Feasibility of whole genome and transcriptome profiling in pediatric and young adult cancers.

The utility of cancer whole genome and transcriptome sequencing (cWGTS) in oncology is increasingly recognized. However, implementation of cWGTS is challenged by the need to deliver results within clinically relevant timeframes, concerns about assay sensitivity, reporting and prioritization of findings. In a prospective research study we develop a workflow that reports comprehensive cWGTS results in 9 days. Comparison of cWGTS to diagnostic panel assays demonstrates the potential of cWGTS to capture all clinically reported mutations with comparable sensitivity in a single workflow. Benchmarking identifies a minimum of 80× as optimal depth for clinical WGS sequencing. Integration of germline, somatic DNA and RNA-seq data enable data-driven variant prioritization and reporting, with oncogenic findings reported in 54% more patients than standard of care. These results establish key technical considerations for the implementation of cWGTS as an integrated test in clinical oncology.

Skin Lesion Area Segmentation Using Attention Squeeze U-Net for Embedded Devices.

Melanoma is the deadliest form of skin cancer. Early diagnosis of malignant lesions is crucial for reducing mortality. The use of deep learning techniques on dermoscopic images can help in keeping track of the change over time in the appearance of the lesion, which is an important factor for detecting malignant lesions. In this paper, we present a deep learning architecture called Attention Squeeze U-Net for skin lesion area segmentation specifically designed for embedded devices. The main goal is to increase the patient empowerment through the adoption of deep learning algorithms that can run locally on smartphones or low cost embedded devices. This can be the basis to (1) create a history of the lesion, (2) reduce patient visits to the hospital, and (3) protect the privacy of the users. Quantitative results on publicly available data demonstrate that it is possible to achieve good segmentation results even with a compact model.

Retrolabyrinthine Meatotomy as Part of Retrosigmoid Approach to Expose the Whole Internal Auditory Canal: Rationale, Technique, and Outcome in Hearing Preservation Surgery for Vestibular Schwannoma.

BACKGROUND: Vestibular schwannoma extending to the fundus of the internal auditory canal is currently considered an unfavorable condition for hearing preservation surgery via a retrosigmoid approach because the lateral end of the canal is hard to view directly during microsurgery. OBJECTIVE: To present an improved retrolabyrinthine meatotomy (RLM) technique that enables the full length of the cochlear and facial nerves to be inspected up to their orifices on the fundus. Long-term results are briefly reported. METHODS: A consecutive series of 100 cases with various degrees of fundus involvement underwent surgery via a retrosigmoid approach and RLM. The follow-up ranged from 4 to 14 yr. Outcomes on hearing and facial nerve function were recorded, and preoperative MRI findings of the tumor on the fundus were correlated with the surgical findings and the long-term radicality of the tumor resection. RESULTS: Residual tumor on the fundus was identified in 3 cases, all belonging to the group with tumors adhering to the fundus. The functional results were in line with the best reported outcomes of this surgery. CONCLUSION: RLM via a retrosigmoid approach seemed adequate for the purposes of hearing preservation surgery and enabled the full course of the facial and cochlear nerves through the internal auditory canal to be exposed to direct view. Tumors adhering to the vestibular quadrant of the fundus were more difficult to remove, and there were a few cases of local residual tumor.

Skin lesion image segmentation using Delaunay Triangulation for melanoma detection.

Developing automatic diagnostic tools for the early detection of skin cancer lesions in dermoscopic images can help to reduce melanoma-induced mortality. Image segmentation is a key step in the automated skin lesion diagnosis pipeline. In this paper, a fast and fully-automatic algorithm for skin lesion segmentation in dermoscopic images is presented. Delaunay Triangulation is used to extract a binary mask of the lesion region, without the need of any training stage. A quantitative experimental evaluation has been conducted on a publicly available database, by taking into account six well-known state-of-the-art segmentation methods for comparison. The results of the experimental analysis demonstrate that the proposed approach is highly accurate when dealing with benign lesions, while the segmentation accuracy significantly decreases when melanoma images are processed. This behavior led us to consider geometrical and color features extracted from the binary masks generated by our algorithm for classification, achieving promising results for melanoma detection.

The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients off therapy.

INTRODUCTION: Nonerosive reflux disease (NERD) is the most common form of gastroesophageal reflux disease. While the role of acid reflux has been established, the relevance of nonacid reflux in generating symptoms in NERD is unknown. AIM: To evaluate the diagnostic utility of impedance-pH monitoring in NERD patients. METHODS: Patients with typical reflux symptoms (heartburn and/or regurgitation) and normal endoscopy (NERD) underwent a combined impedance-pH monitoring off proton pump inhibitor (PPI) therapy. Previously investigated 48 healthy volunteers served as controls. Distal esophageal acid exposure (% time pH < 4), number of acid and nonacid reflux episodes, 2-min window symptom index (SI; positive if > or = 50%), and symptom association probability (SAP; positive if > or = 95%) were calculated. RESULTS: Between June 2004 and June 2007, 150 NERD patients (82 women, mean age 48 yr, range 18-78 yr) reported symptoms during the impedance-pH monitoring. NERD patients had more reflux episodes (median [25th-75th percentile]) compared with healthy volunteers (total: 46 [26-65] vs 32 [18-43], P < 0.05; acid: 29 [14-43] vs 17 [8.5-31.0], P < 0.05; and nonacid: 20 [15-27] vs 18 [13.5-26.0], P = NS). Sixty-three (42%) patients had abnormal % time pH < 4. Among 87 patients with normal % time pH < 4., 22 (15%) had a positive SAP for acid, 19 (12%) for nonacid reflux, and 7 (5%) for both. Classifying patients with symptomatic nonacid reflux as having a hypersensitive esophagus reduced the number of patients with functional heartburn from 65 (43%) to 39 (26%). CONCLUSION: Monitoring for nonacid reflux in NERD patients reduces the proportion of patients classified as having "functional heartburn." Studies assessing the clinical implications of these findings are warranted.

Effects of magnesium sulphate on leptin-dependent platelet aggregation: an ex vivo study.

Magnesium sulphate has well known antiplatelet properties. Its effect on leptin-dependent platelet aggregation has not been studied previously. Thus, we performed this ex vivo study to investigate whether magnesium sulphate is able to inhibit leptin-dependent aggregation of human platelets. We obtained platelet rich plasma (PRP) from venous blood samples of 16 healthy male volunteers, and we measured ADP-induced platelet aggregation in the presence of leptin alone (5-500 ng/mL) or leptin and magnesium sulphate (0.25-8 mM). Platelet pre-incubation with leptin led to a significant and dose-dependent increase in ADP-induced platelet aggregation. Magnesium sulphate was able to inhibit the pro-aggregating effect of leptin in a dose-dependent manner. The inhibitory effect was apparent at 1 mM of magnesium sulphate concentration (% maximal aggregation=38.1 +/- 12.2) and reached its maximum at 8 mM (% maximal aggregation=20.0 +/- 7.8). Our results demonstrate that leptin-dependent platelet aggregation is inhibited by magnesium sulphate in a dose-dependent manner. It seems conceivable that the blocking of hydrolysis of phosphoinositide and of intracellular calcium mobilization by magnesium sulphate may be involved in these findings.

Identifying pathways involved in leptin-dependent aggregation of human platelets.

OBJECTIVE: To investigate the role of phospholipase C (PLC), phospholipase A(2) (PLA(2)), calcium, and protein kinase C (PKC) in mediating leptin-enhanced aggregation of human platelets. DESIGN: In vitro, ex vivo study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital of Messina, Italy. SUBJECTS: In total, 14 healthy normal-weight male (age 31.4+/-1.9 y; body mass index 22.7+/-0.6 kg/m2) subjects. MEASUREMENTS: Adenosine diphosphate-(ADP-) induced platelet aggregation and platelet free calcium were measured after incubation of platelets with leptin alone (5-500 ng/ml), or leptin (50 and 100 ng/ml) in combination with anti-human leptin receptor long form antibody (anti-ObRb-Ab, 1:800-1:100 dilutions), PLC inhibitor U73122 (3.125-25 microM), PLA(2) inhibitor AACOCF3 (1.25-10 microM), or PKC inhibitor Ro31-8220 (1.25-10 microM). RESULTS: Platelet stimulation with leptin leads to a significant and dose-dependent increase in ADP-induced platelet aggregation and platelet free calcium concentrations. Leptin effects on both platelet aggregation and calcium mobilization were completely abated by the co-incubation with leptin and anti-ObRb-Ab. Leptin-induced platelet aggregation was dose-dependently inhibited by U73122, AACOCF3, or Ro31-8220. The effect of leptin on intracellular calcium was inhibited in a dose-dependent manner by incubation with U73122 and AACOCF3, but not with Ro31-8220. CONCLUSIONS: Our study confirms that leptin is able to enhance ADP-induced aggregation of human platelets, and raise the possibility that PLC, PKC, PLA(2), and calcium could play a relevant role in mediating the proaggregating action of leptin.

Leptin-dependent platelet aggregation in healthy, overweight and obese subjects.

OBJECTIVE: To investigate the effects of leptin on platelet aggregation and platelet free calcium (Ca(2+)) concentrations, and the role of the long form of leptin receptor (ObRb) and the phospholipase C (PLC) in mediating leptin effects on platelet function. DESIGN: Cross-sectional, clinical study. SETTING: Outpatient's Service for Prevention and Treatment of Obesity at the University Hospital of Messina, Italy. SUBJECTS: A total of 19 healthy, 14 overweight, and 16 obese male subjects. MEASUREMENTS: ADP-induced platelet aggregation and platelet Ca(2+) were measured after incubation of platelet-rich plasma with leptin alone 5-200 ng/ml, leptin 200 ng/ml and anti-human leptin receptor long-form antibody (ObRb-Ab) 5-10 microl, or leptin 200 ng/ml and PLC inhibitor U73122 0.5-1 nmol/l. RESULTS: Platelet stimulation with leptin lead to a significant and dose-dependent increase in platelet aggregation in healthy subjects. This effect was blunted in overweight, and strongly reduced in obese subjects. Similarly, the incubation with leptin induced a significant and dose-dependent increase in platelet free calcium, which was blunted in overweight and obese patients. The effect of leptin on platelet aggregation and platelet Ca(2+) was completely abated by the anti-ObRb-Ab and the PLC inhibitor U73122. CONCLUSIONS: Leptin produces a dose-dependent enhancement of ADP-induced platelet aggregation in humans. Platelet aggregation response to leptin is blunted, but not completely abolished in overweight/obese subjects, thus suggesting that platelet may represent a site of leptin resistance in human obesity. Leptin increases platelet free calcium in a dose-dependent manner. The inhibition of PLC completely abates the effect of leptin on both platelet aggregation and Ca(2+) levels. These findings suggest that signaling pathway other than JAK-STAT tyrosine phosphorylation (ie PLC and calcium) may be involved in mediating the prothrombotic action of leptin.

Carcinoid tumors of the pancreas. Status report based on two cases and review of the world's literature.

CONCLUSION: The diagnosis of a pancreatic carcinoid should be based on the measurement of serotonin in serum or its demonstration in the tumor and/or by the measurement of its derivative (5-HIAA) in urine. Carcinoid of the pancreas is a rare but definite entity; usually having metastasized by the time of diagnosis. The term "serotonin-producing tumor of the pancreas" has been suggested as an alternative designation for "pancreatic carcinoid." BACKGROUND: The literature on carcinoid tumors of the pancreas is confusing because much of it preceded the development of the more specific immunological, chemical and staining techniques currently available. METHODS: 43 case reports were collected from the world's literature, based on a demonstrable pancreatic neuroendocrine tumor plus a positive finding of at least one of the following without another dominant hormone being demonstrated: elevation of 5-Hydroxytryptamine (5-HT) (serotonin) in the serum or detected in tumor tissue, and/or elevation of 5-Hydroxyindole acetic acid (5-HIAA) in the urine. In addition to these two hormone-specific assays, information was collected on the silver-staining properties of the tumor; properties which have traditionally been associated with carcinoid tumors. Positive silver staining in tumor cells (argyrophilic and/or argentaffin reaction) is strongly indicative of the carcinoid tumor but the findings are less specific than the hormone assays and immunohistologic stains. RESULTS: In this review of 43 cases, including two current ones, the pancreatic carcinoid tumor has the following important features: 1. It is a rare tumor that is usually diagnosed late when the tumor is large and has metastasized. Thirty-eight (88.4%) have been malignant. They are, therefore, associated with a high incidence of the "carcinoid syndrome." 2. To date, prognosis in therapy is poor, based on delayed diagnosis, a resultant low incidence of resectability, and an uncertain duration of survival after resection. 3. Pancreatic carcinoid tumors remain difficult to differentiate from other endocrine tumors. The measurement of urinary 5-HIAA excretion or the demonstration of elevated serotonin level in the tumor or in serum is essential to its distinction. Silver staining of the tumor, although of historic importance, has been superceded by the hormone-specific studies. 4. To distinguish it from other endocrine tumors of the pancreas, the terms "pancreatic serotoninoma" or "serotonin-producing tumor of the pancreas" have been suggested as possible alternatives. Its growth characteristics may be related more to its cell of origin than to its extent of hormone secretion. Not all of the tumors result in recognizable hyperserotoninemia.

Bropirimine as neoadjuvant therapy decreases residual disease and expression of markers PCNA and TGF-beta 1 in a rat orthotopic prostate adenocarcinoma.

The role of bropirimine in prostate cancer remains unexplored. To address the efficacy of this immune modulator as neoadjuvant therapy we utilized the orthotopic placement of the Dunning AT-3 tumor. 2.4-2.6 x 10(6) Dunning AT-3 cells were injected into the ventral prostates of 50 Copenhagen X Fischer rats. Animals were then divided into 5 groups consisting of: 1) untreated controls; 2) those treated with ventral prostatectomy alone (performed 10-12 days following tumor cell inoculation); 3) those treated with ventral prostatectomy plus bropirimine (10 mg/kg) on postimplantation days 1, 3, 5, 10 and 11; 4) those treated with ventral prostatectomy plus bropirimine (100 mg/kg), at the same schedule; and 5) those treated with ventral prostatectomy plus bropirimine (500 mg/kg), at the same schedule. Animals were sacrificed 10 days after prostatectomy, autopsied, and residual disease was weighed. Prostate weights upon removal following neoadjuvant treatment and residual disease remaining after 20-22 days were expressed in grams (g). Following prostatectomy, mean prostate weights were: Group 2, 0.67 +/- 0.11; Group 3, 0.53 +/- 0.11; Group 4, 0.54 +/- 0.12; Group 5, 0.44 +/- 0.09. The effect of bropirimine was significant (p = 0.0001) by multiple regression analysis. In addition, mean residual tumor weights (expressed in grams) after 20-22 days were: Group 1, 12.7 +/- 1.9; Group 2, 6.7 +/- 4.8; Group 3, 5.2 +/- 5.9; Group 4, 3.8 +/- 3.5; and Group 5, 2.8 +/- 3.5. The effect of bropirimine was not significant (p = 0.07) by multiple regression analysis. However, prostatectomy alone, by Student's test, significantly (p = 0.04) reduced residual mean tumor weights by 47% and the additional effect of bropirimine upon residual disease was significant (p = 0.038) if a Chi-square analysis is applied. Finally, a multivariate analysis of the overall effect of bropirimine in rats treated with prostatectomy was significant (p = 0.002). The effect of bropirimine on expression of proliferating cell nuclear antigen (PCNA) and transforming growth factor beta 1 (TGF-beta 1) was also evaluated immunohistochemically and expression of both tumor markers was significantly reduced (p < 0.05). We conclude that bropirimine may have a role as a neoadjuvant therapy when combined with prostatectomy.

Survival of Mexican-American males with seminoma.

OBJECTIVE: The objective was to determine if ethnicity was a prognostic variable in survival outcomes for testicular seminoma. MATERIALS: Eighty-seven consecutive patients with a histologic diagnosis of seminoma treated at University of illinois Hospitals were evaluated. RESULTS: There were 52 (57%) white, 22 (24%) African-American, 16 (18%) Mexican-American and 1% Asian patients. Adjusted survivals for the life-table method were 84% and 80% for the whites and Africa-American patients and 69% for the Hispanic patients. The poorer outcome appeared to be related to stage at diagnosis. CONCLUSION: In this population with testicular seminoma Mexican-American patients appear to have a worse prognosis than other ethnic groups. These differences were associated to a delayed diagnosis probably due to cultural influences.

Prognostic characteristics of surgical stage I endometrial adenocarcinoma.

PURPOSE: To evaluate and correlate the expression of pathologic characteristics, flow cytometric DNA content analysis, and estrogen and progesterone receptor levels with survival in patients with surgical Stage I endometrial carcinoma. METHODS AND MATERIALS: Hospital tumor registry records were surveyed, and this identified 232 patients diagnosed with endometrial adenocarcinoma between July 1, 1989, and December 30, 1993. DNA content analysis was performed on either paraffin-embedded or fresh tissue samples. Survival was calculated from the date of diagnosis by the Kaplan-Meier method. Postoperative irradiation (whole pelvis external beam therapy and low dose rate vaginal cuff brachytherapy) was delivered to patients felt to be at high risk for failure. RESULTS: One hundred seventy-one patients had Stage I tumors and were available for analysis. Patients with Stage 1C tumors had a statistically significant lower survival rate compared to patients with Stages IA or IB (p = 0.03 and p < 0.01, respectively). Patients with DNA content diploid tumors had a slightly increased (but nonsignificantly so) survival compared to patients with non-DNA content diploid tumors (p = 0.12). Logistic regression analysis failed to identify an independent prognostic factor that could predict for disease specific survival in patients with Stage I cancers. CONCLUSION: Logistic regression analysis did not identify a single independent prognostic factor in patients with Stage I tumors. Pathologic characteristics reported to predict survival advantage correlated with pathologic stage. Additional translational research is needed to identify molecular characteristics of tumors that may indicate more aggressive treatment for patients at high risk for recurrence.

Metastatic pancreatic neuroendocrine carcinoma causing Cushing's syndrome. ACTH secretion by metastases 3 years after resection of nonfunctioning primary cancer.

CONCLUSION: Following resection of a nonfunctioning neuroendocrine carcinoma of the pancreas, subsequent metastases, in the absence of a primary cancer (resected), developed the capacity to secrete ACTH and create the Cushing syndrome. BACKGROUND: Although neuroendocrine carcinomas of the pancreas may produce one or more hormones and may switch secretion to a different hormone, no report is identified of a metastasis, in the absence of the primary tumor, developing de novo the capacity to secrete ACTH. METHODS: A nonfunctioning islet cell carcinoma was resected and immunochemically stained for multiple hormones. Three years later hepatic metastases were partially resected and stained as before. RESULTS: The primary cancer stained negative for ACTH and cortisol, positive for serotonin, and focally positive for gastrin. Three years later, after the development of a florid Cushing syndrome, the metastasis stained strongly for ACTH and negative for serotonin.

Clinicopathologic correlation of DNA flow cytometric content analysis (DFCA), surgical staging, and estrogen/progesterone receptor status in endometrial adenocarcinoma.

DNA flow cytometric content analysis (DFCA) and estrogen (ER) and progesterone (PR) receptor levels are reported to be prognostic with regard to the malignant potential of endometrial adenocarcinoma. We retrospectively reviewed the records of 50 patients presenting with endometrial adenocarcinoma between July 1990 and December 1992, to determine the extent of any pathologic features reported at the time of hysterectomy. Patients whose tumors were nondiploid (aneuploid) by flow cytometry generally presented with a higher pathologic stage, higher grade, and more frequent lymph node involvement. In addition, the majority of clear cell and uterine papillary serous (UPS) adenocarcinoma were also nondiploid. Fourteen of 21 ER-positive tumors aneuploid, as were 18 of 37 PR-positive tumors. We also found DNA-A (DNA content aneuploid) patterns frequently associated with tumor characteristics implicated by other authors as related to aggressiveness. Further studies comparing the molecular biology of tumors to their clinicopathologic features and behavior are needed to fully understand the ultimate malignant potential.

Adenocarcinoma of duodenum and ampulla of Vater: clinicopathology study and expression of p53, c-neu, TGF-alpha, CEA, and EMA.

Oncogenes, tumor suppressor genes, and growth factors are being explored as to their role in the initiation and progression of most neoplasms, but little information exists on the expression of oncoproteins or growth factors in adenocarcinoma of the duodenum or ampulla of Vater. This report covers expressions of p53, c-neu, TGF-alpha, CEA, and EMA in duodenal adenocarcinoma and ampullary adenocarcinoma, as well as correlations between expressions and tumor stage, histological grade and patient survival. The expression of p53, c-neu, TGF-alpha, CEA, and EMA has been studied in 15 duodenal adenocarcinomas and in eight ampullary adenocarcinomas by avidin-biotin-peroxidase complex indirect immunoperoxidase technique. The positive reaction for p53, c-neu, TGF-alpha, CEA, and EMA in duodenal adenocarcinoma was 20%, 60%, 60%, 73%, and 100%, respectively, and in ampullary adenocarcinoma, 13%, 100%, 50%, 63%, and 100%. Among the duodenal tumors, C-neu and p53 expression was noted more frequently in groups with high histological grades. Patients with c-neu positive duodenal adenocarcinoma had a shorter survival than the patients with c-neu negative duodenal adenocarcinoma (P < 0.01). C-neu product may serve as an unfavorable prognostic indicator in duodenal adenocarcinoma. No statistically significant correlation was found between the expressions of CEA, EMA, p53, and TGF-alpha and patient survival, tumor stage, or histological grade in either duodenal or ampullary adenocarcinomas.

Papillary cystic and solid tumors of the pancreas: a pancreatic embryonic tumor? Studies of three cases and cumulative review of the world's literature.

BACKGROUND: The papillary cystic and solid tumor of the pancreas is rare. It occurs predominantly in young women, and most present a benign behavior. The pathogenesis of this tumor has attracted a number of investigations but remains unclear. METHODS: We present three patients with this tumor and a review of 289 others from the world's literature, a total of 292 cases. On the basis of the analyses of the clinical and pathologic features from the reported cases, the pathogenesis of this unusual tumor has been further explored. RESULTS: Ninety percent of the patients were female, with a mean age of 23.9 years. The tumors were usually quite large with a mean diameter of 10.3 cm. Ninety-two percent of these tumors were totally or partially cystic. Rupture of the capsule resulted in hemoperitoneum in eight cases, five of which were without any identifiable cause. Forty-three tumors (14.7%) have been recognized as malignant. The overall prognosis has been excellent and an aggressive approach to resection is indicated. CONCLUSIONS: The results of immunohistochemical staining and electromicroscopy were rather diverse, but most, including the current cases, support the hypothesis that the tumor originates from pleuripotential embryonic stem cells. Thus the term pancreatic embryonic tumors seems preferable to papillary cystic and solid tumor of the pancreas to delineate the origin of the tumor and to reflect some of its biologic characteristics.

Adjuvant treatment in operable stage II and III rectal cancer.

AIMS AND BACKGROUND: To date adjuvant treatments of rectal cancer generally include radiotherapy and more recently a combination of radiotherapy and chemotherapy. Trials have benn generally restricted to patients with stage II and III rectal cancer. The purpose of the present study is to determine the efficacy of a preoperative combination of radiation therapy and chemotherapy in operable locally advanced rectal cancer. METHODS: From March 1990 to June 1994, 58 patients with histologically documented adenocarcinoma of the rectum entered our protocol. 35 neoplasms were located in the lower third of the rectum and the remaining 23 in the middle third. At pre-treatment clinical staging 46 tumors were judged as stage III and 12 as stage II. Chemotherapy and radiotherapy were started jointly on day one of the treatment. Mitomycin-C was given as a bolus intravenous at a dosage of 10 mg/m2, the first day. 5-Fluorouracil was given in a dosage of 1000 mg./m2/day as a continuous 24 h infusion for 4 days. Radiation therapy was given at a total dosage of 37.8 Gy. Surgery was generally performed four to five weeks following completion of the radiation therapy. RESULTS: Patients compliance to the treatment was 96 percent. A reduction of tumor size > 50 percent was observed in 65 percent of patients. Tumor distance from anal canal increased in 75 percent of patients. Morbidity rate was 31 percent; no postoperative mortality was reported. Histological examination of surgical specimens showed that in 54 percent of patients tumor disappeared or was confined to the rectum; there was no evidence of tumor cells in 5 cases and stage I lesions were diagnosed in 19 cases (35 percent). Preliminary data on recurrences show a 5 percent local recurrence rate and a 7 percent distant metastases rate. CONCLUSIONS: It may be concluded that preoperative radiochemotherapy is generally well tolerated; surgery does not present additional technical difficulties; the effect of stage reduction has been observed in a consistent number of cases.