Defining prognostic parameters of well-differentiated gastric neuroendocrine tumors based on metastatic potential: a two-center experience.

Background: Gastric neuroendocrine tumors [gNETs] are heterogeneous tumors and we are still unable to predict the behavior of these tumors. We aim to define the prognostic parameters of well-differentiated gNETs based on metastatic potential and to evaluate the current classification systems. Patients and methods: We retrospectively retrieved 44 well differentiated gNET cases who underwent radical surgery between 2000-2015 at two tertiary-care centers. Results: Among the 44 well-differentiated gNET patients, 17 (38%) patients had metastatic disease to lymph nodes and/or distant sites, while 27 (62%) were confined to the stomach. Higher risk of metastasis was observed with increasing tumor size, grade, depth of invasion and with type-3 and solitary tumors. 30 (68%) patients had type-1 gNET and 14 (32%) had type-3 gNET. Majority of the type-1 cases (76,6%) were Grade 1 [G1] and type-3 cases (78,5%) were Grade 3 [G3]. Type-1 subgroup had no G3 tumor, and type-3 had no G1. Grade 2 [G2] tumors were more controversial, with metastatic and non-metastatic cases. G2 cases with a >10% Ki67 expression or type-3, had a worse prognosis. Although most of the type-1 gNETs had an indolent course, 6 of 30 (20%) patients had metastatic disease. Metastasizing type-1 gNETs were >10 mm in diameter or extended to/beyond the submucosa. Conclusion: Regarding our results, tumor type, grade, size, focality and depth of invasion are the prognostic parameters for gNETs, based on metastatic potential. Besides these parameters, a two-tiered grading system with a 10% Ki-67 proliferation index cut-off value could be considered for right treatment choice.

The frequency of HLA class I and II alleles in Turkish childhood acute leukaemia patients.

In this study, blood samples were taken from 200 patients with childhood acute leukaemias, including acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML), and from 100 healthy volunteers (controls). The frequency of the human leucocyte antigen (HLA)-DRB1*04 allele was significantly higher, and the frequencies of the HLA-A23 and HLA-B7 antigens were significantly lower, in patients with ALL compared with controls. Among patients with AML, the frequency of the HLA-B49 antigen and the HLA-DRB1*15 allele were significantly higher, whereas the frequencies of the HLA-A11 and HLA-B38 antigens were significantly lower compared with controls. The frequency of the HLA-DRB1*04 allele was also significantly higher in male patients with ALL and AML, whereas the HLA-DRB1*13 allele was found significantly less frequently in male AML and female ALL patients than in controls. To date, this is the only study to evaluate the associations between HLA molecules and leukaemia in a Turkish population with acute childhood leukaemia.

Differentiation-inducing liposoluble vitamin deficiency may explain frequent secondary solid tumors after hematopoietic stem cell transplantation: minireview.

Secondary cancers are among the most threatening long-term health problems of hematopoetic stem cell- transplant (HSCT) patients. There are several lines of evidence indicating the possibility of a prolonged Vitamin A deficiency for solid tumor-type secondary cancers: I- Solid tumors such as oral cavity, head/neck region squamous carcinomas, skin cancers and melanomas, where lowered Vitamin A concentrations and chemo-preventing activity of its derivatives (retinoids) are most explicitly proven, arise much more frequently than others. II- Early monitorings: A significant retinol deficiency in HSCT patients is detectable along with a severity of mucositis and the vulnerability to infection. III- Monitoring of other liposoluble vitamins: Vitamin D, a differentiation-inducing vitamin like Vitamin A, showed a sustained decrease. Another similarity of these two vitamins is that they also depend on intestinal absorption and are decreased due to bowel injury by conditioning agents and chronic graft-versus-host disease. IV- Peroxidative reactions and inflammation can directly exhaust retinol levels despite sufficient intake. Considering the similar inhibitory role of Vitamin D analogs (deltanoids) on squamous carcinomas, skin tumors and melanomas, we propose that animal studies and extended vitamin surveillance studies in HSCT patients may unfold a preventive strategy against long-term complications.

Oxidative DNA base damage and antioxidant enzyme levels in childhood acute lymphoblastic leukemia.

We have investigated the levels of several antioxidant enzymes and the level of oxidative DNA base damage in lymphocytes of children with acute lymphoblastic leukemia (ALL) and in disease-free children. Children with ALL had just been diagnosed with the disease and had received no therapy prior to obtaining blood samples. A multitude of typical hydroxyl radical-induced base lesions in lymphocyte DNA of children were identified and quantified by gas chromatography-isotope dilution mass spectrometry. Higher levels of DNA base lesions were observed in patients with ALL than in children without the disease. The levels of the antioxidant enzymes glutathione peroxidase, catalase and superoxide dismutase in lymphocytes of ALL patients were lower than in lymphocytes of controls. These findings are in agreement with earlier observations in various types of adulthood cancer. Some of the identified DNA base lesions are known to possess premutagenic properties and may play a role in carcinogenesis. The results may indicate a possible link between decreased activities of antioxidant enzymes and increased levels of DNA base lesions due to oxidative damage, and support the notion that free radical reactions may be increased in malignant cells.

Spastic paraparesis associated with portal-systemic venous shunting due to congenital hepatic fibrosis.

We report a case of progressive spastic paraparesis in a 45-year-old man with total portal-systemic shunting, which developed spontaneously due to congenital hepatic fibrosis. Cellular functions of the liver, except for an elevated blood ammonia level, were within normal limits, as is usual in congenital hepatic fibrosis. This case shows that spastic paraparesis following portal-systemic shunting may occur without liver failure.

The effects of bosentan, aminoguanidine and L-canavanine on mesenteric blood flow, spleen and liver in endotoxaemic mice.

The modulatory effects of a non-selective endothelin receptor antagonist, bosentan, were investigated together with those of relatively selective inducible nitric oxide synthase inhibitors, aminoguanidine and L-canavanine, on mesenteric blood flow decrease, liver and spleen injury elicited by endotoxaemia. Swiss albino mice (20-40 g) were administered intraperitoneally bosentan (3, 10 or 30 mg kg(-1)), aminoguanidine (15 mg kg(-1)) or L-canavanine (20 or 100 mg kg(-1)) 10 min before they received saline or Escherichia coli endotoxin (10 mg kg(-1)). After 4 h, the mice were anaesthetized, mesenteric blood flow values were measured, spleen and liver weight/body weight ratios were determined and the organs were examined histopathologically. Endotoxin decreased mesenteric blood flow (ml min(-1), saline: 3.0 +/- 0.2; endotoxin: 2.2 +/- 0.2: n = 10, P < 0.05), increased the weight of liver (g per kg body weight, saline: 47.5 +/- 2.0; endotoxin: 60.8 +/- 1.9: n = 10, P < 0.05) and spleen (g per kg body weight, saline: 3.9 +/- 0.5; endotoxin: 8.6 +/- 0.9; n = 10, P < 0.01) while it inflicted significant histopathological injury to both organs. Bosentan was ineffective at 3 mg kg(-1) but at 10 and 30 mg kg(-1) doses, it abolished all the deleterious effects of endotoxin without exception. Aminoguanidine blocked most of the effects of endotoxin except those on spleen. In contrast, L-canavanine blocked only the endotoxin-induced increase in liver weight but itself increased spleen weight and failed to block any other effects of endotoxin. Thus, it can be speculated that the beneficial effects of aminoguanidine are produced largely by mechanisms other than selective inducible nitric oxide synthase inhibition since L-canavanine was not fully effective. The beneficial effects of endothelin inhibition by using bosentan in endotoxaemia can be further exploited for the understanding and the therapy of sepsis-related syndromes.

Effect of intratympanic steroid application on the development of experimental cholesteatoma.

By introducing certain irritants into the middle ear it is possible to produce cholesteatoma. Propylene glycol, the main agent used for this purpose, produces a long-standing inflammation that causes hyperplasia and migration of the epithelium through an intact tympanic membrane. In the present investigation topical prednisolone was used in order to inhibit the production of cholesteatoma. The results indicate that there is a marked decrease in inflammation and hence experimental cholesteatoma production when prednisolone is administered into the middle ear.

Prognostic significance of depth of invasion in cancer of the larynx.

To determine the prognostic significance of depth of invasion in laryngeal cancer, the depth of invasion of tumor was measured with an ocular micrometer on the laryngectomy specimens of 94 surgically treated patients with T1, T2, and T3 laryngeal cancer and was expressed in millimeters. There was a significant negative correlation between the depth of invasion and disease-free survival. The tumors with no clinical involvement of regional lymph nodes in neck (NO neck) had significantly less depth of invasion than those with involvement (N+ neck). The tumors with pathologically confirmed cervical lymph node metastasis had significantly more depth of invasion than those without metastasis. For tumors with a depth of invasion equal to or greater than 3.25 mm, the rate of cervical metastasis in this study has always been significantly higher than for those with a depth of invasion less than 3.25 mm (P < .05). The mean depths of invasion for cases with and without recurrence were not significantly different. According to the multivariate analysis, depth of invasion (P = .047) and patient age (P = .113) significantly affected the disease-free survival independently. The depth of invasion did not significantly affect the recurrence and the interval between surgery and the development of recurrence (P > .15). The depth of invasion should be measured in every laryngectomy specimen. The depth of invasion influences the cervical metastasis and disease-free survival significantly but does not affect the recurrence rate. The depth of invasion plays an independent role in determining the disease-free survival.

Spleen damage in endotoxaemic mice: the involvement of nitric oxide.

The association between Escherichia coli endotoxin-induced organ damage and nitric oxide-related mechanisms was investigated in the spleen of male Swiss albino mice (20-40 g) by using (1) Pt/Ir electrochemical sensor connected to an amperometric detection system (NO-501, InterMedical Co., Japan), (2) nitrotyrosine immunohistochemistry, (3) conventional light microscopy and (4) immunoblotting techniques in parallel. 1 h before endotoxin injection, animals were pretreated with either nitric oxide synthase inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME, 20 mg kg(-1), i.p.) or inducible nitric oxide synthase expression inhibitor, dexamethasone (5 mg kg(-1), i.p.) or the inhibitor of murine inducible nitric oxide synthase in vivo, 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT, 1 mg kg(-1), i.p.). 5 h after endotoxin treatment, electrochemically detected concentration of nitric oxide was significantly elevated (nM, endotoxin: 716.6 +/- 178.2, n = 10 vs saline: 209.4 +/- 127.8, n = 9, P = 0.0312, unpaired Student's t-test) and remained so throughout the 30 min monitorization period. Neither dexamethasone nor AMT blocked the endotoxin-induced overproduction of nitric oxide indicating that the enhanced inducible nitric oxide synthase activity cannot be the only explanation. When dexamethasone and L-NAME combination was used to block both the constitutive and the inducible isoforms, nitric oxide production was virtually abolished, indicating a significant contribution from the constitutive isoform of nitric oxide synthase. The results of nitrotyrosine immunohistochemistry and the conventional light microscopy were also in agreement with the amperometric method while immunoblotting revealed the expression of both the endothelial and the inducible isoforms of nitric oxide synthase were induced endotoxaemic animals. Thus, conclude that endotoxin-induced splenic damage in endotoxaemia can be explained by enhanced production of nitric oxide due to the induction of both endothelial and inducible nitric oxide synthases while causal relationship and the roles of other deleterious mediators such as oxygen-derived free radicals are yet to be established.

The effect of calcitonin on osseous healing in guinea pig mandible.

Calcitonin (CT) is reported to be an effective medication for the treatment of inflammatory root resorption and to be capable of stimulating osteoblast proliferation in cell culture studies. In this study the effect of CT on the healing of osseous defects was evaluated in the mandibles of guinea pigs. After raising tissue flaps two experimental cavities were created on both sides of the corpus mandible of 33 guinea pigs. CT was applied into cavities either in hydroxypropyl methycellulose (HPMC) gel or gelatin as carrier. HPMC and gelatin alone and an empty cavity were also examined as control groups. Histopathological examinations under light microscopy were performed on weeks 1, 3, and 6. At week 1 in CT+gelatin and CT+HPMC groups, prominent osteoblastic activity was observed when compared with control groups. At week 3 the presence of woven bone in the experimental cavity areas reflected the increased osteoblastic activity in all groups. At the end of week 6 woven bone was gradually replaced by osteogenic tissue undergoing remodelization with Haversian systems in all groups. It is suggested that the osseous healing of the experimental cavity was enhanced by CT application in early stages (i.e. at week 1). However there was no significant difference of osteogenic activity between the control and CT-treated groups at the end of weeks 3 and 6.

[The effect of changes in the bones of the skull due to Mediterranean anaemia on the shape of the skull and the formation of the cranial cavity (author's transl)]. / Welchen Einfluss haben die Veränderungen an den Schädelknochen bei den Mittelmeeranämien auf den Bauplan des Schädels und auf die Gestaltung der Schädelhöhle?

The head and skull in patients with Mediterraneen anaemia show often a marked change of the external shape due mainly to the considerable enlargement of the cranial bones. From the abnormal external appearance the suspicion may arise that the form and space of the internal cranial cavity are likewise affected and even the basic structure of the skull is altered. However, a detailed investigation of the principal angles, distances and characteristic structures of the skull made on lateral roentgenograms of these patients, a comparison of the results between cases with different intensity of the osseous changes and a confrontation with the findings in normal individuals proved that there were no major discrepancies. The essential features of the human skull were always preserved. Only in some cases with severe alterations of the cranial bones a few small deviations from the normal values could be noticed and in a little number of them signs of a slight narrowing of the cranial cavity werde to be observed. This way was probably caused by a very early, rapid and extreme enlargement of the cranial bones resulting in a kind of "premature panzer-skull."

[Deformity of the skull vault due to hypertrophy of red marrow in cases of anaemia ]. / Deformation der Schädelkapsel bei Anämien durch Wucherung des roten Knochenmarks.

The shape of the head is often markedly changed in certain anaemic disorders, e.g. thalassaemia, congenital haemolytic anaemia and severe juvenile iron deficiency anaemia. However, this does not affect the basic structure of the skull and its characteristics. Rather, there is a strong thickening of the cranial bones; careful examination shows a deformation of the bones and skull cap. These changes are due to the overgrowing red marrow, which occurs in the same manner in anaemics although the origin of their disease is of course an entirely different one.

Solitary skull metastasis from occult thyroid carcinoma.

Metastatic tumors to the skull, though relatively rare, are most often from lung, breast or prostate. In this report, we describe a case of skull metastasis from occult thyroid carcinoma and discuss the differential diagnosis of these lesions.

Cerebellar ataxia associated with hypogonadotropic hypogonadism and chorioretinopathy: a poorly recognized association.

We report a male with cerebellar ataxia, hypogonadism and chorioretinopathy. The age of onset was 12. The parents were first cousins. Endocrinologic studies demonstrated hypogonadotropic hypogonadism due to pituitary dysfunction. The ocular disorder involved the choriocapillaris and the retina. The association may represent a separate syndrome, seldom recognized in the past.

Ewing's sarcoma: experience with 12 cases.

Twelve patients with localized Ewing's sarcoma were treated between 1980-1990 at the Istanbul School of Medicine, Department of Pediatric Oncology-Hematology, Oncology Research and Treatment Center and Our Children Leukemia Foundation. There were 8 boys and 4 girls, with a mean age of 8.1 (range 3-17) years. The tumors were in the femur in 3 patients, in the humerus and rib in 2 patients each and in the tibia, radius, vertebra, clavicula and pelvis in 1 patient each. Chemotherapy alone was applied in 2 patients, 1 patient had chemotherapy and radiotherapy. The remaining 9 cases were treated with Chemotherapy and radiotherapy (during the chemotherapy). The chemotherapy protocols were: VAC (n = 5), VACA (n = 3), IVAD (n = 3) and T.9 (n = 1). One patient died from the disease itself. Remissions were achieved in the other 11 patients. After 5 to 95 months (mean: 22 months) 7 patients had relapsed (4 had local and 3 had distant metastases). Three patients were not able to be followed, 3 died due to additional problems (infection, cardiotoxicity). The best prognosis was achieved when Ewing's sarcoma initiated in the long bones, with less than 100 ml tumor volumes and patients were under 5 years old. There were no significant differences among chemotherapy protocols.

The efficacy of mezlocillin-amikacin combination in febrile neutropenic children with oncologic disease.

The efficacy of mexlocillin-amikacin combination as empirical therapy for febrile neutropenic patients was studied in 30 children (21 males, 9 females) with various oncologic diseases aged 1-15 years (mean age 7.3 +/- 4.4) in the Istanbul Medical School, Oncologic Disease Research and Treatment Center, and Department of Pediatric Hematology-Oncology between January 1 and May 31, 1988. The response rate was 76.6%. Profound persistent granulocytopenia (fewer than 100 ml) was present in 70% of the patients. In 63.3% of patients, the infections were microbiologically documented (60%) Gram(+) and 40% Gram(-). The combination was well tolerated with hepatic and/or renal disturbances in 8 cases (26.6%). We conclude that mezlocillin-amikacin is an effective empirical combination in the initial treatment of infections in febrile neutropenic children with various oncologic diseases.

Cost-effectiveness of cefepime + netilmicin or ceftazidime + amikacin or meropenem monotherapy in febrile neutropenic children with malignancy in Turkey.

Infection remains the major cause of morbidity and mortality in immunocompromised children with malignancy. In addition, the economic impact of antibiotic treatment should always be evaluated, especially in developing countries. In our center between January 1998 and January 1999, 73 children with hematological malignancies [acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML)]; 9 children with solid tumors (rhabdomyosarcoma, neuroblastoma) had 87 febrile neutropenic episodes (related to chemotherapy). These children were randomized prospectively into three treatment groups. The first group (n: 28) received cefepime plus netilmicin, while the second group (n: 29) was treated with ceftazidime plus amikacin and the third (n: 30) with meropenem as monotherapy. The aim of the study was to compare the success rates and cost of fourth generation cephalosporin plus aminoglycoside and monotherapy of meropenem with ceftazidime plus amikacin, which is the standard therapy for febrile neutropenia. Microbiologically documented infections were 29.9%, clinically documented infections were 9.2% and 60.9% of the febrile neutropenic episodes were considered to be FUO. Gram-positive microorganisms were the most commonly isolated agents from blood cultures [MRSA (Methicillin Resistant Staphylococcus aureus) in 6 patients and MSSA (Methicillin Sensitive Staphylococcus aureus) in 4 patients]. The success rates were 78.5%, 79.3% and 73.3 % for the 1st, 2nd and 3rd groups respectively. In 4 patients (4.5%) fever responded only to amphotericin-B therapy. There was no statistically significant difference between the three treatment regimens with respect to efficacy, safety and tolerance (chi2 test, p>0.05), but while the third and fourth generation cephalosporins + aminoglycosides were comparable for cost, the monotherapy regimen was the most expensive. The main determining factors for the choice of treatment of febrile neutropenic children, especially in a developing country, are cost, presence of indwelling catheter and the bacterial flora of the unit, as well as efficacy.

Tumor thickness as a predictor of cervical lymph node metastasis in squamous cell carcinoma of the lower lip.

Tumor thickness is a relatively new prognostic factor that has been investigated for lower lip cancer. This study was performed in 27 patients, 13 of whom had histopathologically confirmed cervical metastasis, to investigate whether tumor thickness could be used as a predictor of cervical lymph node metastasis. The mean tumor thickness of those cases with neck metastasis was 5.60 mm (SD = 2.24), and the mean thickness of cases without neck metastasis was 3. 79 mm (SD = 1.68). The difference between tumor thicknesses of both groups was found to be statistically significant (P < 0.05). The tumor thickness of 5 mm was determined as a cutoff point, above which the cervical lymph node metastasis rate was significantly increased. As a conclusion, tumor thickness is an objective histopathologic factor that is easily reproducible; it significantly influences cervical lymph node metastasis in lower lip cancer, and it may be used in the assessment of prognosis.

Prognostic value of p53, proliferating cell nuclear antigen, and Ki-67 expression in undifferentiated nasopharyngeal carcinomas.

In this study the prognostic importance of p53, proliferating cell nuclear antigen (PCNA), and Ki-67 expression was analyzed along with the clinical parameters in 35 consecutive patients with undifferentiated nasopharyngeal carcinomas. Immunohistochemistry was used to detect p53, PCNA, and Ki-67 staining. Among the clinical findings, stage IV disease (P = 0.01), cranial nerve paralysis (P = 0.02), and lymph node metastasis (P = 0.06) were associated with shorter survival. The p53 positivity correlated with the presence of lymph nodes, but it was not a significant factor to predict the outcome. PCNA expression was not found to be a prognostic indicator. On the other hand, the proliferative value of Ki-67 staining was suggestive of prognosis. A proliferation index of Ki-67 less than 10% indicated longer survival (P = 0.03). There was no correlation between Ki-67 staining and PCNA index. As a result, the prognostic value of Ki-67 may alert the physician to more aggressive and adjuvant treatment modalities.