Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer.

S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m-2 over 30 min followed by doxorubicin given at 50 mg m-2 as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m-2 in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24- or 48-h Holter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severe cardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results in relevant plasma concentrations in humans and can safely be administered in combination with doxorubicin.     

Mitochondrial DNA variability detected in a single wheat regenerant involves a rare recombination event across a short repeat

The mitochondrial genome of the selfed progeny of a plant regenerated from long-term somatic tissue culture displays specific structural rearrangements characterized by the appearance of novel restriction fragments. A mitochondrial DNA library was constructed from this selfed progeny in the SalI site of cosmid pHC79 and the novel fragments were subsequently studied. They were shown to arise from reciprocal recombination events involving DNA sequences present in the parental plant. The regions of recombination were sequenced and the nucleotide sequences were aligned with those of the presumptive parental fragments. We characterized an imperfect short repeated DNA sequence, 242 bp long, within which a 7-bb DNA repeat could act as a region of recombination. The use of PCR technology allowed us to show that these fragments were present in both parental plants and tissue cultures as low-abundance sequence arrangements.     

Neuroradiological features of vertigo

Neurological Sciences - The diagnostic pathway in a patient with vertigo starts with the accurate evaluation of medical history followed by a general physical and neurological examination. This...     

Diclofenac does not modify morphine bioavailability in cancer patients.

We determined morphine plasma concentrations in 6 cancer patients before and with administration of diclofenac for 5 days. The non-steroidal anti-inflammatory drug does not modify morphine bioavailability. This observation suggests that diclofenac can be used in association with morphine during cancer pain treatment, without increasing the risk of overdosage or side effects of the opiate.     

Inhaltsstoffe von Fagaceae (Cupuliferae), 19. Mitt.: Triterpensaponine und Acylflavonoide aus Quercus robur var. stenocarpa Beck.

Constituents of Fagaceae (Cupuliferae), XIX: Triterpene Saponins and Acylated Flavonoids from Quercus robur L. var. stenocarpa Beck. In addition to four known glycosides from leaves of Quercus robur L. var. stenocarpa Beck. a new triterpene saponin has been isolted and identified as 28-β-d-glucopyranosyl ester of the 2α,3β,19α-trihydroxy-olean-12-ene-24,28-dioic acid ( I ).     

Dog-ears: a useful artifice in the closure of extensive wounds

BACKGROUND: Wounds too extensive to permit primary repair by suturing can be closed using a skin graft or skin flap and the choice of method depends on a series of factors. Practice and personal experience play a role, as well as the characteristics of the lesion and its site. Each case poses special problems, so it is not possible to establish firm rules. OBJECTIVE: To present a surgical technique for the closure of a circular defect located on the dorsum of the foot, which resulted from the extirpation of a melanoma by surgery. METHODS: In this case we used a mixed procedure consisting of skin flaps and a double full-thickness skin graft. For this operation we used dog-ears resulting from the circular exeresis performed for the extirpation of the tumour. RESULTS: The reconstructive results were good and there were no postoperative complications. CONCLUSIONS: We consider this procedure particularly suitable for certain anatomical sites, such as the dorsum of the foot, where the skin is less elastic and thinner; and for patients who are not willing to accept skin removal from other sites or for flaps to be made with more invasive operations and more constructed scars.     

Effects of preoperative chemoradiotherapy on postsurgical morbidity and mortality in cT3-4 +/- cM1lymph cancer of the oesophagus and gastro-oesophageal junction.

OBJECTIVE: Very few studies have examined post-operative morbidity after resection of oesophageal carcinoma, especially in patients treated with induction chemo- and radiotherapy for locally advanced stages. This study assessed the effects of induction chemoradiotherapy on post-operative course after resection of locally advanced oesophageal carcinoma (cT3-4 + cM1lymph). METHODS: Induction therapy consisted of 5-fluorouracil days 1-5 and days 21-25, cisplatin day 1 + day 21 and concomitant radiotherapy 18-20 fractions of 2Gy (total dose 36-40Gy). Induction chemoradiotherapy was completed in 109 patients. Surgery was performed in 90 patients (operability: 90/109 = 83%): 85 patients underwent resection with curative intent (resectability: 85/109 = 78%), bypass operation was performed in five patients. Nineteen patients could not be operated on. Results were compared to a matched group of pT3M1LYM/pT4 patients (n = 86) who underwent primary surgery in the same period. RESULTS: Resection was complete (R0) in 68 patients (68/90 = 76%). Mean duration of surgery was 428 min (range: 240-690). Peroperative complications were haemorrhage in three patients (3/90 = 3.3%), tracheobronchial perforation in three patients (3/90 = 3.3%). Median total hospital stay was 20.5 days (range: 8-355). Mean duration of intubation was 7 days (range: 1-190); 67 patients (67/90 = 74.4%) were intubated for less than 24 h. Non-tumour related hospital mortality after resection was 8.3% (7/84 patients). Mortality after two-field lymphadenectomy was 5.2 versus 11.7% after three-field lymphadenectomy. After primary surgery (n = 86) overall mortality was 2.3% (P = 0.015) and nil after two- and three-field lymphadenectomy (P = 0.011). Medical morbidity consisted of pneumonia in 43 patients (43/90 = 48%), atelectasis in ten patients (10/90 = 11%), dysrhythmia in 21 patients (21/90 = 23%), sepsis in 11 patients (11/90 = 12%) and adult respiratory distress syndrome in ten patients (10/90 = 11%). Surgical morbidity included pleural effusion in 16 patients (16/90 = 18%), tracheal fistula in two patients (2/90 = 2%), chylothorax in two patients (2/90 = 2%) and acute pancreatitis in one patient (1/90 = 1%). Ten patients (10/90 = 11%) had a radiologically confirmed anastomotic leak; however only in four out of them with clinical manifestation; treatment was conservative in all four patients. Major morbidity occurred in 27 patients (27/90 = 30%). Overall rate of morbidity was significantly higher after three-field lymphadenectomy (85%) as compared to two-field lymphadenectomy (68.7%; P = 0.023). CONCLUSIONS: Chemoradiotherapy followed by resection of cT3-4 +/- cM1lymph oesophageal carcinoma is feasible with acceptable mortality. Mortality, however, seems to be significantly higher when compared to a group of pT3M1LYM/pT4 patients who underwent primary surgery (8.3 versus 2.3%; P = 0.015) in the same period in our department.