Dose-finding and pharmacologic study of chronic oral idarubicin therapy in metastatic breast cancer patients.

Oral idarubicin (IDA) is an active drug in metastatic breast cancer, but its role in the management of this tumor is yet not established completely. To investigate a new modality of IDA administration, a dose-finding study was designed with hyperfractionated doses. The purpose was to determine the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT), and the pharmacokinetics of this schedule. IDA was administered twice daily as outpatient therapy in cycles of 3 weeks followed by a 1-week rest. Thirty-one patients with progressive metastatic breast cancer and pretreated with chemotherapy (including epirubicin and doxorubicin) were enrolled. DLT was defined as G4 hematological toxicity or any other toxicity G3 or higher (Bloom and Richardson grading). Inter- and intrapatient dose increases were studied. Pharmacokinetics of IDA and its metabolite idarubicinol (IDOL) were evaluated. IDA dose was increased from 2 mg/day to 10 mg/day, by steps of 1 mg/day, with the larger dose given in the evening. MTD was reached at 10 mg/day. Overall, the therapy cycles were 69 (median/patient, 2; range, 1-6). DLTs were G4 neutropenia associated with leukopenia and thrombocytopenia in one patient and G3 diarrhea in another of the 5 patients in the 10 mg/day cohort. The two patients developing DLT at the daily dose of 10 mg received a dose normalized for body surface of 6.85 and 5.65 mg/m2/day, respectively. We considered 5.5 mg/m2/day to be the MTD. Other toxicities were nausea, vomiting, neutropenia, and diarrhea, grades G1 to G2. By univariate analysis, significant correlations were observed between absolute neutrophil count at nadir and IDA area under the curve (P = 0.022; r = -0.33), IDA Cmax (P = 0.0067; r = -0.38), IDOL area under the curve (P = 0.0009; r = -0.43), and IDOL Cmax (P = 0.0016; r = -0.41), respectively. By multivariate analysis, IDA Cmax was the strongest determinant for neutropenia (R2 = 0.14; P = 0.01). Among the 21 patients evaluable for response, 3 (14.3%) had partial response (lasting 3, 6, and 8 months, respectively), and 6 (28.6%) had a complete arrest of disease progression (lasting 2-6 months). In conclusion, the MTD of this schedule is 10 mg/day and the DLTs are neutropenia and diarrhea. Tolerance was good, and the treatment is feasible as home therapy. Some objective measurable responses were documented in this group of anthracycline-pretreated patients. IDOL could have a role for the pharmacological effect. Further evaluation of this schedule is warranted to assess the activity and toxicity of prolonged oral IDA administration.

[2 cases of a true splenic cyst]. / Due casi di cisti splenica vera.

The nonparasitic cysts of the spleen are uncommon and their pathogenesis has not been precisely determined. Often asymptomatic, the cysts are recognised during an investigation of the abdomen for other pathological conditions; if present, the symptoms are not specific and mild. The authors report two cases of non parasitic cysts of the spleen: in the first case the onset of the disease was insidious, with dyspeptic symptoms and epigastric pain; in the second case, the cyst was initially interpreted like a metastatic localisation of a an abdominal melanoma.

Pharmacology of chronic oral daily administration of idarubicin.

Idarubicin (4-demethoxydaunorubicin) (IDA) is a daunorubicin analogue with substantial activity in hematologic malignancies and solid tumors. Among several reasons, IDA is of interest because of its main metabolite derivative, the C-13 alcohol analogue, idarubicinol (IDOL). Previous studies have suggested that IDOL, unlike other anthracycline metabolic derivatives, possesses a striking growth-inhibitory activity in tumor cell lines. This suggests that IDOL, like IDA could be useful in circumventing MDR. IDA is bioavailable in an oral dosage form. After oral administration of IDA to the patients, the concentration of IDOL quickly exceeds that of IDA and is retained in the plasma for a longer period. Hence, administration of IDA to cancer patients results ina much greater overall exposure of the tumor to IDOL than to the parent compound. At the Oncology Center (CRO) in Aviano we performed a dose-finding and pharmacokinetic (PK) study of chronic daily oral IDA with intrapatient escalation in patients with metastatic breast cancer (MBC). All the patients were pretreated with anthracyclines (the cumulative dose was 530 mg and 264 mg, respectively, for epirubicin and (DOX) and had at admittance a PS < or = 2 and a left ventricular ejection fraction > 50%. IDA (1 mg capsules) was administered orally twice a day for 21 days every two weeks. Treatment was continued at escalating doses until progression or intolerance. Twenty-five patients were enrolled. MTD has not yet been reached and clinical results are reported in Table 1. Treatment was well-tolerated in all but one patient (300 ANC at day 28). Three patients had tox G3 ANC for more than three weeks after 3, 6, and 7 mg doses, respectively. Two of them stopped chemotherapy after 1 cycle and 1 patient stopped after 2 cycles (6 mg doses). Despite previous treatments with anthracyclines (the mean cumulative dose before entering the study was 530 and 264 mg, respectively, for epirubicin and DOX) no cardiotoxicity due to IDA treatment was observed. This trial demonstrates the feasibility of chronic daily IDA administration. At the dosage reported, treatment was generally well tolerated. The PK findings (high IDOL concentrations) and the unexpected G4 myelotoxicity in patients with the highest IDOL plasma concentrations suggest that IDOL is clinically relevant.

Uptake and intracellular distribution of idarubicin in secondary cultures of normal and neoplastic urothelium.

This study analyzes the uptake and endocellular distribution of idarubicin (IDA) in normal and neoplastic urothelial secondary cultures in relation to the changes in concentration and time of exposure. The urothelial lines were isolated by Freshney's method from biopsy fragments taken from five patients with superficial bladder cancer. Pharmacological experiments were carried out on subcultures previously immunophenotypically characterized and did not exceed ten passages. The uptake and endocellular distribution of IDA was analyzed by densitometric image analysis on cells treated for 10, 20, 30 and 60 min and 2 h with scalar dosages from 10 ng/ml to 2430 ng/ml. Microscopic observations and densitometric analyzes revealed that in the cells treated with IDA, fluorescence was higher in the cytoplasm compared to the nucleus and increased with the change in dosage. Moreover, densitometric data showed that IDA uptake in the first 20 min was higher in the neoplastic cells, but after that period its behavior became heterogeneous at 30 and 60 min, while at 2 h there was an inversion of the trend. These results suggest that the in vitro cytotoxicity should be evaluated in order to verify whether the elevated uptake of IDA in the first 20 min of treatment is really correlated to a more elevated toxicity in the neoplastic cells with respect to the normal cells. This is presently under investigation.

[Small cell carcinoma of the esophagus: a case report]. / Il carcinoma a piccole cellule dell' esofago: descrizione di un caso clinico.

The authors present the case of a primitive small cell esophageal carcinoma. It is a rare and biologically aggressive neoplasm which occurs mainly in the elder male. The case observed concerns a 69 year old female treated with surgical therapy consisting in esophagectomy and intrathoracic esophagealgastrictype plasty. Diagnostic problems either histological or immunohistochemical and the choice of the following treatment are discussed. The cases of patients treated in other Surgical or Oncological centers are reported. Therapeutic orientation adopted by our group is stressed. In this case we have chosen surgical therapy because a sure diagnosis come be given only on the base of the attent histological examination of the entire specimen (endoscopic biopsies are not sufficient); survival data reported are in favour of surgical treatment where secondary metastases are not evident in the respect of antiblastic therapy and/or radiotherapy. Neoplastic recurrence occurred ten months after and a metallic endoscopic esophageal prothesis was positioned. The patient died 1 year after surgery by mediastinal syndrome.

[Reconstructive microsurgery]. / La microchirurgia ricostruttiva.

Since Microsurgery was born, it has been employed in different surgical fields offering more recently good chances even in sterility. Furthermore microsurgical techniques offer a great support to Plastic Surgery. In fact, it is possible to repair wide tissue damages of the skin, muscles or bones using free flaps. The percentage of success of this surgery increased the overall rate of success of surgical procedures. Therefore a close multidisciplinary relation between the different fields is absolutely required for a correct application of microsurgical techniques.

[Surgical treatment of Basedow's disease: total thyroidectomy]. / Il trattamento chirurgico del morbo di Basedow: la tiroidectomia totale.

The Authors report their experience in the treatment of Graves disease. After a short review of the literature, the Authors stress the medical trait of such disease with possible spontaneous resolution. Therefore the number of cases surgically treated is necessarily low. Thirty patients, all with specific antibodies, were treated with total thyroidectomy. The therapy chosen and the results obtained are herein shown. No definitive hypoparathyroidism and inferior laryngeal nerve injuries were registered.

[Total thyroidectomy technique: suggestions and proposals of surgical practice]. / Tecnica della tiroidectomia totale. Suggerimenti e proposte di pratica chirurgica.

Total thyroidectomy at present depicts a diffuse surgical procedure in the management of benign and malignant disease of thyroid gland. It is followed by a low incidence of iatrogenic damages (nervous lesions or permanent hypoparathyroidism), just like subtotal thyroidectomy and lower than surgery for nodular recurrences. Authors present the surgical technique they follow to perform total thyroidectomy, used in over 400 cases of benign thyroid diseases operated since 1986. The most important points of this surgical procedures are represented by exposure and sparing of inferior laryngeal nerve and by preservation of parathyroid function. Parathyroid glands can be exposed to direct surgical trauma but, more often, they are injured by damage of their vascular supply. To avoid this complication, vascular ligations of inferior thyroid artery have to be done never on the trunk of the artery, but on its branches just near the glandular capsula. Sparing of inferior laryngeal nerves comports the exposure of this structure for all its cervical course especially in the terminal edge, when the nerve is nearest to the gland. Systematical application of illustrated procedure has produced no operative mortality, no inferior laryngeal nerve permanent palsy, transient hoarseness in 0.5%, and transient symptomatic hypocalcemia in 2.7%.

[Surgical treatment of differentiated thyroid carcinomas: results in 440 cases operated between 1970 and 1994]. / Trattamento chirurgico dei carcinomi differenziati della tiroide: risultati su 440 casi operati dal 1970 al 1994.

The authors report their experience and surgical treatment of 440 patients with differentiated carcinoma of the thyroid (DCT) from 1970 to 1990 in the III Surgical Dept. at the University of Rome "La Sapienza". Considering 305 cases of papillary carcinoma, 103 Total Thyroidectomy (TT), 118 TT with Functional Regional Lymphadenectomy (FRL), 32 TT with Node-Picking, 51 TT with curative FRL and one TT with Radical Neck dissection were performed. In 135 cases of follicular carcinoma TT associated with Node-picking were performed on two patients, TT associated with FRL on 8 patients and TT associated with RND on 2 patients. Overall survival to 10 years was 90%; 98% for N- papillary carcinoma and 66% for N+ follicular carcinoma. There were no permanent recurrence of disease. Out of the patients who did not undergo cervical lymphadenectomy 30% developed temporary hypocalcemia; 53% (mediastinal lymphadenectomy) to 87% (FRL) of the patients submitted to lymphadenectomy developed temporary hypocalcemia with permanent hypoparathyroidism in 0.9%-23% of the cases. On the base of what has been observed by Pasieka and Grant, the Authors believe TT as the absolute solution for patients with DCT because it allows the removal of both the original tumor and the possible neoplasms in the residual gland tissue, and enables early identification of other metastases which can be treated efficaciously with I131.

[Lateral cervical metastases from unknown primary]. / Le metastasi laterocervicali precessive.

The authors report their experience about cervical metastasis of unknown primitive neoplasms. Epidemiology, histological type and topography are exposed. Primaries which are responsible, in a high incidence, of the preceding cervical localizations are described. Diagnostic iter, non-invasive/low-price clinical and instrumental procedures, advanced endoscopic and radiologic procedures are discussed. 64 patients were treated. Only in one case we could diagnose the primitive site of the neoplasm with non-invasive procedures. The other cases (63 patients) underwent the excision-biopsy of the cervical nodes. In 52 cases we have been able to define the primitive site of the neoplasm. 11 patients, in which the primary was unknown, underwent the radiotherapy of the cervical nodes and the eventual primitive "foci"; we had no survival, on the average, after six months for the diffuse dissemination of the neoplastic disease.

[The Soupault-Bucaillle operation in the treatment of Billroth II gastric resection syndrome]. / L'intervento di Soupault e Bucaille nel trattamento della sindrome da gastroresezione sec. Billroth II.

The study analyzes the benefits related to the gastroduodenojejunoplasty (GDJP) according to Soupault & Bucaille, adopted as the corrective treatment of the Billroth II gastric resection syndrome in those cases resistant to the dieting-pharmacological supports. Our experience is based on 18 cases (13 males, 5 females, mean age 39 yrs), treated from 1982 to 1987 with GDJP for a gastric resection syndrome. The patients were observed 5 years after their resection: 10 presented with an atrophic gastritis/gastric atrophy and all had a diffuse acute phlogosis in presence of biliary storage. Manual anastomoses were performed in the first 8 cases, while staplers were used in the remaining cases. Results were quite satisfying; no operative mortality or specific complications, nor pain and biliary vomiting were registered; 14 patients over 18 (77%) gained weight significantly; only 1 patient reported low-intense early "dumping-like" symptoms easily controlled by medical therapy. Endoscopy showed no biliary reflux in all cases. Biopsies of the stump, carried on before and after the GDJP intervention, showed a marked reduction of the inflammatory aspects in 76% (13) of the patients. Among the 10 patients with atrophic gastritis/gastric atrophy, only 2 (20%) presented a significant increase in the number of gastric parietal cells and gastric principal cells.

[Anastomosis or closure of the pancreatic stump after duodenopancreatectomy?]. / Anastomosi o chiusura del moncone pancreatico dopo duodenocefalopancreatectomia?

From 1986 to June 1990, 10 pancreaticoduodenectomies were performed in our Department (VIII Patologia Chirurgica, Università "La Sapienza", Roma). The reconstructive sequence was based on the pancreaticojejunal anastomosis (2 end-to-end pancreaticojejunostomies after invagination, 3 end-to-side Wirsung jejunostomies) in 5 patients. The pancreatic stump was sutured using a 50mm linear stapler in the remaining 5 patients. There was a high incidence (75%) of fistulization after direct suture of the pancreatic stump, although related mortality was null. Among patients treated with pancreaticojejunal anastomosis, a fistula on the end-to-end pancreaticojejunostomy with exitus of the patient, was registered in 1 case. On principle, we believe a end-to-side Wirsung jejunostomy should be performed after pancreaticoduodenectomy. When a safe anastomosis of the pancreatic stump cannot be performed (because of the soft parenchyma, easily lacerable) the technique of the direct suture with stapler is advisable.

[Reconstructive microsurgery]. / Microchirurgia ricostruttiva.

Progress in microsurgery has been accomplished by the technical improvements of the operative microscope and other delicate surgical instruments. Therefore, even small arteries as well as female tuba and male deferens, either presenting mechanical obstruction or a section, can be reconstructed. The same procedure may be applied in case of nerve injuries. Since Microsurgery was born, it has been employed in different medical fields offering lately good chances in sterility. Furthermore, microsurgical techniques offer a great support to Plastic Surgery. In fact, it is possible to repair wide tissue damages of the skin, muscles or bones using free flaps. The percentage of success of this Surgery increased the overall percentage obtained in General Surgery. Therefore a close multidisciplinary relation between the different Medical fields is absolutely required for a correct application of microsurgical techniques.

Use of a radioimmunoassay for 5-hydroxytryptamine (5-HT) in thrombocytosis.

A decrease in intra-platelet 5-hydroxytryptamine (5-HT) may be a possible marker for primary thrombocytosis and there are several different methods for the measurement of platelet 5-HT content (e.g. fluorimetry, high-performance liquid chromatography and radioimmunoassay). The present study has shown that, in laboratories with radioprotected areas, radioimmunoassay of 5-HT is a simple method which correlates well with a standard fluorimetric technique and yields satisfactory results in patients with thrombocytosis.

Thrombosis and hemorrhage in thrombocytosis: evaluation of a large cohort of patients (357 cases).

We report clinical and laboratory findings in a large cohort of patients with thrombocytosis (357 cases). At the time of study, the patients showed a platelet number greater than 500 x 10(9)/L. The follow-up of patients ranged between 3 and 16 years. 123 patients were affected by polycythemia vera (PV), 97 by essential thrombocythemia (ET), 13 by chronic myeloid leukemia (CML) and 31 by myelofibrosis (MF). In 93 subjects, the thrombocytosis was reactive (ST). We found the highest incidence of thrombosis in PV patients, especially concerning the cerebro-vascular system; thrombosis, but in a lower percentage, was recognized in MF patients. Also, ET patients showed a number of thrombosis in peripheral arteries. Thrombosis of the coronary arteries were quite rare while 25% of MPD subjects showed peripheral vein thrombosis. We take into account that many patients showed thrombocytosis associated to one or more atherosclerotic risk factors. Hemorrhages were present especially in CML and in ET, but were not as frequent as thrombosis. The most common bleeding manifestations affected skin and mucosa. Hemorrhages after surgical procedures were also frequent. Gastro-intestinal bleeding was not strictly related to anti-aggregating therapy and occurred not only in PV but also in ET patients.

Multiple, relapsing thrombosis in a young man with primary thrombocytosis.

We report the case of a relatively young man with multiple and fatal thrombosis associated with essential thrombocythaemia. The clinical and laboratory examinations performed before his death were in agreement with the diagnostic criteria proposed by PVSG. The autopsy revealed myocardial infarction and pulmonary embolisms. This case suggests that young patients with primary thrombocytosis should be treated with antiplatelet agents in spite of the absence of other thrombotic risks.