Association of multiple endocrine neoplasia type 2 and Hirschsprung disease.

In a few patients with Hirschsprung disease (HSCR) and no clinical symptoms of multiple endocrine neoplasia type 2 (MEN-2A) or medullary thyroid carcinoma (MTC), missense mutations in the cysteine residues 609 and 620 of the Ret gene have been identified. In several pedigrees with either MEN-2A or familial MTC (FMTC) a documented germline mutation in cysteine 618 or 620 follows the segregation of the disease phenotype. The appearance of the HSCR phenotype in such patients and pedigrees cannot be easily reconciled with the gain of function which is associated with the dominant oncogenic effect of MEN-2A mutations. Gastrointestinal manifestations are known to occur also in association with MEN-2B but, to the best of our knowledge, in only very few cases the intestinal phenotype of MEN-2B has been investigated by enzymo-histochemical techniques, as in the present work. We report an extensive molecular study of patients, two with HSCR and FMTC carrying a Cys620Arg or Ser mutation and two with MEN-2B and gastrointestinal symptoms carrying a Met918Thr mutation. One of the latter two patients showed aganglionosis of the last 5 cm of rectum which caused a congenital megacolon leading to the diagnosis and operation for HSCR. The mutation screening of all the exons of Ret in 3 of these patients did not reveal any additional mutation. Therefore these results do not support the hypothesis of additional constitutional Ret mutations in patients showing association of MEN-2 and HSCR, whilst the histochemical and clinical data in one of these patients indicate that MEN-2B can be associated with a true form of short segment HSCR.

Development of nerve fibres in the temporomandibular joint of the human fetus.

The development of nerve fibres in the temporomandibular joint (TMJ) in relation to the development of bone, muscle and fibre components was investigated in human fetuses ranging from 9 weeks of gestation to birth. Immunohistochemistry for the glia-associated protein S-100 and for the neuro-specific marker protein gene product 9.5 (PGP 9.5) were used; specimens were compared to specimens of adult TMJ capsule and disc. At 9-10 weeks, a small number of neural elements are already present in the connective tissue around the joint and in the mesenchyme between the two articular blastemas from which the disc will differentiate. By 19 weeks many nerve fibres are clearly visible. Immunohistochemical results suggest diffuse disc innervation extending along the entire disc but not in the thin central area. More complex structures, i.e. encapsulated corpuscles, were also seen. The fetal disc appears highly innervated compared to adult tissue; already at this developmental stage morphology and distribution of nerves and corpuscles in the joint capsule are comparable to those in the adult joint. It may be concluded that the innervation of the TMJ is detectable from the end of the second month and that it develops fully between the third and the fifth month of gestation. Nerve endings in the disc are most numerous at 20 weeks, after which a progressive reduction, possibly secondary to the growth of articular tissues, is observed throughout the last trimester of fetal life and into adult life. The innervation of the lateral pterygoid muscle, on the contrary, is much less than that seen in adult muscles, even at full-term.

Palmar-plantar erythrodysestasia syndrome associated with 5-fluorouracil treatment.

Palmar-Plantar Erythrodysestasia Syndrome (PPES) or Hand-Foot Syndrome (H&F S) is an underestimated adverse reaction to chemotherapeutic agents, mainly related to 5-Fluorouracil. From March 1991 to February 1992, at the San Giovanni Oncologic Hospital of Torino, we observed 12 out of 163 patients (7.3%) displaying PPES while being treated with 5-FU containing regimens. No correlation with type of neoplastic disease, sex, age and total dose of administered 5FU was observed. Dose reductions or drug suspension achieved PPES reversal. The etiopathogenesis remains unclear. Both an idiosyncratic pattern and cutaneous drug accumulation are suggested.

Non small cell lung cancer treatment with carboplatin and vindesine: a phase II study.

A phase II trial aiming to verify the effectiveness of a regimen including carboplatin and vindesine was performed. From November 1989 to September 1990, nineteen patients with advanced small cell lung cancer entered this study. Polychemotherapy treatment included: carboplatin 400 mg/sm, on day 1 and vindesine 3 mg/sm, on days 1 and 15, repeated every 4 weeks, as an outpatient regimen. Observed toxicity was mild; myelodepression, and nausea and vomiting were the main adverse events. No objective response was obtained; 14 no changes in the disease and 4 progressions were detected. The low objective response rate observed in this study is strongly influenced by a set of unfavourable prognostic factors. The median overall survival time [32 weeks] is comparable with the results of other studies.

[Splenic arteriovenous fistula (a clinical case)]. / Fistola artero-venosa splenica (un caso clinico).

A splenic arteriovenous fistula is a situation often presenting with signs of portal hypertension and with a characteristic murmur. Though rare, the possibility of a splenic arteriovenous fistula must be borne in mind in differential diagnosis, since it can be corrected surgically by resolving the portal hypertension.

4'-EPI-doxorubicin in advanced lung cancer. A phase II trial.

Fifty evaluable patients with advanced lung cancer (28 small cell and 22 non-small cell carcinomas), mainly pretreated by chemotherapy, received 4'-epi-doxorubicin 90 mg/m2 every 3 weeks. Two partial responses were obtained in small cell lung cancer patients, which lasted 153 and 168 days. Leukopenia, emesis and alopecia were the most frequent side effects. Two patients who previously received anthracyclines died suddenly of cardiac failure, another patient had severe congestive heart failure, and four others had minor cardiac dysfunctions. 4'-epi-doxorubicin has a modest activity in advanced lung cancer, mainly pretreated by chemotherapy and is not devoid of significant cardiotoxicity in this patient population.

Doxorubicin and etoposide in the treatment of advanced measurable breast cancer.

Nineteen evaluable patients with advanced breast cancer were treated with a combination of doxorubicin and etoposide. Patients had measurable disease, received only mild pretreatment and most had good general conditions at start of therapy. Strict criteria for dose adjustments according to nadir counts were applied. A 42% response rate was obtained. Toxicity was mild and treatment well-tolerated. Doxorubicin-etoposide is an active regimen for patients with breast cancer and warrants further testing in a larger patient population with less stringent criteria for evaluation and treatment monitoring.

The role of induction chemotherapy in inoperable ovarian cancer.

Thirty patients with bulky advanced ovarian cancer surgically not resectable, received combination chemotherapy (median of 4.1 cycles; range, 3-7) including cisplatin or carboplatin, followed by a second surgical effort. Clinical CR + PR was observed in 24/30 (80%) patients after chemotherapy. Our study deals only with these 24 patients, and the 6 patients who did not respond to chemotherapy are not part of this report. At debulking, 7/24 (29.1%) patients had a complete macroscopic resection; 9/24 (37.5%) patients had a partial resection (residual tumor less than 2 cm). These data suggest that debulking is feasible and successful after chemotherapy containing cisplatin or its derivative. Overall median survival from diagnosis was 18.9 months; the 3-year survival rate was 28%. Median progression-free survival from diagnosis was 13.5 months. The results observed in our study indicate that the use of induction chemotherapy can play an important role in increasing the chances of optimal debulking in patients presenting with unresectable ovarian cancer.

[Piperacillin and amikacin in the treatment of infections in neoplasm patients with granulocytopenia]. / Piperacillina ed amikacina nel trattamento delle infezioni in pazienti neoplastici in corso di granulocitopenia.

Infections are the most common cause of death in tumor patients. The risk of infection is progressively increased in relation to the severity of neutropenia. It is therefore essential to start empirical antibiotic therapy in these patients at the first sign of infection. Forty-three neutropenic tumor patients were entered into the above study when it was assumed that they had bacterial infections (temperature above 38.5 degrees C and/or signs and symptoms of infection). Patients with greater than 1000 neutrophils/mm3 were given piperacillin alone while those with more severe neutropenia (less than 1000/mm3) were given a combination of piperacillin plus amikacin. Of the 43 patients who had entered the study, 41 could be evaluated whereas the remaining two were considered dropouts either because of non-compliance with the study protocol or because the infection was found to be non-bacterial. In both groups of patients (greater than 1000 and less than 1000 neutrophils/mm3) infection resolved completely in a large percentage of cases (92% and 82%, respectively). The efficacy of piperacillin was therefore reconfirmed for the management of infection in oncologic patients with neutropenia, and proved to be an effective therapeutic resource in patients with both slight and severe neutropenia.

Isolated central nervous system metastasis from ovarian carcinoma: a case report.

Ovarian adenocarcinoma usually disseminates and recurs the abdominal cavity. The detection of central nervous system metastases is rare. In this report we describe a case of intracranial recurrence that developed during a complete local surgical and pathological response and was treated radically with surgery followed by radiation.

Phase II study of alpha-interferon plus bleomycin in advanced non-small cell lung cancer.

A synergistic effect between alpha-Interferon and Bleomycin has been recently shown in in vitro and in vivo experimental systems. Although active, Bleomycin and other antineoplastic drugs give low response rates in non-small cell lung cancer, but, like the other antineoplastic agents, responses are short-lived. We treated 13 patients with advanced non-small cell lung cancer with the combination Bleomycin 15 mg/m2 i.v. at hour 0 and alpha-Interferon 9 X 10(6) U i.m. given at hours 6, 30 and 54. Major side effects were pyrexia, astenia and anorexia; only one case of moderate leukopenia was observed. No major responses were obtained and stable disease lasted a median of 5 months. Further study of this combination is not warranted in patients with pretreated non-small cell lung cancer.

Renal function studies with cadralazine in conscious dogs: a comparison with hydralazine.

The effect of the antihypertensive vasodilator, cadralazine, on renal function in the conscious dog was compared to that of hydralazine using inulin and para-aminohippurate clearances. Both drugs were administered as intravenous bolus, at the dose of 1 mg/kg. As expected, hydralazine rapidly decreased mean blood pressure (from 110 to 89 mmHg), significantly increased heart rate (from 109 to 190 beats/min), markedly decreased urine volume (from 0.90 to 0.47 ml/min) and sodium excretion (from 101 to 45 microEq/min), and increased potassium excretion (from 28 to 53 microEq/min). Cadralazine displayed a similar activity on blood pressure and on heart rate, but differently from hydralazine, these effects appeared more slowly and were not accompanied by sodium and water retention. Hydralazine, but not cadralazine, caused a quick and transient decrease in glomerular filtration rate (from 55 to 40 ml/min), whereas both compounds increased renal plasma flow and reduced renal vascular resistance, renal extraction of para-aminohippurate and filtration fraction. Moreover, cadralazine increased plasma renin activity to a lesser extent than hydralazine, and this could explain the different effect on water and sodium excretion after acute administration of the two drugs.

Lonidamine versus polychemotherapy in advanced non-small-cell lung cancer. A preliminary analysis.

No clear evidence of survival benefit has been definitely shown by chemotherapy in advanced non-small-cell lung cancer. We evaluated in a randomized trial the activity of the new drug lonidamine (up to 1050 mg/day) versus MVP (mitomycin C, 10 mg/m2, vinblastine, 5 mg/m2, cisplatin, 100 mg/m2). The preliminary findings on 25 patients showed that lonidamine can be easily administered at these dose ranges, and main toxicity was represented by myalgia and testicular pain. Tolerance to combination chemotherapy (MVP) was superimposable to our prior experience. Responses were recorded in both arms, and no survival difference was apparent. The study is in progress.

Teniposide in the treatment of small-cell lung cancer: the influence of prior chemotherapy.

Fifty patients with small-cell lung cancer (SCLC) were treated with teniposide (VM26) at 120 to 140 mg/m2 on days 1, 3, and 5, every 3 weeks. Twelve elderly patients were administered VM26 as first-line chemotherapy. Toxicity was manageable, myelosuppression being the major side effect. The response rate for 44 evaluable patients was 34% (36% for untreated patients); the median durations of response and survival were 230 and 208 days, respectively. Effectiveness of prior chemotherapy and time from last administration was found to influence patient response to VM26: 42% of responders to prior chemotherapy responded to VM26, while 0% of the nonresponders to prior chemotherapy responded to the new agent. Moreover, among patients pretreated with chemotherapy, 12% of those recently treated (earlier chemotherapy ending less than or equal to 2.6 months before administration of VM26) responded to VM26, while 53% of patients treated greater than 2.6 months earlier responded to VM26. Survival was influenced by common prognostic factors (performance status, weight loss, prior chemotherapy exposure). Selection of pretreated patients by type of exposure to prior chemotherapy may help in the testing of new drugs in this disease.

Teniposide (VM26): an effective treatment for brain metastases of small cell carcinoma of the lung.

Despite good results of chemotherapy in small cell lung cancer (SCLC), occurrence of brain metastases is frequent and unaffected by commonly employed antineoplastic drugs, mainly because they do not cross the blood-brain barrier. We treated eight patients with SCLC and cerebral metastases with VM26 at 120 mg/m2 given on days 1, 3 and 5 and repeated every 3 weeks. Two patients achieved complete response and one had partial response. Mean response duration was 8.2 months and survival was more than 9 months in responding patients. Toxicity was manageable. VM26 is an active drug in SCLC with brain metastases.

Influence of food on the absorption of flurithromycin in man.

Oral absorption of flurithromycin, a new fluorinated macrolide, has been evaluated on eight healthy volunteers on fasting and after a standard meal. Serum levels from 0 to 8 hours, peak serum concentrations, times to peak and areas under the curves were compared using a balanced sequence cross-over design. The highest mean concentration was reached after 3 h from administration on fasting (1.36 +/- 0.31 mcg/ml) and after 1 h following a meal (1.36 +/- 0.30 mcg/ml). All the pharmacokinetic parameters considered showed no statistical change. Therefore a meal does not reduce or delay the absorption of flurithromycin, while in the presence of food other macrolides may behave differently. Moreover the tolerability to the drug was good, lacking any report of side-effects, either on fasting or after the food.

Mitomycin C, vinblastine and cis-platin. An active regimen for advanced non-small cell lung cancer.

Fifty-one patients with advanced non-small cell lung carcinoma were treated with a combination of mitomycin C, vinblastine and cis-platin (MVP). Most cycles were given on an out-patient basis. Major side effects were leukopenia and peripheral neurotoxicity; one patient died of sepsis while leukopenic. In 44 evaluable patients the response rate was 50%, with one complete response. Overall median survival time was 280 days and median duration of responses was 232 days. A better performance status, disease limited to one hemithorax and no prior exposure to chemotherapy positively influenced the survival. MVP is an effective chemotherapy for non-small cell lung cancer and further experience with this combination is warranted.

Synthesis and calcium antagonistic activity of a new class of 1,4-dihydropyridines having an alkoxyimino group in position 3.

The synthesis of new 1,4-dihydropyridines having an alkoxyimino group in position 3 is described. Pharmacological evaluation included calcium antagonistic activity in the guinea pig Taenia coli test, acute toxicity and oral antihypertensive activity in SHR. The compounds had a remarkable calcium antagonistic activity in vitro and low toxicity, but no antihypertensive activity in vivo, probably due to an unfavourable pharmacokinetic profile.