular differentiation. Microscopically, the tumor is composed of tubular structures that characteristically show intraluminal non-villous papillary projections and a peripheral myoepithelial cell layer. A tumor that is histologically and immunohistochemically identical to tubulopapillary hidradenoma occurred in the mandible of a 73-year-old man and resulted in considerable diagnostic difficulty. The neoplasm developed in a mandibular cyst and recurred 5 years after initial enucleation. This is the first report of a central (intraosseous) sweat gland adenoma of the mandible. The differential diagnosis and possible histogenesis are discussed.

Malignant melanoma of the uveal tract; report of case with death thirty years after enucleation.

THE PRESENT case is of interest because of the extremely late postponement of death, a matter of some 30 years subsequent to initial enucleation for malignant melanoma of the eyeball. The case brings out a series of factors which appear to have considerable bearing on the apparent slowness of development of metastases and death. The case would suggest that the postoperative collapsed Tenon's capsule exerts a protective control of a residual optic nerve extension. Initial complications of glaucoma, rupture of the eyeball and probable necrosis of the initial neoplasm may have been important factors in the remarkable delay in the case. REPORT OF CASE History. —T. D., a man aged 59, entered the hospital complaining of neuritis of a week's duration, intermittent in character, involving the thigh. The pain was severer while he was lying in bed and appeared to recede on walking. Pain had also appeared in the small