Virtual fracture clinic delivers British Orthopaedic Association compliance.

INTRODUCTION The British Orthopaedic Association recommends that patients referred to fracture clinic are thereafter reviewed within 72 hours. With the aim of improving care by seeking to meet this target, waiting times for fracture clinic appointments in a district general hospital were audited prospectively against this national guideline, with the intervening implementation of a virtual fracture clinic. MATERIALS AND METHODS The study was conducted as a prospective closed-loop audit in which the second cycle took place several months after a change in the clinical pathway for all referrals from the emergency department to fracture clinic. Data were gathered in real-time via a pro forma during fracture clinic consultations. RESULTS The first cycle demonstrated a non-compliant mean waiting time of 10.7 days, with 6% of patients being seen within the 72-hour target. Following the implementation of the virtual fracture clinic, the second cycle found that all patients were reviewed within the 72-hour target (mean 1.3 days). DISCUSSION The improvement in performance was delivered with no increase in clinic capacity. The cost of implementation was negligible. CONCLUSION A simple virtual fracture clinic model delivered a significant reduction in waiting times and achieved compliance with the British Orthopaedic Association guideline. Similar results could be achieved in subsequent deployment elsewhere in the NHS.

Disruption of MBD5 contributes to a spectrum of psychopathology and neurodevelopmental abnormalities.

Microdeletions of chromosomal region 2q23.1 that disrupt MBD5 (methyl-CpG-binding domain protein 5) contribute to a spectrum of neurodevelopmental phenotypes; however, the impact of this locus on human psychopathology has not been fully explored. To characterize the structural variation landscape of MBD5 disruptions and the associated human psychopathology, 22 individuals with genomic disruption of MBD5 (translocation, point mutation and deletion) were identified through whole-genome sequencing or cytogenomic microarray at 11 molecular diagnostic centers. The genomic impact ranged from a single base pair to 5.4 Mb. Parents were available for 11 cases, all of which confirmed that the rearrangement arose de novo. Phenotypes were largely indistinguishable between patients with full-segment 2q23.1 deletions and those with intragenic MBD5 rearrangements, including alterations confined entirely to the 5'-untranslated region, confirming the critical impact of non-coding sequence at this locus. We identified heterogeneous, multisystem pathogenic effects of MBD5 disruption and characterized the associated spectrum of psychopathology, including the novel finding of anxiety and bipolar disorder in multiple patients. Importantly, one of the unique features of the oldest known patient was behavioral regression. Analyses also revealed phenotypes that distinguish MBD5 disruptions from seven well-established syndromes with significant diagnostic overlap. This study demonstrates that haploinsufficiency of MBD5 causes diverse phenotypes, yields insight into the spectrum of resulting neurodevelopmental and behavioral psychopathology and provides clinical context for interpretation of MBD5 structural variations. Empirical evidence also indicates that disruption of non-coding MBD5 regulatory regions is sufficient for clinical manifestation, highlighting the limitations of exon-focused assessments. These results suggest an ongoing perturbation of neurological function throughout the lifespan, including risks for neurobehavioral regression.

Dental abnormalities in Schimke immuno-osseous dysplasia.

Described for the first time in 1971, Schimke immuno-osseous dysplasia (SIOD) is an autosomal-recessive multisystem disorder that is caused by bi-allelic mutations of SMARCAL1, which encodes a DNA annealing helicase. To define better the dental anomalies of SIOD, we reviewed the records from SIOD patients with identified bi-allelic SMARCAL1 mutations, and we found that 66.0% had microdontia, hypodontia, or malformed deciduous and permanent molars. Immunohistochemical analyses showed expression of SMARCAL1 in all developing teeth, raising the possibility that the malformations are cell-autonomous consequences of SMARCAL1 deficiency. We also found that stimulation of cultured skin fibroblasts from SIOD patients with the tooth morphogens WNT3A, BMP4, and TGFß1 identified altered transcriptional responses, raising the hypothesis that the dental malformations arise in part from altered responses to developmental morphogens. To the best of our knowledge, this is the first systematic study of the dental anomalies associated with SIOD.

Sclerostin levels during growth in children.

UNLABELLED: Serum sclerostin levels are associated with cortical porosity, suggesting that changes in sclerostin production during growth may play a role in defining cortical structure. INTRODUCTION: Sclerostin, produced by osteocytes, is a potent inhibitor of Wnt signaling and bone formation. While sclerostin levels increase with age in adults and are higher in men compared to women, there is currently no information on changes in circulating sclerostin levels during growth in humans. METHODS: We measured serum sclerostin levels in 6- to 21-year-old girls (n = 62) and boys (n = 56) and related these to trabecular and cortical bone microarchitectural parameters using high-resolution peripheral quantitative computed tomography and to markers of bone turnover. RESULTS: Serum sclerostin levels were higher in boys as compared to girls and declined in both sexes following the onset of puberty. There was no consistent relationship between sclerostin levels and trabecular bone parameters in either sex. However, serum sclerostin levels were inversely associated with cortical volumetric bone mineral density and cortical thickness in girls and positively associated with the cortical porosity index in both girls and boys. Bone turnover markers were positively correlated with serum sclerostin levels in both sexes. CONCLUSION: The gender difference in serum sclerostin levels appears to be established during puberty, and sclerostin levels tend to decline in late puberty in both girls and boys. Serum sclerostin levels are associated with cortical porosity, suggesting that changes in sclerostin production during growth may play a role in defining cortical structure.

Increase in tumor GADD153 mRNA level following treatment correlates with response to paclitaxel.

PURPOSE: We investigated the relationship between the basal and treatment-induced change in the tumor expression of the drug resistance gene MDR1 and the cellular injury response gene GADD153, and clinical response to paclitaxel treatment. METHODS: MDR1 and GADD153 mRNA levels were measured by reverse transcriptase polymerase chain reaction (RT-PCR) in tumor samples obtained by fine needle aspiration biopsy from 14 patients before and 24 h after paclitaxel infusion. RESULTS: There was no difference between responders and non-responders with respect to either the basal MDR1 mRNA level or the change in MDR1 mRNA level at 24 h after treatment (P = 0.464). Likewise, there was no difference in basal GADD153 mRNA level between responders and non-responders. However, there was a significantly greater increase in GADD153 mRNA at 24 h in responders compared with non-responders (P = 0.005). An increase in GADD153 mRNA level of 1.5-fold or higher predicted response with a sensitivity of 86% and a specificity of 100%. CONCLUSIONS: An increase in GADD153 mRNA level reflects chemotherapy-induced damage sufficient to be manifest as a clinically detectable reduction in tumor volume. Measurement of the change in GADD153 mRNA level successfully identified patients destined to respond as early as 24 h post-treatment.

A phase II/pharmacokinetic trial of high-dose progesterone in combination with paclitaxel.

PURPOSE: The purpose of this study was to investigate the effect of high-dose progesterone, an inhibitor of P glycoprotein, on the pharmacokinetics and toxicity of paclitaxel. PATIENTS AND METHODS: A total of 29 patients with various tumors were treated with single-agent paclitaxel (125 mg/m2 administered over 3 h once every 3 weeks) until progression of disease, at which point high-dose progesterone (3 g administered i.v. over 24 h) was added to the paclitaxel treatment program in 20 patients (13 women, 7 men). Pharmacokinetic studies of paclitaxel administered alone and with progesterone were performed in eight patients. RESULTS: The pharmacokinetic parameters of paclitaxel were highly variable. High-dose progesterone increased the peak plasma levels (3.00 +/- 0.94 vs. 4.15 +/- 1.63 microM; P = 0.029; mean +/- SD) and the area under the curve (AUC; 14.3 +/- 4.75 vs. 17.3 +/- 5.59 microM x h; P = 0.006) of paclitaxel. The absolute neutrophil and platelet nadir counts did not differ significantly between the paclitaxel and the combined treatment cycles. Three of the 20 patients documented to have progressive disease on paclitaxel alone had partial responses when high-dose progesterone was added to the paclitaxel regimen. CONCLUSION: Progesterone had a statistically significant impact on the pharmacokinetics of paclitaxel. The addition of high-dose progesterone to paclitaxel is feasible, but the small number of patients prevents conclusions being drawn about the clinical efficacy of combined progesterone and paclitaxel.

Quantitation of the change in GADD153 messenger RNA level as a molecular marker of tumor response in head and neck cancer.

Cells injured by exposure to cisplatin (cDDP) undergo a cellular injury response that shares characteristics with responses produced by many other injurious agents. We sought to determine whether the increase of the message of the "growth arrest and DNA damage-inducible" gene, GADD153, could be used to assess the extent of the cellular injury response in model systems and in patients with head and neck cancer after treatment with cDDP. The mRNA levels of GADD153, a gene highly transcriptionally activated by cDDP damage, were increased in a transient, concentration-dependent manner by cDDP when human UMSCC10b head and neck carcinoma cells were treated with cDDP both in vitro and when grown as tumor xenografts in nude mice. There was a good correlation between the change in level of GADD153 mRNA and UMSCC10b cell kill by cDDP in vitro (r = 0.98). The magnitude of the increase was proportionally reduced in UMSCC10b sublines that were 3- or 6-fold resistant to cDDP. GADD153 mRNA levels were measured in biopsies obtained before and 24 h after treatment with cDDP from 32 patients with stage III/IV head and neck cancer. There was a relationship between the increase in GADD153 mRNA levels and the response rate. Seven of the 32 patients had no response and no increase in GADD153 mRNA level. Among the eight patients who attained a partial response, the increase in GADD153 message ranged from 0.7-2.5-fold. In contrast, 17 of 32 patients had a complete response, and this was accompanied by a 2-9-fold induction of GADD153. The mean increase in the complete responders (3.8+/-2.2-fold) differed significantly from that for the partial responders (1.6+/-0.9) and nonresponders (0.8+/-0.5; P <0.05); the difference between the partial responders and nonresponders was also significant (P <0.05). An increase of GADD153 mRNA of 1.75-fold or higher predicted a complete response, with a sensitivity of 94% and a specificity of 87%. We conclude that the magnitude of the increase in GADD153 mRNA is a promising candidate for service as an intermediate marker of head and neck tumor response to cDDP. The fact that the change in GADD153 mRNA reflects the actual extent of injury sustained by the tumor makes it particularly attractive as a potential marker. One strength of this approach is that it can provide a measure of the effectiveness of therapy as early as 24-48 h after the first dose of treatment.

Phase I trial of retinoic acid and cis-platinum for advanced squamous cell cancer of the head and neck based on experimental evidence of drug synergism.

OBJECTIVE: Cis-platinum and 13-cis-retinoic acid have received much attention in the treatment of head and neck squamous cell cancer. Even though they have different mechanisms of action, little information is available on their interaction. This paper reviews experimental evidence for retinoic acid-cis-platinum synergy and presents toxicity data from patients with stage IV head and neck squamous cell cancer participating in a phase I trial combining 13-cis-retinoic acid and cis-platinum. METHODS: Patients were given 13-cis-retinoic acid orally daily for 7 days before and daily during high-dose (150 mg/m2 per week for 4 weeks) intraarterial cis-platinum treatment with concurrent radiation. Toxicity was scored with use of the cancer and leukemia group B scale. RESULTS: In the phase I clinical trial, 15 patients were treated to determine a maximum tolerated dosage for 13-cis-retinoic acid of 20 mg/day. Grade 4 hematologic toxicity was dose limiting in 3 of 8 patients treated with 40 mg/day and in 1 patient treated with 60 mg/day. There were no deaths caused by toxicity; 12 of the 15 patients received all four weekly doses and the remaining 3 received three doses. Of 10 patients with fully evaluable data, all achieved a complete response at the primary site and 9 had a complete response in the neck. One patient had persistent neck disease after chemoradiation, and this tumor was removed with neck dissection. CONCLUSIONS: 13-Cis-retinoic acid and cis-platinum are strongly synergistic against head and neck squamous cell cancer in vitro. Pretreatment with retinoic acid results in stronger synergy than concurrent drug exposure alone. Preliminary clinical experience with combined retinoic acid and cis-platinum in a design that parallels the in vitro study indicates that toxicity is acceptable with 13-cis-retinoic acid dosages of 20 mg/day in a high-dose-intensity intraarterial chemoradiation regimen.

A phase II trial of intraperitoneal high-dose carboplatin and etoposide with granulocyte macrophage-colony stimulating factor support in patients with ovarian carcinoma.

Based upon results obtained in a Phase I study, we conducted a Phase II trial of high-dose CBDCA and etoposide administered via the intraperitoneal (IP) route in patients with ovarian cancer. CBDCA at a dose of 600 mg/m2 and etoposide at a dose of 400 mg/m2 were administered rapidly into the peritoneal cavity. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one-third of the total dose. On day 1 of therapy, one-third of the dose was mixed in 2 liters of D5W and administered intraperitoneally as rapidly as possible. On days 2 and 3, one-third of the dose was mixed in 1 liter of D5W and administered similarly. GM-CSF was begun on day 4 as a subcutaneous injection at a dose of 500 micrograms/m2/day. A total 53 courses of treatment was administered to 18 patients; 9 of 13 patients (69%) with evaluable disease demonstrated evidence consistent with a partial response; however, the majority were response determined by a decrease in tumor marker (CA-125). One patient who had pathologic evidence of disease at second look laparotomy, but no measurable disease, was treated and shown at subsequent reexploration to have no further evidence of disease. This patient remains free of disease at 17+ months. The toxicity encountered in this trial was formidable, resulting in the removal of 78% of the patients from the study prior to completing 6 cycles of therapy.

Phase I trial of cisplatin in combination with glutathione.

We treated 16 patients in a phase I trial of escalating doses of intravenous cisplatin in combination with the chemoprotectant glutathione given every 21 days. Forty-three of 44 cycles (98%) were evaluable, 85% of cycles were given on time, and the median number of cycles per patient was 2. Dose-limiting nephrotoxicity was reached at a dose of 175 mg/M2 of cisplatin. Other toxicities included ototoxicity in 7 patients (44%) and grade 3 to 4 nausea and vomiting in 15 evaluable cycles (34.9%). Myelosuppression was infrequent. An increase to 175% of standard cisplatin dose intensity is attainable with the administration of glutathione; however, toxicity is substantial and the number of tolerated cycles is limited. Alternatives to the single bolus dose schedule studied in the present trial should be explored in order to better define the clinical utility of glutathione in combination with high-dose cisplatin.

A comparison of intravenous versus intraperitoneal chemotherapy for the initial treatment of ovarian cancer.

A phase III study was conducted comparing intraperitoneal (ip) versus intravenous (iv) cisplatin-based therapy for patients with newly diagnosed ovarian cancer to determine if the pharmacologic advantage of ip delivery could be translated into an improved response and survival rate. Twenty-nine patients were randomized to receive six cycles of ip cisplatin 200 mg/m2 plus ip etoposide 350 mg/m2 with iv thiosulfate protection given every 4 weeks; thirty-three patients were randomized to receive six cycles of iv cisplatin 100 mg/m2 plus iv cyclophosphamide 600 mg/m2 administered every 3 weeks. Patients were stratified by stage (IIC-IV) and size of residual disease (> or < or = 1 cm). The study was conducted in a community-wide setting. The complete response in evaluable patients was 48% in the ip group and 52% in the iv group. The surgical complete response rate for all patients on study, underestimated because not all patients in complete clinical remission had a second-look laparotomy, was 31% in the ip group and 33% in the iv group. There was no difference in the response rates between the treatment arms as a function of residual disease < or = or > 1 cm. With a median follow-up of 46 months (range 21-70 months) there is no difference in response duration or survival. Both regimens were well tolerated with comparable hematologic and nonhematologic toxicity.

A phase I trial of intraperitoneal carboplatin and etoposide with granulocyte macrophage colony stimulating factor support in patients with intraabdominal malignancies.

BACKGROUND: Although somewhat controversial, there are data to suggest that patients with ovarian cancer may experience a survival advantage if the dose intensity of platinum-containing regimens can be maximized. Administration of chemotherapeutic agents via the intraperitoneal route offers the opportunity to increase dose intensity of several chemotherapeutic agents. METHODS: The authors conducted a Phase I trial of intraperitoneal carboplatin and etoposide in combination with granulocyte macrophage colony stimulating factor (GM-CSF) in an attempt to determine the maximum tolerated dose of carboplatin. The starting dose for carboplatin was 300 mg/m2 and for etoposide 400 mg/m2. The dose of carboplatin was escalated while the etoposide was maintained at the initial dose. The total dose of each agent was calculated and given daily over 3 days in amounts equal to one-third of the total dose. On day 1 of therapy, one-third of the dose was mixed in 2 liters of dextrose (D5W) and administered intraperitoneally (IP) as rapidly as possible. On Days 2 and 3, one-third of the dose was mixed in 1 liter of D5W and administered similarly. GM-CSF was begun on Day 4 as a subcutaneous injection at a dose of 500 micrograms/m2/d. RESULTS: Unacceptable hematologic toxicity was encountered at a carboplatin dose of 800 mg/m2; therefore, a carboplatin dose of 600 mg/m2 is recommended for Phase II studies. An overall response rate of 54% with a complete response rate of 17% was observed in patients with ovarian cancer. The overall response rate for all patients was 45%. CONCLUSION: Because of the significant toxicity encountered in this study, it is recommended that this regimen be used only in the context of a clinical study. The recommended Phase II study dose for this combination is carboplatin 600 mg/M2 and a total dose of etoposide 400 mg/M2 total dose given as three equal parts IP over 3 days. GM-CSF should begin on Day 4 at a dose of 500 micrograms/m2/day subcutaneously and should continue until the absolute neutrophil count is greater than 1000 granulocytes on 3 successive days.

Phase I/pharmacokinetic study of high-dose progesterone and doxorubicin.

PURPOSE: We developed a new formulation of progesterone that permits administration of up to 10 g of progesterone as a continuous intravenous infusion over 24 hours and conducted a phase I clinical trial to determine whether progesterone could modulate the in vivo cytotoxicity of the P-glycoprotein substrate doxorubicin. PATIENTS AND METHODS: Thirty-four patients with advanced malignancies were treated with increasing doses of progesterone and a fixed dose of 60 mg/m2 of doxorubicin given as an intravenous bolus 2 hours after starting a 24-hour intravenous infusion of progesterone. RESULTS: Progesterone enhanced doxorubicin-induced myelotoxicity in a dose-dependent fashion without altering the pharmacokinetics of doxorubicin. The steady-state plasma concentration of progesterone at a dose level of 4 g was 4.1 +/- 0.9 mumol/L, which was higher than the minimal concentration required to reverse multidrug resistance (MDR) in vitro. CONCLUSION: Progesterone enhanced the hematologic toxicity of doxorubicin without altering its pharmacokinetics, suggesting that progesterone could modulate P-glycoprotein at the level of pluripotent hematopoietic stem cells. Adequate tissue concentrations of progesterone could be achieved in vivo to modulate doxorubicin toxicity in the bone marrow and thus potentially in tumor tissue as well. Selectivity may potentially be gained by using hematopoietic growth factors to offset the enhanced hematologic toxicity of doxorubicin while leaving the enhancement of toxicity to tumor cells unchanged.

A phase I and pharmacokinetic study of intraperitoneal carboplatin and etoposide.

BACKGROUND: We attempted to determine the maximum tolerated dose and toxicity of etoposide (VP-16) when administered in combination with carboplatin (CBDCA) (300 mg m-2) and administered via the intraperitoneal (IP) route. METHODS AND MATERIALS: A total of 26 patients were treated on this trial. CBDCA was administered at a fixed dose of 300 mg m-2) while VP-16 was started at a dose of 200 mg m-2 and escalated at 50 mg m-2 increments. Both agents were mixed together in 2 litres of 5% Dextrose and administered as quickly as possible into the peritoneal cavity. Pharmacokinetic studies were performed at the maximum tolerated dose (MTD). RESULTS: The MTD for this regimen was CBDCA 300 mg m-2 and VP-16 350 mg m-2. Patients > or = 70 years of age or who had received more than six cycles of previous chemotherapy, tolerated this regimen poorly. The MTD for this group of patients was CBDCA 200 mg m-2 and VP-16 50 mg m-2. Neutropenia was the dose limiting toxicity for both groups. The mean peritoneal/plasma peak ratio was 18.3 for CBDCA and 12.7 for VP-16. The pharmacologic advantage (peritoneal/plasma AUC ratio) was 14.9 for CBDCA and 8.8 for VP-16. Although measurable disease was not a requirement for entrance into this study a response rate of 27% was noted in 15 patients with evaluable disease who had ovarian cancer. CONCLUSIONS: A pharmacologic advantage exists for both CBDCA and VP-16 when administered together via the IP route.

Phase I and pharmacokinetic study of intraperitoneal ormaplatin.

Ormaplatin is a cisplatin analog which has demonstrated activity against cisplatin-resistant tumors in preclinical studies. We delivered 28 cycles to 14 patients in a phase I trial of intraperitoneal ormaplatin given every 28 days. The maximum tolerated dose was 88.4 mg/m2 and acute dose-limiting toxicity was abdominal pain. Other toxicities include nausea, emisis, fever, and severe neuropathy seen in 1 patient at a cumulative dose of 399 mg/m2. No objective responses were observed. Hematologic toxicity was mild. The dose recommended for future trials of intraperitoneal ormaplatin is 66.5 mg/m2. Pharmacokinetic analysis performed at a dose of 66.5 mg/m2 demonstrated that the initial phase of elimination from the peritoneal cavity follows first-order kinetics with k = 0.69 hr-1 and half-life of 1.4 hr. Plasma pharmacokinetic behavior is best described by biexponential model with k1 = 0.369 hr-1, k2 = 0.107 hr-1, and first half-life of 2.9 hr and second half-life of 8.4 hr. Pharmacologic advantage, calculated by ratio of peritoneal to plasma AUC, is 17.1. If site-specific activity is demonstrated, then the intraperitoneal route of administration of ormaplatin at 66.5 mg/m2 may be beneficial.

High-dose biweekly intraperitoneal cisplatin: an effective way to increase cisplatin dose intensity.

The amount of cisplatin (DDP) delivered per unit time (dose intensity, expressed in mg/m2/week) may be an important factor in determining the clinical outcome in tumors such as ovarian carcinoma. In this neoplasm, intraperitoneal chemotherapy is an effective form of treatment. In this trial we have explored the tactic of shortening the cycle interval as a way to increase the dose intensity of ip DDP. Sixteen patients with a variety of solid tumors received a total of 77 cycles of DDP 180 mg/m2 instilled ip concurrent with i.v. sodium thiosulfate at the dose of 4 g/m2 as loading dose, followed by 12 g/m2 over 6 hr. Each cycle was repeated every 2 weeks. The number of cycles delayed for 3 or more days was 28 (36%). The mean DDP dose intensity received by these patients was 77% of the planned dose or 69 mg/m2/week (confidence interval 95%, 60.5-77.5). The treatment was generally well tolerated: myelotoxicity was mild, only 1 patient had an increase in serum creatinine to > 2 mg/dl. Five patients (31%) developed symptoms of peripheral neuropathy. All patients were evaluable for response. The overall response rate (complete plus partial) in these heavily pretreated patients was 19%. When DDP is given in high doses by the ip route concurrently with systemic sodium thiosulfate, the dosing interval can be reduced to every 2 weeks permitting a marked increase in DDP dose intensity.

Profiles of women age 30-39 and age less than 30 with epithelial ovarian cancer.

OBJECTIVE: To study a group of women diagnosed with epithelial ovarian cancer at a young age (less than 40). METHODS: Tumor registry data were analyzed with respect to age at diagnosis, stage, grade, frequency of nulligravidity, and family history of breast or ovarian cancer. Frequencies were analyzed using contingency tables, and survival distributions were analyzed according to the method of Kaplan and Meier. Multivariate survival analysis was performed with the Cox method. RESULTS: We found significantly higher frequencies of low-grade tumors (90 versus 37%; P = .0003, chi 2 test) and early-stage tumors (45 versus 17%; P = .03, Fisher exact test) in women less than 30 at the time of diagnosis (very young patients) than in those between 30-39. We also found a significant (P = .017, Breslow statistic) survival advantage for the very young women. Multivariate analysis demonstrated tumor grade as the independent variable for survival. CONCLUSION: These findings support the concept of a preclinical phase of epithelial carcinoma and show that young women may derive substantial benefit from ovarian cancer screening programs.

Nerve conduction studies and its importance in diagnosis of acute poliomyelitis.

Motor nerve conduction velocities was performed on 50 subjects in the pediatric age group. Thirty two patients with acute poliomyelitis and 18 controls. The MNCV was studied in the median nerve in the upper limb and the posterior tibial in the lower limb. The motor nerve conduction velocity in polio patients matched well with the controls, as well as within the accepted standards for normal. The MNCV of the median nerve ranged from 41.8 +/- 2.76 m/sec in under 1 year to 44 +/- 2.1 m/sec in 3-8 years, in polio patients, while the range in controls varied from 37 to 53 m/sec. Similarly, for the posterior tibial nerve, in polio patients the value of MNCV varied from 38.7 +/- 4.9 m/sec to 42.5 +/- 3.1 m/sec. In the controls, also the MNCV ranged from 38.5 +/- 6.3 m/sec to 48.4 +/- 3.42 m/sec. Thus, no delay on the motor nerve conduction velocity was seen. Poliomyelitis is a major problem in developing countries like Pakistan and India, where serological diagnosis is a luxury. The determination of motor nerve conduction velocity provides a quick and easy method of distinguishing poliomyelitis from other motor nerve disorders esp. Guillain Barre syndrome.

Dose intensification of cisplatin chemotherapy through biweekly administration.

PURPOSE: Dose intensity (DI, expressed in mg/m2/wk) may be an important factor in the clinical use of cisplatin (DDP). We have explored the shortening of the cycle interval as a way to increase the DI of DDP. PATIENTS AND METHODS: DDP 180 mg/m2 was given intravenously (i.v.) over 4 hours; sodium thiosulfate (STS) was given i.v. in the opposite arm at a loading dose of 4 g/m2, followed by 12 g/m2 over 6 hours. Each cycle was repeated every two weeks. Seventy-five cycles were administered to 28 patients in this clinical trial. RESULTS: In 19 patients who received 2 or more cycles of chemotherapy, a delay of three or more days was required on 17/66 courses (26%); the mean DDP DI actually received by these patients was 83 mg/m2/wk (88% of the planned DI). The major side effect was ototoxicity; this occurred in 9 patients (33%), but none required a hearing aid. Myelosuppression was moderate with thrombocytopenia greater than neutropenia. Nephrotoxicity (creatinine > 2 mg/dl) occurred on only 2 cycles (3%). Three patients (11%) developed symptoms of peripheral neuropathy. In 23 evaluable patients, the overall response rate was 39%. CONCLUSION: It is feasible to give 180 mg/m2 of DDP and STS every two weeks with tolerable nephrotoxicity but without blocking other types of toxicity, such as myelosuppression and ototoxicity. The shortening of cycle intervals resulted in a markedly increased DI.