Mutation frequencies of GNAQ, GNA11, BAP1, SF3B1, EIF1AX and TERT in uveal melanoma: detection of an activating mutation in the TERT gene promoter in a single case of uveal melanoma.

BACKGROUND: Uveal melanoma is the most frequent primary tumour of the eye. It is molecularly clearly distinct from cutaneous melanoma and shows a different pattern of driver mutations. The influence of sunlight ultraviolet (UV) exposure on the aetiology of uveal melanoma is a matter of debate. The recent identification of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene with UV-induced cytidine-to-thymidine transitions in cutaneous melanoma prompted us to investigate whether these mutations also occur in uveal melanoma. METHODS: We analysed 50 cases of uveal melanoma obtained from enucleation surgery for mutations in the genes GNAQ, GNA11, BAP1, SF3B1, EIFAX1 and TERT, measured gene expression using microarrays and analysed gene copy numbers by SNP arrays. RESULTS: We detected a TERT mutation in only one case of a 57-year-old white male patient with clinical and histopathological features typical for uveal melanoma. The tumour showed mutations in GNA11 and EIF1AX that are typical for uveal melanoma and absent from cutaneous melanoma. No mutations were detected in GNAQ, BAP1 and SF3B1 that are frequently mutated in uveal melanoma. Both copies of chromosome 3 were retained. Several tumours among which the one carrying the TERT promoter mutation showed elevated TERT expression. Consistent with previous reports, GNAQ is inversely associated with chromosome 3 monosomy and metastasis. BAP1 mutations are significantly associated with chromosome 3 monosomy but not with relapse. CONCLUSION: These data indicate that TERT mutations are rare in uveal melanoma. No conclusion can be drawn on their potential influence on tumour progression.

Osteonecrosis of the jaws and bevacizumab therapy: a case report.

Bevacizumab is a humanized recombinant monoclonal antibody that blocks vascular endothelial growth factor (VEGF). Recently, its use has been related with osteneocrosis of the jaws (ONJ), a disease showing a histological pattern similar to bisphosphonate-related ONJ. The aim of this study is to describe an ONJ case-report following bevacizumab chemotherapy without bisphosphonate therapy. We monitored ONJ development associated with the use of bevacizumab in a 47-year-old male with primitive adenocarcinoma of the parotid gland. Our results could suggest a possible correlation between the eruption of the lower third molar tooth and ONJ development following bevacizumab therapy. Clinicians should be aware of the potential risk of bevacizumab-related ONJ complication; moreover, since there are no effective therapeutic protocols for ONJ treatment, it is very important that patients develop good oral hygiene habits and undergo regular dental status evaluation by dentists.

Uncommon association of germline mutations of RET proto-oncogene and CDKN2A gene.

INTRODUCTION: Calcitonin measurement is advised in the diagnosis of thyroid nodules, as it is an accurate marker of medullary thyroid carcinoma (MTC). C-cell hyperplasia (CCH)-induced hypercalcitoninemia cannot be distinguished from that induced by MTC, unless surgery is performed. CASE: We report the clinical and biological features of a patient with a family history of cancer, including melanoma and pancreatic cancer, who had previously undergone surgery for melanoma. He presented the unusual association of papillary thyroid carcinoma (PTC), normocalcemic hyperparathyroidism, and hypercalcitoninemia with a pathological response to pentagastrin, which was histologically deemed secondary to CCH. Multiple endocrine neoplasia (MEN) 2A was diagnosed. RET gene analysis showed a p.V804M missense mutation in exon 14, a low- but variably penetrant defect found in both sporadic and MEN2A-associated MTC/CCH, and a p.G691S polymorphism in exon 11. Furthermore, the germline P48T mutation was found in the CDKN2A gene exon 1, which is known to be associated with melanoma and pancreatic cancer. The patient showed the uncommon coexistence of a germline mutation in two suppressor genes, RET and CDKN2A; this finding, deemed to be a mere coincidence, did not modify the phenotype expected by each single mutation. CCH associated with V804M RET mutation is a precancerous condition and surgery is recommended. In order to exclude MTC, surgery is advised in patients with a pathological calcitonin response to pentagastrin, in the absence of thyroid autoimmunity. CCH-induced hypercalcitoninemia can be associated with thyroid cancers other than MTC (e.g., PTC). Family history is important in scheduling specific genetic screening in high-risk patients and their relatives.

Hypopituitarism in the elderly: multifaceted clinical and biochemical presentation.

UNLABELLED: Hypopituitarism (HYPO) is a rare and under-investigated pathology in the elderly. AIM: to review our case records of patients > or =65 yrs with first diagnosis of anterior global hypopituitarism, in order to evaluate presentation symptoms, etiology, biochemical and hormonal pictures, pituitary morphology, and efficacy of therapy. PATIENTS: 15 patients (65-82 yrs) were studied: in 11 (73%) HYPO was secondary to pituitary macroadenoma (non-secreting in 10 and GH-secreting in 1); in 3 it was associated to empty sella, and in 1 to pituitary hypoplasia. RESULTS: major presenting symptoms were visual-field defects and asthenia (40%) but also memory and/or gait impairment and nausea (30%) and depression (20%) were significantly observed. Dyslipidemia (73%), anemia (20%) and severe hyponatremia (13%) were found. After starting substitutive therapy and clinical improvement, 10 patients with macroadenoma underwent uneventful neurosurgery, which improved visual alterations but not pituitary function. Immunohistochemistry showed positivity for FSH in one patient and for GH in one patient. Six out of the eight patients with a post-surgical tumor remnant required treatment (surgery/radiotherapy/somatostatin analogue treatment in the acromegalic patient). CONCLUSIONS: The diagnosis of HYPO is often delayed in the elderly, since symptoms may be ascribed to aging and associated comorbidities. In our series, most of the aspecific symptoms were retrospectively addressed to HYPO since their resolution/improvement with replacement therapy. The prevalent cause of HYPO remains non-functioning pituitary macroadenomas. Hyponatremia can be a life-threatening presenting symptom. Symptoms considered apparently aspecific in the elderly should be investigated in order to possibly diagnose an important treatable disorder as HYPO.

TSH-secreting adenomas: rare pituitary tumors with multifaceted clinical and biological features.

TSH-secreting pituitary adenomas (TSH-omas) are a rare cause of hyperthyroidism in clinical practice. As their diagnosis is often delayed, these tumors are mostly diagnosed as macroadenomas, preventing an effective and radical cure and leading to serious local and systemic comorbidities. In addition to neurosurgery, medical therapy with the effective and tolerable SS analogs is a fundamental tool for the treatment of TSHomas. We report 3 cases of TSH-macroadenomas which displayed different clinical presentations. All patients showed increased free-thyroid hormone levels with inappropriately normal (2 patients) or high (1 patient) TSH levels. Magnetic resonance imaging (MRI)/computed tomography (CT) evidenced a pituitary macroadenoma and octreoscan was positive in all patients. In the 2 patients who underwent neurosurgery, hormonal hypersecretion by the tumor normalized. Histology showed nuclear pleomorphism and fibrosis, whereas immunohistochemistry showed positivity for TSH and, in a lesser amount, for FSH. In one of these patient (case 1), however, the presence of a tumor remnant inside the left cavernous sinus prompted us, in accordance with the patient, to start therapy with octreotide- long-acting release. As the third patient had a cardiac comorbidity which contraindicated neurosurgery, he underwent satisfactory treatment with long-acting SS analogs alone which normalized thyroid hormone levels. In this case, previous treatment with amiodarone confused and delayed the correct diagnosis of TSH-oma. As a result of improved laboratory and morphological techniques, TSH-omas should currently be diagnosed in early stages, thus enabling most patients to be managed satisfactorily through a combined approach.

Thymidylate synthase protein expression in colorectal cancer metastases predicts for clinical outcome to leucovorin-modulated bolus or infusional 5-fluorouracil but not methotrexate-modulated bolus 5-fluorouracil.

BACKGROUND: Different 5-fluorouracil (5-FU) schedules and/or biochemical modulators may result in different mechanisms of cytotoxicity, potentially affecting the correlation between thymidylate synthase (TS) expression and the clinical response to the fluoropyrimidine. PATIENTS AND METHODS: TS levels were measured immunohistochemically on archival specimens of colorectal cancer metastases from 124 patients homogeneously treated in a series of clinical trials at our institutions with: (A) leucovorin (LV)-modulated infusional 5-FU (n = 48); (B) LV-modulated bolus 5-FU (n = 41); (C) methotrexate (MTX)-modulated bolus 5-FU (n = 35). RESULTS: A statistically significant correlation between TS levels and the clinical response was observed with the regimens involving continuous infusion and/or LV modulation (response rate in patients with low and high TS: 66% versus 24%, P = 0.003, and 50% versus 0%, P = 0.0001, in group A and B, respectively). Conversely, TS levels failed to predict the clinical response within the group of patients treated with MTX-modulated bolus 5-FU (response rate 21% versus 13%, P = 0.50, with low and high TS, respectively). Consistently, the median time to progression/overall survival time in patients with low and high TS were 9 versus 6 months/19 versus 14 months (P = 0.009/0.035, group A), 8 versus 2 months/12 versus 6 months (P = 0.002/0.0006, group B) and 3 versus 2 months/12 versus 13 months (P = 0.14/0.74, group C). CONCLUSIONS: The correlation between intratumoral TS levels and the clinical response to 5-FU depends strongly on the schedule of administration/biochemical modulators that are used in different 5-FU regimens. These data strengthen the notion that different 5-FU schedules have different mechanisms of cytotoxicity.

Role of p53 mutations on survival after pancreatoduodenectomy for ductal adenocarcinoma of the pancreatic head.

BACKGROUND/AIMS: To determine the role of p53 mutations on survival after pancreatoduodenectomy for adenocarcinoma of the pancreatic head. METHODOLOGY: Resected specimens were assessed for expression of wild-type or mutated p53. Survival of p53-negative and- positive patients was investigated, and differences noted at 0.05 level. RESULTS: Expression of wild-type p53 is associated with a significant improvement in overall survival, especially for patients without nodal metastases. CONCLUSIONS: Preoperative p53 determination could enable further patient selection for aggressive surgery.

Immunohistochemical determination of p53 protein does not predict clinical response in advanced colorectal cancer with low thymidylate synthase expression receiving a bolus 5-fluorouracil-leucovorin combination.

BACKGROUND: We assessed the hypothesis that a compromised p53 function could account for the non response of colon cancer patients with low thymidylate synthase (TS) expression receiving a bolus 5-fluorouracil (5-FU) leucovorin (LV) combination. PATIENTS AND METHODS: The study population consisted of 41 patients with unresectable metastatic colon cancer, homogeneously, treated with bolus 5-FU and LV. RESULTS: Twenty-seven patients (66%) showed high levels of TS expression. The difference in the proportion of objective responses between patients with low (CR + PR: 7 of 14, 50%) and high (CR + PR: 0 of 27) TS levels was statistically significant (P = 0.0001, chi-square test). p53 nuclear over-expression was found in 27 of 41 patients (66%). No differences were observed in p53 overexpression in patients with high (66%) or low (66%) TS expression. p53 status was not found to be associated with response even in patients with low TS expression. CONCLUSIONS: p53 status measured by immunohistochemistry does not seem to be useful to identify unresponsive patients with low TS expression.

[Clinical cases of teeth previously treated by endodontic restoration using intra-canal pins of gold-coated brass]. / Casi clinici di ritrattamento di elementi dentari precedentemente ricostruiti mediante perni endocanalari in ottone dorato.

The authors, in previous studies, showed that morphological alterations on gold coated brass pins, extracted after some years of staying in dental roots, are the consequence of a localized corrosion attack, produced by anaerobic bacteria, whose presence is confirmed by the high concentration of sulphur on the most attacked spots. Since, by using a suitable technique of pin inserting, the corrosion should not occur, it was supposed that root resorption could lead to favourable conditions to create corrosion. In order to bear out this assumption, 10 meaningful clinical cases of teeth previously restored by gold coated radicular pins are critically evaluated.

[Morphological changes on gold-coated brass endodontic pins]. / Studio di alterazioni morfologiche su perni endocanalari in ottone dorato.

Scanning electron microscope (SEM) connected with X-ray microanalysis (EDX) was used to study surface alterations of gold-coated brass dental pins (Dentatus), taken out after some years from restored teeth due to necessity for repeating a restorative therapy. The study method led to establish that: --the gold coating of the base material, constituted of copper alloy, absolutely insufficient to prevent corrosion attack; --the observed morphological alterations are the consequence of a localized corrosion attack, produced by anaerobic bacteria, which origin is confirmed by the presence of S on the most attacked points; --finally the corrosive phenomenon does not cause a periapical pathology, but the process is contrary, or rather, it is the pathology that leads to the favourable conditions to create corrosion.

Primary malignant melanoma of male urethra.

A case of primary malignant melanoma of the male urethra is reported. Treatment included partial urethrectomy, bilateral inguinal and iliac lymphadenectomy, and post-surgical systemic chemotherapy. After thirty-six months, the patient is alive with cutaneous, pelvic lymph node, and gastric metastases.

Antibacterial activity in vitro of tigemonam, a new oral monobactam.

Using a broth microdilution method, the antibacterial activity of tigemonam, a novel oral monobactam, was evaluated against 217 gram-negative aerobes freshly isolated from clinical specimens. Reference antibiotics were amoxicillin, amoxicillin-sulbactam, cephalexin, cefaclor, norfloxacin, and co-trimoxazole. At a concentration of less than or equal to 8 mg/L, tigemonam inhibited 88% of the members of the Enterobacteriaceae family. Its activity was poor against the nonfermenter pathogens. In comparison with the other drugs, tigemonam generally exhibited superior antibacterial activity (with the exception of norfloxacin, which showed similar potency against the strains tested). Minimum bactericidal concentrations and time-kill determinations indicated that tigemonam showed remarkable bactericidal activity, with a 9% reduction in colony-forming units after 2 h at a dose corresponding to fourfold its minimum inhibitory concentration. When tigemonam was used in combination with netilmicin and amikacin against susceptible representative isolates of Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Escherichia coli, a synergistic effect was obtained.

In vitro antimicrobial activity and postantibiotic effect of lomefloxacin, a new difluoroquinolone.

The in vitro activity of lomefloxacin, a new difluorinated quinolone, was compared with that of ofloxacin and norfloxacin against 154 Gram-negative and 200 Gram-positive aerobes freshly isolated from clinical specimens. MIC and MBC values were in the range of those reported in the literature showing lomefloxacin as potent as the other quinolones tested. Time-kill studies indicated that this drug was rapidly bactericidal against Gram-negative and staphylococcal isolates. After 6 hr survivors were reduced to 0.1% with both Enterobacteriaceae and Staphylococcus strains, and to 0.01% with Pseudomonas aeruginosa isolates. A postantibiotic effect of about 2 hr was observed with Gram-negative bacteria and staphylococci exposed for 1 hr to a concentration of lomefloxacin corresponding to 4 x MIC. The results obtained indicate that lomefloxacin compares favorably with the other drugs tested.

Antibacterial Activity In Vitro of Tigemonam, a New Oral Monobactam.

Using a broth microdilution method, the antibacterial activity of tigemonam, a novel oral monobactam, was evaluated against 217 gram-negative aerobes freshly isolated from clinical specimems. Reference antibiotics were amoxicillin, amoxicillin-sulbactam, cephalexin, cefaclor, norfloxacin, and co-trimoxazole. At a concentration of ≦ 8 mg/L, tigemonam inhibited 88% of the members of the Enterobacteriaceae family. Its activity was poor against the nonfermenter pathogens. In comparison with the other drugs, tigemonam generally exhibited superior antibacterial activity (with the exception of norfloxacin, which showed similar potency against the strains tested). Minimum bactericidal concentrations and timekill determinations indicated that tigemonam showed remarkable bactericidal activity, with a 9% reduction in colony-forming units after 2 h at a dose corresponding to fourfold its minimum inhibitory concentration. When tigemonam was used in combination with netilmicin and amikacin against susceptible representative isolates of Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and Escherichia coli, a synergistic effect was obtained.

Effects of antrectomy and proximal duodenectomy on duodenal G-cell activity and proliferation in the rat.

The role of the antrum and duodenal bulb in gastrin regulation was investigated in 60 white rats, submitted to 1) simple laparotomy, or 2) antrectomy, or 3) antrectomy with additional removal of the duodenal bulb (1.5 cm). Serum gastrin levels 3-4 months after surgery were repeatedly measured with radioimmunoassay in fasted and in freely fed rats. The duodenum was thereafter removed and its proximal third used to assess the number and cytoplasmic granule content of duodenal G-cells. Basal serum gastrin levels were significantly increased by antrectomy, but reduced by additional resection of the duodenal bulb. Antrectomy, with or without proximal duodenectomy, completely abolished the gastrin response to feeding. Duodenal G-cell density was increased following antrectomy, but the phenomenon was not further enhanced by additional removal of the duodenal bulb. No significant changes in the patterns of gastrin granule maturation were found after antrectomy and proximal duodenectomy.

Original features in neurofibromatosis: report of a case.

A case of von Recklinghausen disease with unusual anatomoclinic and genetic aspects. The authors discuss the peculiar evolution of a neurosarcomatosis degeneration.