Early Gastric Cancer: Clinical Behavior and Treatment Options. Results of an Italian Multicenter Study on Behalf of the Italian Gastric Cancer Research Group (GIRCG).

BACKGROUND: Early gastric cancer (EGC) generally has a good prognosis. However, the current definition of EGC includes various subgroups of patients with different pathological characteristics and different prognoses, some of whom have aggressive disease with a biological behavior similar to that of advanced carcinoma. MATERIALS AND METHODS: We retrospectively evaluated 1,074 patients with EGC who had undergone surgery between 1982 and 2009. The cumulative incidence function of cancer-specific mortality and competing mortality were estimated using the Fine and Gray method. RESULTS: The median follow-up period was 193 months (range 1-324). Five hundred and sixty-two (52.3%) patients died, 96 (8.9%) from EGC. The 5-, 10-, and 15-year cumulative incidence rates for mortality of all causes were 20.5% (95% confidence interval [CI] 18.0-22.9), 37.1% (95% CI 34.7-40.7), and 52.6% (95% CI 49.1-56.0), respectively; for cancer-specific mortality, 6.0% (95% CI 4.5-7.6), 9.9% (95% CI 7.9-11.9), and 11.1% (95% CI 8.8-13.3), respectively; and for mortality of other causes, 14.4% (95% CI 12.1-16.6), 27.2% (95% CI 24.2-30.2), and 41.5% (95% CI 38.1-43.3), respectively. A significant increase in the risk of cancer-specific mortality was observed for lesions >2 cm (adjusted hazard ratio [HR] = 1.44, 95% CI 1.07-1.94), Pen A-type disease (adjusted HR = 1.73, 95% CI 1.15-2.61), and node-positive cancers (adjusted HR = 2.28, 95% CI 1.61-3.21). CONCLUSION: Patients with EGC with tumors >2 cm, Pen A-type disease according to Kodama, or lymph node metastases show a poorer prognosis and an increased risk of cancer-specific mortality. IMPLICATIONS FOR PRACTICE: Early gastric cancer generally has a good prognosis, and some patients can be treated radically by endoscopic resection. However, the current definition of early gastric cancer includes subgroups of patients with an aggressive disease. In particular, patients with lymph node metastases and Pen A-type tumors according to Kodama's classification need a more invasive treatment, such as subtotal or total gastrectomy with an extended D2 lymphadenectomy, plus eventual adjuvant chemotherapy.

Dirofilariasis Mimicking an Acute Scrotum.

Human infections caused by Dirofilaria repens have been reported in many areas of the world. We describe a case of a 3-year-old child with an intrascrotal mass caused by D repens mimicking an acute scrotum. This represents the first case of scrotal dirofilariasis described in pediatric age with such an unusual presentation.

Endoscopic and histological pitfalls in the diagnosis of celiac disease: A multicentre study assessing the current practice.

BACKGROUND AND AIMS: the diagnosis of celiac disease requires small bowel biopsies to identify the characteristic mucosal changes. The current biopsy practice among endoscopists for celiac disease is in most part unknown. The aim of this study was to compare the different diagnostic policies in various centers in their current practice. METHOD: information from a total of 931 confirmed celiac disease patients was retrospectively obtained retrospectively from nine centers in European and Middle Eastern countries. The number of small-bowel biopsies obtained from the duodenal bulb and the second part of the duodenum was compared among different centers. RESULTS: the most frequent stage of mucosal changes amongst Iranian subjects was Marsh IIIa whereas in the rest of the study population was Marsh IIIc. Marsh I and Marsh II were more prevalent in adults (P < 0.05) and Marsh IIIc was significantly higher in pediatric ages between 1 and 15 (P < 0.05). The most common number of biopsy specimens obtained from Romanian subjects was 1 (52% of cases), followed by 2 for Iranian (56%), 3 for Lithuanian (66.7%) and British patients (65%) and 4 for Italian patients (48.3%). For majority of cases, anemia was the most prevalent symptom (18.7%) followed by malabsorption (10.5%), diarrhea (9.3%) and dyspepsia (8.2%), respectively. CONCLUSIONS: despite the evidence-based recommendations, this study revealed a poor compliance with major guidelines on diagnosis of celiac disease. We emphasize that taking adequate number of duodenal biopsies should be implemented for an accurate diagnosis and also for the exclusion of celiac disease.

Optimizing the risk stratification of astrocytic tumors by applying the cIMPACT-NOW Update 3 signature: real-word single center experience.

Our work reports implementation of a useful genetic diagnosis for the clinical managment of patients with astrocytic tumors. We investigated 313 prospectively recruited diffuse astrocytic tumours by applying the cIMPACT-NOW Update 3 signature. The cIMPACT-NOW Update 3 (cIMPACT-NOW 3) markers, i.e., alterations of TERT promoter, EGFR, and/or chromosome 7 and 10, characterized 96.4% of IDHwt cases. Interestingly, it was also found in 48,5% of IDHmut cases. According to the genomic profile, four genetic subgroups could be distinguished: (1) IDwt/cIMPACT-NOW 3 (n = 270); (2) IDHwt/cIMPACT-NOW 3 negative (= 10); (3) IDHmut/cIMPACT-NOW 3 (n = 16); and 4) IDHmut/cIMPACT-NOW 3 negative (n = 17). Multivariate analysis confirmed that IDH1/2 mutations confer a favorable prognosis (IDHwt, HR 2.91 95% CI 1.39-6.06), and validated the prognostic value of the cIMPACT-NOW 3 signature (cIMPACT-NOW 3, HR 2.15 95% CI 1.15-4.03). To accurately identify relevant prognostic categories, overcoming the limitations of histopathology and immunohistochemistry, molecular-cytogenetic analyses must be fully integrated into the diagnostic work-up of astrocytic tumors.

Primary lung adenocarcinoma in three adolescent patients affected by bone sarcomas.

Pediatric primary lung carcinomas are extremely rare. Apart from known associations with congenital adenomatoid malformations, cases of primary lung adenocarcinomas after prolonged treatments of pediatric malignancy have been reported. We describe the morphological and molecular features of three cases of lung adenocarcinoma developed in adolescents aged 8 to 17 years during progression of their bone osteosarcoma or Ewing sarcomas. The morphological features overlapped those of adult lung adenocarcinoma including in situ, minimally invasive, and invasive forms. EGFR gene mutations were found in all three cases by targeted next-generation sequencing. The two patients with Ewing sarcoma had no progression of their lung cancer and no further progression of the metastatic bone tumor after additional chemo- and radio-therapy. Conversely, the osteosarcoma patient refused further treatments after thoracic surgery for metastatic osteosarcoma and locally advanced adenocarcinoma and died 2 years later of widespread distant metastases. Our results indicate that primary lung cancer might originate in pediatric patients during prolonged adjuvant therapies for primary bone neoplasm, and this possibility should be considered in the presence of suspected lung disease progression to correctly monitor the primary tumor evolution and define the appropriate therapeutic strategy at each time point. If appropriately treated, second primary lung cancer may not affect the patients' prognosis. The pathogenetic mechanisms of these rare lung adenocarcinomas are not clear, but the presence of EGFR mutations in all three cases indicates an oncogene addiction of the lung tumor, rather than a direct cancerogenic effect of the sarcoma-related treatment.

New somatic TERT promoter variants enhance the Telomerase activity in Glioblastoma.

The catalytic activity of human Telomerase Reverse Transcriptase (TERT) compensates for the loss of telomere length, eroded during each cell cycle, to ensure a correct division of stem and germinal cells. In human tumors, ectopic TERT reactivation, most frequently due to hotspot mutations in the promoter region (TERTp), i.e. c.1-124 C > T, c.1-146 C > T, confers a proliferative advantage to neoplastic cells. In gliomas, TERTp mutations (TERTpmut) mainly occur in oligodendroglioma and glioblastoma. We screened, for TERTp hotspot mutations, 301 adult patients with gliomas and identified heterozygous mutations in 239 cases: 94% of oligodendroglioma, 85% of glioblastoma, and 37.5% of diffuse/anaplastic astrocytoma. Besides the recurrent c.1-124 C > T and c.1-146 C > T, two cases of glioblastoma harbored novel somatic TERTp variants, which consisted of a tandem duplications of 22 nucleotides, i.e. a TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, both located downstream c.1-124 C > T and c.1-146 C > T. In silico analysis predicted the formation of 119 and 108 new transcription factor's recognition sites for TERTp c.1-100_1-79dup and TERTp c.1-110_1-89, respectively. TERTp duplications (TERTpdup) mainly affected the binding capacity of two transcription factors' families, i.e. the members of the E-twenty-six and the Specificity Protein/Krüppel-Like Factor groups. In fact, these new TERTpdup significantly enhanced the E-twenty-six transcription factors' binding capacity, which is also typically increased by the two c.1-124 C > T/c.1-146 C > T hotspot TERTpmut. On the other hand, they were distinguished by enhanced affinity for the Krüppel proteins. The luciferase assay confirmed that TERTpdup behaved as gain-of-function mutations causing a 2,3-2,5 fold increase of TERT transcription. The present study provides new insights into TERTp mutational spectrum occurring in central nervous system tumors, with the identification of new recurrent somatic gain-of-function mutations, occurring in 0.8% of glioblastoma IDH-wildtype.

Synaptic vesicle protein 2A tumoral expression predicts levetiracetam adverse events.

OBJECTIVE: The efficacy of levetiracetam (LEV) in controlling seizures in patients with brain tumor-related epilepsy (BTRE) depends on tumoral expression of synaptic vesicle protein 2A (SV2A). Although LEV is generally well tolerated, neuropsychiatric adverse events (NPAEs) might occur, limiting compliance and seizure control. We aimed to assess the influence of tumoral SV2A expression on the occurrence of LEV-related NPAEs in patients with glioma. METHODS: Specimens from patients enrolled in the multicenter COMPO study, with glioma and BTRE treated with LEV, undergoing neurosurgery were retrieved. Immunohistochemistry-based expression of SV2A in tumoral and peritumoral tissue was scored in a four-point scale from absent (score = 0) to strong (score = 3). Low immunoreactivity (IR) corresponded to scores < 2. Staining ratios (tumoral SV2A IR/peritumoral SV2A IR) were grouped into low (≤ 0.5) and high (> 0.5). NPAEs were assessed longitudinally with the Neuropsychiatry Inventory 12 test (NPI-12). RESULTS: Overall, 18 patients were eligible for analysis. All received LEV monotherapy, with 67% developing NPAEs. Patients with NPAEs had significantly lower median SV2A intensity score compared to patients without NPAEs (score 1 vs 0, p = 0.025). Low staining ratio (≤ 0.5) associated with higher NPAE occurrence compared to SR > 0.5 (85.7% vs 0%, p < 0.01). A SR ≤ 0.5 predicted a consistent increase in risk of NPAEs (OR 45.0; 95% CI 1.8-1128; p = 0.02). CONCLUSIONS: Our results suggest that SV2A expression in tumoral and peritumoral tissue correlates with the occurrence of LEV-related NPAEs. Thus, considering that SV2A expression also influences LEV effectiveness, SV2A staining might help in tailoring treatment to patients.

Isolated fallopian tube torsion with hydrosalpinx: Review of a debated management in a pediatric population.

PURPOSE: To quantify our experience with and assess the literature on diagnosis and management of isolated fallopian tube torsion (IFTT) with hydrosalpinx (HSX) in children. METHODS: A PubMed search was performed on pediatric cases of IFTT with HSX to provide a comprehensive review analyzing details and management of this association, focusing on the problem of fertility preservation. RESULTS: In addition to our 3 cases, 17 patients of pediatric IFTT associated with HSX were identified, for a total of 21 cases (median age 12.2 years). Menarchal status was present in 10/13 (76.9%); blood tests were reported in 9/20 (42%) showing leucocytosis in 7/9 (75%). Ultrasonography was performed in all cases except one. Laparoscopy was the surgical approach in 84.6% of the reported cases. The torsion was to the right in 36.8%, and to the left in 63.2% of the cases. In one case the torsion was bilateral and asynchronous. Performed procedures were salpingectomy (52.4%) and partial salpingectomy (14.3%); conservative management was reported in 33.3% of the cases. CONCLUSIONS: The literature describes different management techniques. Salpingectomy is the most frequently performed procedure but recently conservative management seems to be increasingly applied. A long-term study is necessary to define the most effective treatment for the preservation of future fertility in pediatric patients. TYPE OF STUDY: Treatment study (Retrospective Study): LEVEL IV.

Oxaliplatin with raltitrexed and preoperative radiotherapy in T3-T4 extraperitoneal rectal cancer. A dose finding study.

AIMS AND BACKGROUND: The availability of new drugs offers the opportunity to improve the outcome of locally advanced rectal cancer. Raltitrexed and oxaliplatin are effective in advanced colorectal cancer with acceptable toxicity and can act as radiation enhancers as shown in phase I-II studies. The aim of the study was thus to determine the recommended dose of oxaliplatin concomitantly administered with raltitrexed and concurrent preoperative radiotherapy in patients with stage II-III extraperitoneal rectal cancer. METHODS: From September 2001 to September 2002, 18 consecutive patients with T3/T4 rectal cancer were treated at our Institution with preoperative chemoradiation followed by surgery after 6-8 weeks. Pelvic radiotherapy was delivered at a dose of 45 Gy in 25 fractions in 5 weeks followed by a 5.4 Gy boost at 1.8 Gy daily. Concomitant chemotherapy consisted of 3 mg/m2/i.v. of raltitrexed on days 1, 19, 38 of radiotherapy treatment with incremental doses of oxaliplatin according to dose finding rules (4 dose levels: 65, 85, 110, 130 mg/m2). Dose-limiting toxicity for oxaliplatin was defined as either grade 3-4 hematological or grade 3-4 gastrointestinal or neurological toxicity. We studied a minimum of 3 patients at each dose level. RESULTS: Three patients were treated at 65, 85, and 110 mg/m2/i.v., respectively, while 9 patients were recruited at the last dose level. Neither grade 3-4 gastrointestinal nor neurological toxicity were documented. Dose-limiting toxicity was documented in 2/9 subjects at the 130 mg/m2 level consisting of grade 3 transient asymptomatic leukopenia. Thirteen patients developed transient increase of one or more liver enzymes (grade 3-4) and 2 patients developed grade 3 perineal dermatitis. All patients received the programmed dose of radiotherapy. The chemotherapy regimen was not completed in 4 cases due to grade 2 protracted leukopenia. CONCLUSIONS: The maximum tolerated dose of oxaliplatin was not reached at the maximum dose level (i.v.); 130 mg/m2 can therefore be defined as the recommended dose. The combination of oxaliplatin with raltitrexed and radiotherapy can be considered feasible and well tolerated.

True Precocious Puberty Following Treatment of a Leydig Cell Tumor: Two Case Reports and Literature Review.

Leydig cell testicular tumors are a rare cause of precocious pseudopuberty in boys. Surgery is the main therapy and shows good overall prognosis. The physical signs of precocious puberty are expected to disappear shortly after surgical removal of the mass. We report two children, 7.5 and 7.7 year-old boys, who underwent testis-sparing surgery for a Leydig cell testicular tumor causing precocious pseudopuberty. During follow-up, after an immediate clinical and laboratory regression, both boys presented signs of precocious puberty and ultimately developed central precocious puberty. They were successfully treated with gonadotropin-releasing hormone (GnRH) analogs. Only six other cases have been described regarding the development of central precocious puberty after successful treatment of a Leydig cell tumor causing precocious pseudopuberty. Gonadotropin-dependent precocious puberty should be considered in children treated for a Leydig cell tumor presenting persistent or recurrent physical signs of puberty activation. In such cases, therapy with GnRH analogs appears to be the most effective medical treatment.

Paraganglioma of the cauda equina region.

BACKGROUND CONTEXT: Cauda equina paragangliomas (CEPs) are rare neuroendocrine tumors. The difficulty in differential diagnosis with other tumors of this region may be misleading for surgical planning and prognostic expectations. PURPOSE: To report on a rare case of CEP and review the most current information regarding the diagnosis, treatment options, and outcomes. STUDY DESIGN: Case report and literature review. PATIENT SAMPLE: One patient affected by CEP. METHODS: We report on a 33-year-old woman with a 2-month history of worsening low back pain, aggravated by sitting, bending, and coughing. Neurological examination revealed normal power and muscular tone, no sensory or sphincter abnormality, and normal reflex. Magnetic resonance imaging of the lumbar spine demonstrated an intradural extramedullary lesion at L3, with homogeneous contrast enhancement and hypointense punctate foci. The patient underwent an L3 laminectomy and tumor removal. Relevant articles covering CEPs from 1970 to the present were reviewed. RESULTS: The histopathological examinations described paraganglioma features. The postoperative course was uneventful, and all the symptoms resolved, with no tumor recurrence after 3 years' follow-up. CONCLUSIONS: Cauda equina paragangliomas are rare, benign, and slow-growing tumors. Except for its secreting tumor characteristics, preoperative CEP diagnosis is very difficult. Magnetic resonance imaging is important and may suggest specific radiological features for these tumors; however, these are only relative, and it is rare that diagnosis is made before surgery. Diagnosis is established by histological examination and electron microscopy, and immunohistochemical techniques must be used to achieve a correct diagnosis. Cauda equina paragangliomas are well-encapsulated tumors that may be cured by surgery alone, whereas radiotherapy is reserved for incompletely resected tumors. Overall, prolonged postoperative observation is mandatory because of the slow tumor evolution and the possibility of tumor relapse even up to 30 years after surgery.

Metachronous cardiac and cerebral sarcomas: case report with focus on molecular findings and review of the literature.

Although multiple primary malignancies are relatively rare, they have increased in frequency over the last decades, partly because of advances in diagnosis and therapy. This report describes for the first time the case of a patient with past occupational exposure to asbestos and no family history of cancer who developed 2 rare primary malignancies: a cardiac sarcoma and a gliosarcoma 11 months later. Molecular-cytogenetic studies did not identify common lesions to these 2 rare metachronous sarcomas. The gliosarcoma was associated with monosomy 10 and underlying PTEN monoallelic loss, which has been recurrently observed. In the cardiac sarcoma, MDM2 amplification and CDKN2AB/9p21 biallelic deletion suggested intimal sarcoma. No causal relationship was found between cardiac sarcoma and asbestos exposure, although MDM2 abnormalities were linked to malignant mesothelioma.

[Single cardiac metastasis from colorectal cancer: an unusual localization]. / Singola metastasi cardiaca da adenocarcinoma intestinale: una rara localizzazione.

Metastasis to the heart from malignancy is a frequent but underestimated event. Tumors that are located in the mediastinum, such as pleural mesothelioma, are more frequently associated with cardiac colonization. Few reports have described metastasis from colon adenocarcinoma, which usually colonizes liver and lungs. Moreover, intracardiac localization is more common for primary cardiac neoplasms than for metastasis. We present an unusual case of a patient operated for colon adenocarcinoma who exhibited a single intracardiac secondary localization. Although the mass was huge, the patient was completely asymptomatic. Strict oncologic follow-up facilitates an early identification of the lesion, which could then be promptly resected.

Multiple EWSR1-WT1 and WT1-EWSR1 copies in two cases of desmoplastic round cell tumor.

To provide new insights into the genomic profile of desmoplastic round cell tumors (DSRCT), we applied fluorescence in situ hybridization (FISH) and metaphase comparative genomic hybridization (M-CGH) to two newly diagnosed cases. FISH detected multiple subclones bearing one to three copies of der(11)t(11;22)(p13;q12) and/or der(22)t(11;22)(p13;q12) in both patients. This peculiar genomic imbalance might result from derivative chromosome duplication due to non-disjunction and/or mitotic recombination between normal and derivative chromosomes 11 and 22. Concomitant loss of normal chromosomes (i.e., 11 in patient 1 and 22 in patient 2) caused loss of the WT1 or EWSR1 wild-type allele. M-CGH identified other genomic imbalances: gain at chromosome 3 in both cases and chromosome 5 polysomy in patient 1. Common genomic events (i.e., trisomy 3 and extra EWSR1-WT1 and WT1-EWSR1 copies) probably contributed to disease pathogenesis and/or evolution of DSRCT. Our study demonstrated that an integrated molecular cytogenetic approach identified EWSR1-WT1 cooperating molecular events and genetic markers for prognosis. Thus, FISH and M-CGH might well be applied in a large series of patients to elucidate the genomic background of DSRCT.

Gastrointestinal and non-gastrointestinal presentation in patients with celiac disease.

BACKGROUND: Celiac disease (CD) may have a variety of different presentations. This study has aimed to explore the prevalence of gastrointestinal (GI) and non-GI symptoms in patients with CD according to data collected in Italy and Romania (Europe) and Iran (Middle East). METHODS: This is a retrospective cross-sectional study conducted in Iran, Romania and Italy with data collection during the period from May 2009 - May 2011. For each center we included only patients with CD that was confirmed by endoscopy, small bowel biopsies and positive serology. GI symptoms such as abdominal pain, diarrhea, constipation, nausea and vomiting, weight loss and flatulence, as well as additional signs and symptoms of iron deficiency anemia (IDA), osteoporosis, hypertransaminasemia, and other related abnormalities were collected. RESULTS: Overall, 323 women and 127 men, whose mean age at diagnosis was 34.2 ± 16.47 years were included in this study. Of these, 157 subjects (34.9%) reported at least one GI symptom. The majority of cases had the following primary presenting GI symptoms: diarrhea (13.6%), dyspepsia and constipation (4.0%). Other disease symptoms were reported by 168 (37.3%) patients. The most presenting non-GI symptoms in the majority of cases were anemia (20.7%) and osteopenia (6%). There were statistically significant differences between the majority of symptoms when we compared the reported clinical symptoms from different countries. CONCLUSION: This study indicated that upper abdominal disorders such as abdominal pain and dyspepsia were the most common primary complaints among European patients, whereas Iranian patients had complaints of diarrhea and bloating as the classic presentations of CD. For non-GI symptoms, anemia was the most frequent complaint for both Iranian and Italian patients; however it was significantly higher in Iranians.

Intestinal superinfections in patients with inflammatory bowel diseases.

BACKGROUND: Intestinal superinfections may occur in the setting of inflammatory bowel diseases (IBD), complicating the clinical picture and triggering flares of disease. AIMS: To report our experience with intestinal superinfections in IBD patients over a three-year period. METHODS: Charts of patients hospitalized for moderate-to-severe active disease during the observation period were reviewed, and data of patients with flares due to infections collected and analyzed. RESULTS: Overall, 15 out of 113 IBD patients (13.3%) had flare-ups related to intestinal infections; 143 acute flare-ups were thus documented, with 17 episodes (12%) related to infective agents, represented by Campylobacter jejuni (3 infections), Clostridium difficile (7 infections), and Cytomegalovirus (7 infections). All but two infections occurred in ulcerative colitis patients, and all responded to appropriate treatment. CONCLUSIONS: Intestinal superinfections may complicate the clinical picture of IBD patients, increasing the diagnostic and therapeutic burden. Appropriate early diagnostic and therapeutic measures are thus needed in these patients.

Tumorlets, multicentric carcinoids, lymph-nodal metastases, and long-term behavior in bronchial carcinoids.

BACKGROUND: The clinical significance of lymph-node metastases, multicentric forms, and tumorlets in bronchial carcinoids is still a matter of debate. Aim of this study was to analyze their prevalence and clinical significance in a series of 123 bronchial carcinoids. PATIENTS AND METHODS: Nodal dissection and serial sections of resected lung parenchima for research of multicentric forms and tumorlets were performed in most patients. Survival curve was produced using the Kaplan-Meyer method and multivariate analysis by the Cox proportional hazard model. RESULTS: Lymph-node involvement was present in 14% of typical (14 of 100) and 13.04% of atypical carcinoids (3 of 23). Multicentric forms (syncronous carcinoids or tumorlets) were found in 11.3% of the total with a negative impact on survival (p = 0.021). Multiple tumorlets were found in 7.3% of all cases at the standard pathologic examination, but whenever accurate palpation and serial sections of the surgical specimen were performed, the percentage reached 24% of the cases. Overall survival was 98.2%, 95.8%, and 83.9% for typical and 71.6%, 57.3%, and 24% for atypical carcinoid respectively at 5, 10, and 15 years. Time from surgery was significantly directly correlated with recurrences (p < 0.0001) and disease related death (p = 0.0002). CONCLUSIONS: A high prevalence of tumorlets, multiple carcinoids, and lymph-nodal involvement was found in our series. On the basis of these observations bronchial carcinoids always require major surgical procedures with systematic nodal dissection, and a careful search for multifocal lesions should always be performed. Follow-up should always be accurate and protracted, due to the frequency of very long-term relapses (often more than 10 years after surgery).