Phase I trial of the selective mitochondrial toxin MKT 077 in chemo-resistant solid tumours

Background: MKT 077 is a rhodacyanine dye analogue which preferentially accumulates in tumour cell mitochondria. It is cytotoxic to a range of tumours. In this phase I study, MKT 077 was administered as a five-day infusion once every three weeks.Patients and methods: Ten patients, median age 59 (38–70) years, with advanced solid cancers were treated at three dose levels: 30, 40 and 50 mg/m²/day for a total of 18 cycles.³¹ Phosphorus magnetic resonance spectroscopy (MRS) was used to evaluate the effect of MKT 077 on skeletal muscle mitochondrial function.Results: The predominant toxicity was recurrent reversible functional renal impairment (grade 2, two patients). One patient with renal cancer attained stable disease and the remainder progressive disease. There were no MRS changes in the first or second treatment cycles but one patient received 11 treatment cycles and developed changes consistent with a mitochondrial myopathy. Mean values for all pharmacokinetic parameters were at sub micromolar levels and did not exceed IC50 values (1 µM).Conclusions: Because of the renal toxicity, and animal studies showing MKT 077 causes eventual irreversible renal toxicity, further recruitment was halted. The study shows, however, that it is feasible to target mitochondria with rhodacyanine analogues, if drugs with higher therapeutic indices could be developed.     

Phase I study of the novel cyclic AMP (cAMP) analogue 8-chloro-cAMP in patients with cancer: toxicity, hormonal, and immunological effects.

The cyclic AMP (cAMP)-dependent protein kinase regulatory subunit RI is overexpressed in cancer cells. 8-Chloro-cAMP (8-Cl-cAMP) is an RII site-specific analogue that down-regulates RI and inhibits the growth of a wide range of cancer cells in vitro and in vivo. We performed a Phase I trial of 8-Cl-cAMP in 32 patients with malignancies that were refractory to standard treatments. 8-Cl-cAMP was initially given in a 1-month cycle by constant infusion at 0.005 mg/kg/h for 21 days, followed by 1 week of rest. The dose was escalated to 0.045 mg/kg/h, but hypercalcemia became the dose-limiting toxicity. The length of drug administration was, therefore, reduced to 5 days per week for the first 3 weeks of the cycle, but it was not possible to increase the drug dose without producing hypercalcemia. Hence, the length of drug administration was reduced to 3 days per week for the first 3 weeks of the cycle. The maximum tolerated dose for this regimen was 0.15 mg/kg/h, and the dose-limiting toxicities were reversible hypercalcemia and hepatotoxicity. Stable disease for > or =4 months was observed in two patients treated at > or =0.045 mg/kg. cAMP-dependent protein kinase is involved in hormone- and cytokine-mediated signaling, and so representative hormone, cytokine, and peripheral lymphocyte subsets were measured. The drug had a parathyroid hormone-like effect on calcium homeostasis and significantly increased circulating luteinizing hormone and 17-hydoxyprogesterone levels (P < 0.02 and P < 0.0006, respectively). We conclude that 8-Cl-cAMP is well tolerated without attendant myelotoxicity, and in this study, it was associated with biological effects. In Phase II studies, a dose of 0.11 mg/kg/h for 3 days per week would be appropriate.     

Neuroanatomical correlates of neurological soft signs in antipsychotic-naive schizophrenia

Recent imaging studies suggest that the so-called “soft” neurological signs in schizophrenia might have neuroanatomical validity. We examined gray matter volume correlates of neurological soft signs (NSS) in antipsychotic-naive schizophrenia patients using an automated image analysis technique. NSS were assessed using a modified neurological evaluation scale with good inter-rater reliability. Magnetic resonance images of 30 schizophrenia patients and 27 age-, sex-, education- and handedness-matched healthy controls were processed using optimized voxel-based morphometry (VBM). Logistic regression analysis showed that only the Motor Sequencing Signs (MSS) sub-score was a significant predictor of subject's status among the NSS sub-scores. Optimized VBM analysis showed that the MSS sub-score had a significant negative correlation with total and regional gray matter volumes (prefrontal, posterior cingulate, temporal cortices, putamen, and cerebellum) in schizophrenia patients but not in controls. Prefrontal and temporal cortices, putamen and cerebellum had significant volume deficits in patients. Cortical and cerebellar correlates of the sub-score MSS support the concept of “cognitive dysmetria” in schizophrenia.     

Emblica officinalis exerts wound healing action through up-regulation of collagen and extracellular signal-regulated kinases (ERK1/2)

During wound healing, the wound site is rich in oxidants, such as hydrogen peroxide, mostly contributed by neutrophils and macrophages. Ascorbic acid and tannins of low molecular weight, namely emblicanin A (2,3-di- O -galloyl-4,6-( S )-hexahydroxydiphenoyl-2-keto-glucono-δ-lactone) and emblicanin B (2,3,4,6-bis-( S )-hexahydroxydiphenoyl-2-keto-glucono-δ-lactone) present in Emblica officinalis (emblica), have been shown to exhibit a very strong antioxidant action. We proposed that addition of these antioxidants to the wound microenvironment would support the repair process. The present investigation was undertaken to determine the efficacy of emblica on dermal wound healing in vivo. Full-thickness excision wounds were made on the back of the rat and topical application of emblica accelerated wound contraction and closure. Emblica increased cellular proliferation and cross-linking of collagen at the wound site, as evidenced by an increase in the activity of extracellular signal-regulated kinase 1/2, along with an increase in DNA, type III collagen, acid-soluble collagen, aldehyde content, shrinkage temperature and tensile strength. Higher levels of tissue ascorbic acid, α-tocopherol, reduced glutathione, superoxide dismutase, catalase, and glutathione peroxidase support the fact that emblica application promotes antioxidant activity at the wound site. In summary, this study provides firm evidence to support that topical application of emblica represents a feasible and productive approach to support dermal wound healing.     

DNA polymerase III gene of Bacillus subtilis.

The Bacillus subtilis dnaF (polC) gene that codes for the alpha subunit of the DNA polymerase III holoenzyme has been sequenced. It consists of 4005 base pairs coding for 1335 amino acids (from the start to the stop codon), giving a molecular weight of 151,273. A mutation (azp-12) that confers resistance to the antimicrobial drug 6-(p-hydroxyphenylazo)-uracil is due to a single base change at nucleotide 3523, from TCA to GCA, resulting in a change of the 1175th amino acid, serine, to alanine. It is in the active site and located at the C-terminal part of the enzyme. The amino acid composition in an N-terminal domain has 26% homology to the epsilon subunit coded by the dnaQ gene of Escherichia coli, which is a 3'----5' proofreading exonuclease, supporting an earlier observation that this function is an integral part of the polymerase molecule in B. subtilis.     

Radiotherapy for stage I Hodgkin's disease: 20 years experience at St Bartholomew's Hospital

One hundred and one consecutive patients with newly diagnosed stage I Hodgkin's disease (HD) received treatment at St Bartholomew's Hospital, between 1968 and 1987, with a median follow-up of 12 years. Eleven patients have been excluded from detailed analysis because they either received involved field radiotherapy (RT) or radiotherapy with chemotherapy or were lost to follow-up. Actuarial analysis predicts 78% to be alive and without relapse of Hodgkin's disease at 15 years. Ninety evaluable patients (clinical stage (CS) 24; pathological stage (PS) 66) received either mantle or inverted 'Y' RT and form the basis of this analysis. The median age was 33 years (63 men, 27 women). Histology at presentation was nodular sclerosing (39), lymphocytic predominant (27) or mixed cellularity (24). The presenting site was neck (78), axilla (6) groin (4) and mediastinum (2). Complete remission was achieved in all evaluable patients, the actuarial proportion in remission being 75% at 15 years. Factors predictive of a prolonged remission were pathological staging versus clinical staging (P = 0.02) and lymph node size less than 3 cm (P = 0.04). Actuarial overall survival in these 90 patients was 75% at 15 years and none of the above factors correlated with survival. Relapse of HD has occurred in 18 patients (5 within RT field, 10 without and 3 in both). Second remission was achieved in 15/18. The actuarial rate of second remission and survival was 40% at 10 years. Sixteen patients have died, 7 of Hodgkin's disease, 7 of unrelated causes and 2 of second malignancy. A further 3 patients who developed second malignancy are still alive. At 15 years the actuarial mortality related to HD was 12%. These results confirm the importance of long follow up to assess the efficacy of primary therapy.     

EVA treatment for recurrent or unresponsive Hodgkin's disease

Summary Nineteen patients with recurrent or unresponsive Hodgkin's disease who had previously received combination chemotherapy comprising mustine or chlorambucil with vinblastine, prednisolone and procarbazine (MVPP or ChlVPP), were treated with a combination of etoposide, vincristine and adriamycin (EVA). Clinical remission (complete, CR + good partial, GPR) was achieved in eleven of the nineteen patients (58%). The remission rate was similar for patients who had previously responded well to chemotherapy and for those who had previously been poorly responsive. Six patients have relapsed between 3 and 5 months after completion of therapy. The remainder continue in remission, two without further therapy at 7 and 8 months, respectively, and three having had additional radiotherapy while in remission. Myelosuppression was the most important toxicity, but in general this was manageable. These results suggest that EVA may be non-cross-resistant with MVPP and ChlVPP and that it is of potential value in combination chemotherapy for previously untreated patients, even though it is unlikely to be curative when treatment with either MVPP or ChlVPP has failed.     

Endoscopic sinus surgery for orbital subperiosteal abscess secondary to sinusitis.

Subperiosteal orbital abscess (SPA) is a serious complication of paranasal sinusitis, which can lead to blindness or even death. A quick response is necessary as this condition is treatable. Early surgical intervention is indicated if there is risk of visual loss, or if no improvement is observed within 48 hours of starting medical therapy. Three patients with orbital SPA secondary to sinusitis treated successfully by Functional Endoscopic Sinus Surgery (FESS) are presented in this case series. The surgical indications were impending visual loss with an abscess and cellulitis impinging on the optic nerve in one child and in the other two patients, a lack of clinical response within 48 hours after starting systemic antibiotic. CT scans, nasal endoscopy, and ophthalmologic examinations are mandatory during the evaluation process. The advantages of FESS in these patients were the avoidance of external ethmoidectomy and its external facial scar, an early drainage of the affected sinuses, SPA, and the eradication of the disease from the fronto-ethmoidal region leading to an enhanced recovery and a reduced hospital stay. FESS is also a safe, convenient and minimally invasive procedure in patients presenting with serious complications of sinusitis.     

Noonan's syndrome with mental retardation presenting with an affective disorder--case report

A 30 year old Chinese lady initially thought to have Turner's Syndrome was rediagnosed as Noonan's Syndrome following admission to a psychiatric hospital for treatment of an Affective Disorder (Hypomania). The genetics and morphological features in Noonan's Syndrome are briefly discussed and the patient's psychiatric presentation is described.