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There is no effective treatment for relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We conducted a phase I dose escalation trial of SAR103168, a novel multi-targeted kinase inhibitor with activity against the Src kinase family, the BCR-Abl kinase and several angiogenic receptor kinases. Twenty-nine patients 18-83 years old were treated with SAR103168. Pharmacokinetics was characterized by plasma peak concentration (Cmax) at the end of the infusion, followed by a biphasic decline in the elimination profile. Adverse events were as expected for the patient population and there were no individual toxicities specific to SAR103168. Due to the unpredictable nature of drug exposure, the sponsor decided to discontinue the study prior to reaching the maximum tolerated dose.

While occupational health is a significant driver of population health, productivity, and well-being in Canadian society, most workers do not currently have adequate access to qualified occupational health services. A case study is used to demonstrate the utility of a telehealth approach to service delivery.

SAR103168, a tyrosine kinase inhibitor of the pyrido [2,3-d] pyridimidine subclass, inhibited the kinase activities of the entire Src kinase family, Abl kinase, angiogenic receptor kinases (vascular endothelial growth factor receptor [VEGFR] 1 and 2), Tie2, platelet derived growth factor (PDGF), fibroblast growth factor receptor (FGFR) 1 and 3, and epidermal growth factor receptor (EGFR). SAR103168 was a potent Src inhibitor, with 50% inhibitory concentration (IC50) = 0.65 ± 0.02 nM (at 100 μM ATP), targeting the auto-phosphorylation of the kinase domain (Src(260-535)) and activity of the phosphorylated kinase. Phosphorylation of Src, Lyn and Src downstream signaling pathways (PYK2, P-130CAS, FAK, JNK and MAPK) were inhibited in a dose-dependent manner. SAR103168 inhibited the phosphorylation of STAT5 in KG1 cells and fresh cells from patients with acute myeloid leukemia (AML). SAR103168 inhibited proliferation and induced apoptosis in acute and chronic myeloid leukemic cells at nanomolar IC50. SAR103168 induced anti-proliferation of leukemic progenitors (CFU-L) from 29 patients with AML, and > 85% of AML patient samples were sensitive to SAR103168. These antagonist activities of SAR103168 were independent of FLT3 expression. SAR103168 treatment was effective in 50% of high-risk patient samples carrying chromosome 7 abnormalities or complex rearrangement. SAR103168 administration (intravenous or oral) impaired tumor growth and induced tumor regression in animals bearing human AML leukemic cells, correlating with potent inhibition of Src downstream signaling pathways in AML tumors. SAR103168 showed potent anti-tumor activity in SCID (severe combined immunodeficiency) mice bearing AML (KG1, EOL-1, Kasumi-1, CTV1) and chronic myeloid leukemia (CML) (K562) tumors. The combination of cytarabine and SAR103168 showed synergistic activity in AML and CML tumor models. These results highlight the therapeutic potential of SAR103168 in myeloid leukemias and support the rationale for clinical investigations.

Objectives: The thioxanthone analog, SR271425, is a novel cytotoxic DNA-interacting agent with broad antitumor activity in preclinical models. The objectives of this phase I study were to determine the dose-limiting toxicities, maximum tolerated dose, recommended phase II dose, pharmacokinetic profile, and trend for efficacy in patients with advanced cancer., Methods: SR271425 was administered intravenously over 1-hour, weekly for 2 weeks, followed by 1 week rest. Because of Cmax-related corrected QT (QTc) prolongation in preclinical testing of SR271425, all patients underwent an extensive pretreatment cardiac assessment., Results: Eighteen patients received SR271425 at 5 dose levels ranging from 64 to 675 mg/m/wk. No dose-limiting toxicities were identified. In all tested dose-levels, Grade 3 adverse events were observed in 10/18 patients (55.6%) and Grade 4 in 4/18 patients (22.2%). QTc prolongation was reported at the 3 highest dose levels but did not exceed Grade 2. Six deaths occurred during the study, 5 of them because of disease progression and 1 because of disease related bowel perforation. SR271425 exposure increased in a near dose-proportional manner. The mean terminal plasma half-life of SR271425 was 6 hours and there was no drug accumulation after repeated dosing. Stable disease was the best outcome observed (5 patients)., Conclusions: SR271425 was administered safely at doses up to 675 mg/m/wk on a 2-week on, 1-week off schedule. No dose-limiting toxicities were observed. Grade 2 QTc prolongation was observed at the highest dose levels. Maximum tolerated dose was not reached because of early termination of the SR271425 program by the sponsor.

This study examined the use and effectiveness of the Alert assessment form. The form is part of the Alert system, used by one large acute care hospital to identify patients with a propensity for violence. All reported incidents of patient violence from August 1, 2003, through December 31, 2004, were included in patient charts. One hundred seventeen violent patient charts were reviewed and compared with 161 non-violent patient charts, randomly chosen from the same time period. Overall use of the Alert assessment form for violent and non-violent patients was 75.7% and 35.4%, respectively. The assessment form was found to have moderate sensitivity (71%) and high specificity (94%). It is reasonably effective in identifying potentially violent or aggressive patients when it is used according to protocol. Efforts to improve the tool are warranted, as is evaluation of its benefit in settings with low prevalence of violence. Also, greater effort must be taken to prevent violence once an aggressive patient has been identified.

Tactical displays can quickly become cluttered with large numbers of symbols that can compromise effective monitoring. Here, we studied how heuristic automation can aid users by intelligently "decluttering" the display. In a realistic simulated naval air defense task, 27 experienced U.S. Navy users monitored a cluttered airspace and executed defensive responses against significant threats. An algorithm continuously evaluated aircraft for their levels of threat and decluttered the less threatening ones by dimming their symbols. Users appropriately distrusted and spot-checked the automation's assessments, and decluttering had very little effect on which aircraft were judged as significantly threatening. Nonetheless, decluttering improved the timeliness of responses to threatening aircraft by 25% as compared with a baseline display with no decluttering; it was especially beneficial for threats in more peripheral locations, and 25 of 27 participants preferred decluttering. Heuristic automation, when properly designed to guide users' attention by decluttering less important objects, may prove valuable in many cluttered monitoring situations, including air traffic management, crisis team management, and tactical situation awareness in general.

ELOXATIN (Oxaliplatin) is a novel platinum containing anti-cancer agent with a diaminocyclohexane carrier ligand which has been approved in several major European countries. Clinical studies have demonstrated that the compound exhibits marked activity against colorectal cancers in combination with 5-fluorouracil (5-FU). The aim of this work was to develop and validate a highly sensitive inductively coupled plasma mass spectrometry assay for the determination of oxaliplatin-derived platinum in plasma ultrafiltrate, plasma and whole blood and to apply this technique to clinical pharmacokinetic studies with oxaliplatin. Ultratrace detection of platinum in plasma ultrafiltrate was achieved using ultrasonic nebulisation combined with ICP-MS. This technique allows detection of platinum at the 0.001 microg Pt/ml level in only 100 microl of matrix. Assays in blood and plasma utilised a standard Meinhardt nebuliser and spray chamber, achieving detection limits of 0.1 microg Pt/ml in 100 and 200 microl of matrix, respectively. The assays were validated (accuracy and precision within +/- 15%) over the concentration ranges: 0.001-0.250 microg Pt/ml in plasma ultrafiltrate and 0.1-10 microg Pt/ml for plasma and whole blood. The effect of sample digestion. dilution, long term frozen storage and quantitation in the presence of 5-FU were also investigated and validated. The method was used to monitor platinum exposure following oxaliplatin administration (130 mg/m2) to cancer patients. Following a 2 h i.v. infusion, peak platinum levels declined in a triphasic manner in all blood compartments. Free platinum was detected in plasma ultrafiltrate at low levels (0.001 0.010 microg Pt/ml) for up to 3 weeks. In conclusion, a highly sensitive and specific assay has been developed for the determination of platinum in biofluids. This method enabled characterisation of the long term exposure to platinum in patients following oxaliplatin treatment.

Epirubicin is known to be metabolized in the liver. Therefore, drugs such as cimetidine, which inhibit the cytochrome P-450 enzyme system or reduce liver blood flow, may reduce the plasma clearance of epirubicin. In a small study, epirubicin 100 mg/m2 every 3 weeks was administered intravenously to eight patients, who also received oral cimetidine (400 mg b.d. for 7 days starting 5 days before chemotherapy) with either the first or second cycles. Epirubicin pharmacokinetics and liver blood flow (idocyanine green clearance) were assessed at each course. The areas under the plasma concentration time curves (AUCs) were used to compare the systemic exposure to epirubicin and its metabolites with each course. The estimated median percentage increase (95% confidence interval CI) in the AUC with cimetidine were: epirubicin 50% (95% CI -18 to 193, epirubicinol 41% (95% CI 1 to 92). Despite the small numbers studied, the increase in the active metabolite epirubicinol was significant (P < 0.05). These changes in exposure were not explained by reduced cytochrome P-450 activity as the 7-deoxy-doxorubicinol aglycone AUC was not reduced (357% increase: 95% CI 17 to 719) or by a decrease in liver blood flow (17% increase: 95% CI -39 to 104). Cimetidine is likely to be coprescribed or self-administered with epirubicin and therefore clinicians should be aware of this potential interaction.

Circumvention of multidrug resistance in vitro by resistance modulators is well documented but their clinical use may be limited by effects on normal tissues. We have compared four resistance modifiers, both in terms of modulation of doxorubicin sensitivity in vitro and toxicity in vivo, in order to determine whether it is possible to select agents with clinical potential. Verapamil, D-verapamil and quinidine are all maximally active in the multidrug resistant cell line at about 7 microM and are not cytotoxic at this concentration. The tiapamil analogue Ro11-2933 is a highly potent resistance modulator such that at only 2 microM sensitization is greater than is seen with the other modulators at 7 microM. Since the ID50 concentration for Ro11-2933 is 17.7 microM (5-12-fold less than the other modifiers) we have used isobologram analysis to demonstrate that the interaction with doxorubicin is supra-additive and cannot be explained by additive toxicity. This method of analysis also revealed that when resistance modulation is related to the cytotoxicity of the modulator itself, all four modulators show comparable activity. On the other hand, measurement of the acute toxicity in mice of the modulators did reveal differences. The LD10 for verapamil (51 mg/kg) was about one third of that for quinidine (185 mg/kg) and this is consistent with the known maximum tolerated plasma levels in patients. Furthermore, whilst epirubicin alone was unable to reduce the growth rate of a multidrug resistant human tumour xenograft, the addition of quinidine, but not verapamil, at the maximum tolerated dose did do so. D-Verapamil was only about half as toxic as racemic verapamil and this too is consistent with clinical observations. The LD10 for Ro11-2933 (152 mg/kg) was comparable with that for quinidine. In the human tumour xenograft model maximal growth inhibition was observed with the combination of epirubicin and Ro11-2933 (45 mg/kg) and this degree of growth inhibition was comparable to that obtained with epirubicin alone in the drug sensitive xerografts. Ro11-2933 had no measurable effects on the plasma or tumour pharmacokinetics of epirubicin. These results suggest that it is possible to predict the clinical potential of a resistance modulator. Furthermore, Ro11-2933 is a promising agent for use in the clinic since maximal resistance modulation in vivo is observed at about one third of the LD10 dose.

The multidrug resistance (MDR) phenotype can be reversed in vitro by a number of agents thought to interact with P-glycoprotein (P-gp). Although plasma levels, adequate for MDR modulation, can be achieved with certain modulators, concern has been expressed that tumour levels may be inadequate due to high plasma protein binding. Mice bearing an MDR-positive human tumour xenograft were injected intraperitoneally with quinidine (150 mg/kg). After 2 h the mean plasma quinidine level was 1.9 micrograms/ml (5.1 mumol/l) and the mean tumour quinidine effective in vitro. Three tumour biopsy specimens were obtained from patients who had received oral quinidine prior to surgery. Plasma and tumour levels were similar and were comparable with those measured in mice. This study should dispel fears of inadequate tumour levels of this and other modulators due to high plasma protein binding and encourage future clinical trials of modulators in MDR-positive human tumours.

We reviewed the cases of 41 consecutive men treated for breast carcinoma from 1950 through 1987 at Vanderbilt University Affiliated Hospitals to examine controversies in and methods of therapy for this disease. Twenty-two patients (52%) had stage I or II lesions potentially curable by operative therapy. The overall 5-year survival rates were 100% for stage I, 65% for stage II, 56% for stage III, and 0% for stage IV. Radical mastectomy offered no advantage over modified radical mastectomy in terms of survival or rate of recurrence. Diagnosis at an early clinical stage and no finding of disease in axillary lymph nodes were important factors in survival in this series of patients. All tumors evaluated for hormone receptors were positive. Although experience was limited, encouraging results were obtained with the use of tamoxifen citrate in adjuvant as well as palliative roles. With the exception of a predominance of centrally located lesions and a uniquely high frequency of positive hormone receptor status, carcinoma of the male breast appears biologically similar to the disease in women, and treatment should be guided by similar principles.

Response to cytotoxic agents is assumed to be related to the concentration of drug achieved within tumour tissue. It is also often assumed that, given similar tissue concentrations of drug, normal tissues are less responsive to the same cytotoxic agents. This can partly be explained by the number of cells in normal tissues that are differentiated. These non dividing cells, in a stable testing phase of the cell cycle (G0) are less susceptible to cytotoxic damage. Little is actually known about the relationship between tumour drug concentrations and those in the tissue of the tumour-bearing organ. In this study, we compared doxorubicin concentrations in paired samples of tumour and normal breast tissue from 17 previously untreated women undergoing mastectomy. The relative cellularities of both specimens were estimated by measuring their DNA content. There was wide variation in intra-tumoural doxorubicin concentrations (range, 220-1,590 ng/g). Normal tissue also showed marked inter-patient variation (range, 81-1,000 ng/g). For a single patient the tumour drug concentrations were significantly higher than those in normal breast tissue (P less than 0.05), and tumour: normal tissue ratios ranged from 1.27 to 8.30. Where doxorubicin concentration was expressed in terms of the relative cellularity of the tissues, there was no significant difference between, drug concentrations in the tumour and those in normal breast tissue (tumour: normal ratios, 1.1:1.8). There was a significant correlation (r = 0.76, P less than 0.05) between peak serum values and tumour concentrations of drug. No correlation was found between drug concentrations achieved and the histological grade or oestrogen receptor status of the breast cancer.

An outbreak of ochronosis and colloid milium is described after the use of strong hydroquinone bleaching creams. These phenomena developed only after a few years, and took place when the melanocytes had overcome the bleaching influence. Sun-exposure and thorough inunction of the cream were required for the more advanced changes. Analogous changes have been seen when the skin is exposed to certain crude fuels in individuals working in the sun, and phenolic components in the fuels are suspected. The study presented here covers the clinical, histological, histochemical, electron microscopical and pathogenetic features as seen in thirty-five cases of hydroquinone damage to the dermis in South Africa.

An outbreak of chikungunya fever which occurred during April 1977 among a group of high-school children from Pretoria after a visit to the northern Transvaal bushveld is reported. Some of the adults who accompanied the pupils also contracted the disease. The adults suffered more severely from the chronic arthritic form of the disease than did the children. In some cases the episodic polyarthritis was still present 18 months after the onset of the disease. Rheumatoid factors in low titre could be demonstrated in the circulation of patients with longstanding symptoms.

4'-Deoxydoxorubicin (4'-DOX) is an analogue of the anticancer drug Adriamycin (ADR) believed to lack its cardiotoxicity. Bioreduction to a semi-quinone free radical has been implicated in the etiology of ADR induced cardiotoxicity. We have studied (in a rat model) acute cardiotoxicity (after 16 mg/kg i.v. of both drugs), antitumour activity (after 5 mg/kg i.v.) and the relationship to disposition and metabolism in the target tissues (after 5 mg/kg i.v.). 7-Deoxyaglycones, which are considered inactive lipophilic metabolites derived from ADR semi-quinone, were utilised as markers of in vivo tissue free radical generation. Both drugs produced toxicity of equal severity to hearts after 24 hr, associated with high cardiac levels of 7-deoxyaglycones in the case of ADR (AUC0-48 hr, micrograms/g X hr: ADR, 47; ADR 7-deoxyaglycone (ADR-DONE), 24; and adriamycinol 7-deoxyaglycone (AOL-DONE), 35) compared to low cardiac levels of 7-deoxyaglycones but a times five higher peak cardiac concentration of parent drug in the case of 4'-DOX (AUC0-48 hr, micrograms/g X hr: 4'-DOX, 68; 4'-DOX-DONE, 3.8; and 4'-DOL-DONE, 0.8). 4'-DOX displayed superior antitumour activity to ADR against the MC 40A sarcoma growing sub-cutaneously, achieving higher concentrations of parent drug in tumour (AUC0-48 hr, micrograms/g X hr: 4'-DOX, 150; ADR, 60). There was an absence of 7-deoxyaglycones of both drugs in the tumour. These data suggest that drug bioreduction is involved principally only in ADR induced cardiotoxicity and that the level of unchanged parent drug achieved in the tumour is the most important pharmacokinetic determinant of antitumour activity for both ADR and 4'-DOX.

Necrobiosis lipoidica of the legs, in which deep ulcers resembling erythema induratum, gummas or a variety of other chronic progressive ulcerating skin diseases occur, is described. In 2 cases the lesions were precipitated by a crush injury elsewhere in the same leg, but not at the site of the ultimate lesions. In 2 further pairs of siblings the same problem arose as a familial complaint without trauma. These cases were distinguished by severe necrosis in the absence of diabetes.

A father and son, both suffering from chronic mucocutaneous candidiasis, were successfully treated with oral ketoconazole, a water-soluble imidazole compound. No toxic side-effects occurred during treatment. Treatment was given for about 8 months with diminishing does of ketoconazole. The disease cleared completely about half-way through the course of treatment and did not relapse within 1 month of discontinuing the drug. The only immunological abnormality was a depression in vitro of neutrophil chemotaxis. This became normal during therapy and was regarded as being a result of the disease and not as its cause.

A case of sarcoidosis with generalized erythroderma, exfoliation and micropapule formation in a 6-year-old boy is presented. Follicular spiny keratoses, resembling those seen in pityriasis rubra pilaris, and palmo-plantar pitting were among the other extraordinary features in this case. The epidermis overlying the widespread sarcoid granulomata showed parakeratosis, lymphocytic infiltration and degeneration of the basal layer.

Sixteen patients from seven different families with the Buschke-Ollendorff syndrome have been studied. Osteopoikilosis was found in two-thirds of the patients radiologically examined and all but two had skin involvement. The predominant clinical pattern consisted of grouped skin coloured papules and discs that were distributed asymmetrically and which usually had presented at an early age. The skin lesions showed the characteristic histological changes of juvenile elastoma which, it is suggested, is the specific dermatological abnormality of the Buschke-Ollendorff syndrome.

Two cases of cutaneous schistosomiasis due to ectopic ova have recently been seen. Both patients presented with abdominal papular lesions, which were found on biopsy to contain schistosoma ova. To reach these abdominal sites mature worms probably migrate from the portal circulation to the paraumbilical veins, where they anastomose with veins of the caval system.

A mixed cryoglobulin (IgG/IgM) was detected in a patient with erythema elevatum diutinum. Cold exposure activated the complement system and provoked a fixed urticarial reaction with the histology of a leukocytoclastic vasculitis.

Three young adults are described with features of lichen verrucosus et reticularis of Kaposi (porokeratosis of Nékam). Serological evidence of toxoplasmosis (active or recent infection) was found in all three. Marked improvement on appropriate treatment occurred in the one patient who presented evidence of systemic toxoplasmosis.

Nine patients with eczema were treated with the immunosuppressive drugs cyclophosphamide and azathioprine. In all patients the eczema was severe and incapacitating and had not responded satisfactorily to systemic and topical corticosteroid therapy. The eczema improved in all patients and systemic corticosteroids, which had resulted in undesirable side-effects, could be decreased or stopped. Leukopenia was not necessary for achieving clinical improvement. Several months of treatment were needed to obtain significant improvement in the eczema and long term remissions followed cessation of therapy.

A retrospective review of patients with Crohn's disease treated at our institution from 1973 to 1986 revealed 12 patients operated on for rectovaginal fistula. Disease involved the large intestine in 10 patients. Primary fistula repair was performed in four patients and four others had staged repair with preliminary fecal diversion. Four patients with severe colonic and anorectal disease had proctocolectomy performed as the first procedure. Of eight patients who underwent fistula repair, complete healing occurred in six. One patient has a persistent fistula, which is minimally symptomatic, and the other required proctocolectomy after three unsuccessful repairs. Success of operation correlated with quiescent intestinal disease and absence of rectal involvement. In selected patients with symptomatic fistulas, surgical repair is indicated and healing can be anticipated.

A lesion of unknown etiology and histogenesis, the granular cell tumor usually arises in the skin or soft tissue. It has been reported, however, in other sites and can be multifocal. The authors have seen 31 such tumors in 26 patients in their institutions since 1970. Most (21) patients were females, and 12 patients were black. The average age was 41.8 years, excluding two newborns with a congenital granular cell myoblastoma of the gingiva. The most common site of occurrence was the skin; seven tumors originated from the trunk and five from the extremities. Four lesions were found in the breast, three on the vulva, two in the axilla, two in the gum, two in the buccal cavity, two in the esophagus, and one each in the stomach, gluteus muscle, eyelid, and bronchus. Two patients had multiple synchronous lesions. These were bilateral hand lesions in one patient, and lesions of the breast and axilla in the other. A third patient had three separate lesions which arose over the course of 5 years, involving the bronchus, the gluteus muscle, and the buccal mucosa. An additional esophageal lesion was an incidental finding 3 years after excision of a granular cell tumor of the breast. All of the tumors were removed with local, simple excision, except for the 2-cm lesion in the stomach for which a wedge resection of the fundus was necessary and the bronchial lesion for which a wedge resection of the left upper lobe of the lung was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

This case of villous adenoma of the appendix reported is unique by virtue of its having been diagnosed preoperatively using colonoscopy. Only 45 such lesions have been described previously, and a review of those cases reveals that 93 percent were discovered at appendectomy performed either incidentally or for acute appendicitis. The malignant potential of this entity is unknown and its treatment is controversial. Because of a report association between adenomas of the appendix and other gastrointestinal neoplasms, long-term surveillance is recommended.

Radical pancreatoduodenectomy for treatment of pancreatic carcinoma has been the surgical standard of care for the past four decades. The recent popularization of pylorus-sparing pancreatoduodenectomy to treat benign pancreatic disease, because of its decreased morbidity and long-term nutritional consequences, has led to the use of this procedure in cases of pancreatic carcinoma. We report recent experience with three patients with pancreatic carcinoma in whom pyloric preservation would have compromised the potential chance for curative resection or compromised palliation because of occult spread of tumor to a region not resected with this new operative approach. Two patients had proximal, microscopic intramural spread of pancreatic adenocarcinoma within the duodenum or antrum--a mode of spread not previously reported with pancreatic carcinoma. Both patients had no other evidence of metastatic involvement, and both would have had positive surgical margins in a pylorus-sparing pancreatoduodenectomy. A third case demonstrates a true submucosal recurrence of pancreatic carcinoma after a pylorus-sparing pancreatoduodenectomy. It is debatable that any case demonstrating intramural spread within the duodenum could be cured with a standard Whipple resection as this may well represent another sign of incurability, like lymphatic or perineural spread, but it is clearly a major potential obstacle to palliation if submucosal recurrences occur as a result of the use of the pylorus-sparing pancreatoduodenectomy in cases of pancreatic cancer. The use of pylorus-sparing pancreatoduodenectomy in resectable pancreatic cancers must be viewed skeptically at this time.

A retrospective review of patients with Crohn's disease treated at our institution from 1973 to 1986 revealed 35 patients operated upon for anorectal fistulas. Twenty-nine had low intermuscular fistulas (multiple in seven), and six had high intermuscular (supralevator) fistulas. Fistulotomy alone was performed in 19 patients, and eight underwent partial fistulotomy and seton insertion. Five additional patients had proximal fecal diversion before fistulotomy. Three patients with severe colonic and anorectal disease underwent proctocolectomy as the initial procedure. Of the 32 patients who had fistulotomy performed, complete healing occurred in 30. Seven patients who healed required more than one operation for fistula. One patient was left with an asymptomatic fistula, and one required proctectomy for persistent symptomatic fistula and proctitis. Success of operation correlated with absence of rectal disease and quiescent disease elsewhere in the gastrointestinal tract. Aggressive medical treatment is required to control bowel disease preoperatively. In the majority of patients, subsequent surgery is justified and healing can be anticipated.

The concurrent administration of adriamycin (intravenous) and verapamil (oral) is of considerable interest because of experimental data suggesting that resistance to adriamycin may be overcome by this means. The potential for a pharmacokinetic interaction between the two drugs has therefore been investigated in five patients with small cell lung cancer treated with combination chemotherapy comprising adriamycin, VP16, vincristine and cyclophosphamide. The data indicate that a significant interaction takes place. Adriamycin peak levels, terminal half-life and the volume of distribution at steady state are higher, whereas plasma drug clearance and the volume of the central compartment are lower with co-administration of verapamil. There was no evidence of enhanced drug toxicity in this study; however, the data should be considered in the interpretation of clinical trials in which adriamycin and verapamil are used together, both in terms of toxicity and tumour response.

Crops of distinctive skin lesions appeared after jejuno-ileal by-pass surgery for morbid obesity in three patients. They consisted mainly of large numbers of macules on the extremities, of vague outline and with a tendency to central pustulation and necrosis. Severe arthralgia and myalgia preceded the skin lesions, which histologically showed a dense neutrophil leukocytic infiltrate, nuclear debris, and fibrin deposition around blood vessels in the dermis.

A hitherto undescribed inherited dermatosis, traceable to certain 19th-century inhabitants of Oudtshoorn, CP, has been transmitted as an autosomal dominant to a large number of their present-day descendants. The disease consists of intermittent and recurrent centrifugal peeling, with redness, of the palms and soles in particular. In more severe cases similar patches are found extending up the limbs to the buttocks and the trunk generally. The inconvenience is usually moderate, but it may be incapacitating. Some temporary relief, but so far nothing permanent, can be offered through treatment.

A new autosomal, dominantly inherited epidermal disorder is described in which a spreading dissection of the stratum corneum with redness of the palms and soles occurs as a result of a centrifugal necrobiosis of the Malpighian layer below it. Iis is seen characteristically in winter. In extensive cases the limbs and trunk are affected with gyrate scaling erythemas.

We describe the application of a high-speed spectrophotometric detector and high-performance liquid chromatography to the determination of anthracycline purity in extracted patient specimens and to the identification of chemical reduction products. Blood contained pure anthracyclines whilst in urine, tissue and tumour there was evidence of co-eluting endogenous peaks and complexation. Aerobic reduction yielded two main products: a C13 alcohol and a fully reduced, non-fluorescent, yellow hydroquinone. Anaerobic reduction in the presence of DNA yielded a 7-deoxyaglycone metabolite end product instead of the fully reduced hydroquinone. Eight other separate chromatographic species were identified, all of which showed unique absorbance characteristics, having a visible lambda max at 530 nm and being coloured purple/blue.

A case of nonHodgkin's lymphoma of the perianal region in a patient with AIDS is reported. The unusual features of AIDS-related lymphoma and the possible role of immunodeficiency increasing susceptibility to oncogenic viruses are discussed.