Cisplatin plus capecitabine as first-line chemotherapy for recurrent or metastatic head and neck squamous cell cancer: experience outside of a trial setting.

PURPOSE: Cisplatin/5-fluorouracil (5-FU) is an accepted palliative chemotherapy treatment for head and neck squamous cell carcinoma, improving quality of life but not overall survival. Capecitabine in place of 5-FU removes the morbidity of an infusional regime with potential benefit in patient well-being. This study looks at outcomes for cisplatin plus capecitabine (PX) outside of a trial setting. METHODS: Consecutive patients receiving this treatment in a single centre were retrospectively analysed. Cisplatin (mean dose 75 mg/m²) was given on day 1 of a 3-week cycle and capecitabine (mean dose 808 mg/m² twice daily) on days 1-14, for up to 6 cycles. RESULTS: Sixty-five patients (median age 58.6 years) received a median of 4 cycles of chemotherapy. The overall response rate was 30.7%, with a median overall survival of 7.3 months. Treatment was well tolerated with a 10.7% grade 3 and a 1.5% grade 4 neutropenia rate, with no other grade 4 toxicities. One patient died of neutropenic sepsis whilst on treatment. Twenty-seven percent of patients stopped treatment early due to chemotherapy-related side effects. CONCLUSION: PX is well tolerated outside the trial setting with outcomes similar to historical published literature. Ease of administration and benefit to patient convenience make it an attractive alternative to standard palliative treatment.

Pharmacokinetics of [14C]methylglyoxal-bis-guanylhydrazone) in patients with leukemia.

Methylglyoxal-bis(guanylhydrazone) (MGBG; NSC 32946), a competitive inhibitor of S-adenosyl-L-methionine decarboxylase (EC 4.1.1.50), currently being reevaluated for its clinical antileukemic activity. MGBG labeled with 14C in the guanylhydrazone moiety was administered i.v. (150 microCi; specific activity, 1.9 microCi/mumol; 20 mg total) to six patients with leukemia. All patients in the study had normal renal and hepatic function. [14C]MGBG underwent no in vivo metabolism; it disappeared from the plasma with an average terminal t 1/2 of 4.1 hr. The 72-hr cumulative urinary excretion was only 14.5 +/- 2.2% (S.E.M.) of the total radioactive dose. The apparent volume of distribution was 661 ml/kg and the total clearance rate was 21.2 ml/kg/min. The low urinary excretion rate and the relatively rapid plasma clearance suggest that MGBG may be sequestered in the body. Therefore, if MGBG is administered by a frequent treatment schedule, the prolonged biological half-life in humans may significantly contribute to its clinical toxicity.

Penetration of methylglyoxal bis(guanylhydrazone) into intracerebral tumors in humans.

Methylglyoxal bis(guanylhydrazone) (MGBG; NSC 32946) is currently being reevaluated for its clinical antineoplastic activity against both hematological and solid tumors. MGBG (100 to 200 mg/sq m) was administered by slow infusion over 3 hr to six patients during surgical resection of intracerebral tumors. Excised tumor tissue and plasma were assayed for MGBG by high-pressure liquid chromatography. In all cases, MGBG penetrated rapidly into brain tumor tissue. Viable tumor tissue contained greater concentrations of MBGB than did necrotic tumor tissue. In two patients with glioblastoma multiforme, MBGB concentrations in brain tumor tissue were five- to 19-fold higher than concurrent plasma samples. However, MGBG did not penetrate well into the cerebrospinal fluid of two patients with Ommaya reservoirs given i.v. MGBG (200 mg/sq m). The highest MGBG concentration in cerebrospinal fluid reached only 22% of the concurrent plasma levels. These studies suggest that MGBG may be a useful agent in the treatment of intracerebral tumors but may not be effective against meningeal leukemia and meningeal carcinomatosis.

Phase I study of tricyclic nucleoside phosphate using a five-day continuous infusion schedule.

A Phase I trial of tricyclic nucleoside phosphate (1,4,5,6,8-pentaazaacenaphthylene-3-amino-1, 5-dihydro-5-methyl-1-beta-D-ribofuranosyl 5'-phosphate ester; NSC 280594) was conducted using a 5-day continuous infusion schedule. Thirty-seven patients with advanced cancer were entered on the study, of whom 33 patients were evaluable for response and toxicity. Dose levels ranged from 10 mg/sq m/day X 5 days to 40 mg/sq m/day X 5 days. Initially, courses were repeated every 3 to 4 weeks. As cumulative toxicity became manifested, the interval between courses was changed to every 6 weeks. Major toxicities included hyperglycemia, hepatotoxicity, and thrombocytopenia. Patients with a prior history of diabetes mellitus, extensive radiation therapy, or significant liver metastases were prone to severe toxicity. Other toxicities noted were nausea and vomiting, abdominal discomfort, anemia, and reduction in serum calcium, phosphorus, and albumin levels. Rare side effects included hypertriglyceridemia, hyperamylasemia, diarrhea, and stomatitis. Antitumor activity observed include improvement in s.c. metastases in a patient with papillary thyroid carcinoma, stabilization of disease in a patient with mesothelioma, and mixed responses in three patients (colon cancer, sarcoma, and tonsillar squamous cell cancer). Recommended schedule for Phase II studies is 20 mg/sq m/day for 5 days every 6 weeks.

Bisantrene, an active new drug in the treatment of metastatic breast cancer.

Forty-four patients with metastatic breast cancer who had previously received extensive conventional systemic therapy, including combination chemotherapy with doxorubicin, were treated with Bisantrene, a new anthracene derivative. The dose schedule was 250 to 300 mg/sq m body surface administered as a 1- to 2-hr i.v. infusion. Of 40 evaluable patients, there were nine partial responses, and 18 patients had stable disease. Responses were seen in all major sites of organ involvement with a median time to progression of 28 weeks. Moreover, responses were seen among patients who had either failed to respond or had demonstrated refractoriness to prior therapy with doxorubicin, suggesting an apparent lack of cross-resistance between doxorubicin and Bisantrene. Except for myelosuppression and one incidence of acute anaphylactoid reaction, Bisantrene was generally well tolerated by most patients. We believe that Bisantrene may ultimately have a major role in the effective treatment of metastatic breast cancer, and further clinical trials are warranted.

Exploring the molecular basis for mechanosensation, signal transduction, and cytoskeletal remodeling.

Living cells respond to mechanical stimulation in a variety of ways that affect nearly every aspect of their function. Such responses can range from changes in cell morphology to activation of signaling cascades and changes in cell phenotype. Although the biochemical signaling pathways activated by mechanical stimulus have been extensively studied, little is known of the basic mechanisms by which mechanical force is transduced into a biochemical signal, or how the cell changes its behavior or properties in response to external or internal stresses. One hypothesis is that forces transmitted via individual proteins either at the site of cell adhesion to its surroundings or within the stress-bearing members of the cytoskeleton cause conformational changes that alter their binding affinity to other intracellular molecules. This altered equilibrium state can subsequently either initiate a biochemical signaling cascade or produce more immediate and local structural changes. To understand the phenomena related to mechanotransduction, the mechanics and chemistry of single molecules that form the signal transduction pathways must be examined. This paper presents a range of case studies that seek to explore the molecular basis of mechanical signal sensation and transduction, with particular attention to their macroscopic manifestation in the cell properties, e.g. in focal adhesion remodeling due to local application of force or changes in cytoskeletal rheology and remodeling due to cellular deformation.

Oropharyngeal candidiasis treated with a troche form of clotrimazole.

A randomized double-blind trial was conducted to assess the local effectiveness and safety of a troche form of clotrimazole in the treatment of oropharyngeal candidiasis in cancer patients. One half of the patients received one 10-mg troche and the other half received one 50-mg troche, five times a day for two weeks. Clinical cures were observed in 50 episodes, resulting in a cure rate of 96%. The median duration of oropharyngeal candidiasis after the start of therapy was three days in those treated with the 50-mg troche and four days in those who had received the 10-mg troche. Side effects were minimal, and only one patient experienced nausea and abdominal pain. Both the 10-mg and 50-mg troches appear to be efficacious and safe, but the 50-mg dose may be preferable because it is somewhat more effective without additional toxicity.

Netilmicin in the treatment of infections in patients with cancer.

Ninety-two patients with cancer with 100 infectious episodes were treated with netilmicin sulfate, a new aminoglycoside. Netilmicin was administered intravenously, either intermittently or by continuous infusion. The overall cure rate was 60%. Gram-negative bacilli were the most common causative organisms and the response rate for these infections was 32/53 (60%). The most common pathogens were Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Pneumonia, urinary tract infection, and septicemia were the most common types of infection treated and the response rates were 23/47 (49%), 19/21 (90%), and 9/17 (53%), respectively. Nephrotoxicity occurred in ten patients (6%) who had normal renal function initially. Netilmicin is an effective aminoglycoside with a spectrum of antibacterial activity similar to that of gentamicin sulfate and it appears to be less nephrotoxic.

Surgical management of medullary thyroid cancer: which guidelines should we follow?

BACKGROUND: Surgery is currently the only curative treatment for medullary thyroid cancer. Unfortunately, the surgical strategy that will offer patients at each disease stage the best chance of a biochemical cure remains unclear. The American Thyroid Association and British Thyroid Association guidelines offer different strategies. METHODS: A retrospective analysis of the surgical management of 47 patients with medullary thyroid cancer diagnosed between 1994 and 2013 was performed. Surgical management was compared with current American Thyroid Association and British Thyroid Association guidelines. Outcome was defined as the first post-operative calcitonin measurement. RESULTS: All patients with stage I-III disease achieved a post-operative biochemical cure regardless of the guidelines followed. The overall biochemical cure rate for patients with stage IVa disease was significantly reduced to 10 per cent (p < 0.01), but the biochemical cure rate for stage IVa disease patients who underwent bilateral lateral lymph node dissection was 33.3 per cent. CONCLUSION: The conservative, surveillance-driven approach recommended by the American Thyroid Association is appropriate for stage I-III disease. However, the more aggressive approach advocated by the British Thyroid Association might provide stage IVa disease patients a greater chance of achieving a biochemical cure.

Variations in single/two stage thyroidectomies for cancer may be due to differences in thyroid fine needle cytology provision.

BACKGROUND & AIMS: Recommended treatment for thyroid cancers >10 mm is single stage total thyroidectomy (SST). Cancers diagnosed by diagnostic lobectomy may need completion surgery resulting in two stage thyroidectomies (TST). We noticed significant variation in numbers of SST and TST between hospitals within our cancer network and explored reasons for this using a prospective database containing all cases from 2004 to 2011 (n = 1030). We therefore conducted a survey of thyroid cytology provision across the network during 2010-2011. METHODS: A central university hospital with the largest caseload (21.5% of total) was chosen as "benchmark". Of 14 remaining hospitals 3 were excluded from analysis due to low thyroid operation numbers and the remaining compared with benchmark. We used individual chi-squared tests with Bonferroni correction to explore variation in expected and observed numbers of SST/TST. Analysis of variance (ANOVA) was used to examine reasons for observed differences. RESULTS: Significant variance in SST/TST was seen between hospitals (p < 0.00001). Three hospitals had frequencies of SST statistically similar to reference hospital; each reported 201-300 thyroid cytology cases during the survey period. The remaining 8 had lower rates of SST, the 2 lowest performing hospitals having SST rates of 11% (p = 0.0004) and 9% (p < 0.0001). These eight hospitals reported fewer than 200 cytology cases each, shared amongst 4-7 pathologists per site. Differences were unrelated to patient age, gender, tumour histology or stage (ANOVA). Only the reference hospital had specialist cytopathologists. CONCLUSION: Variation in thyroid cytology provision may increase TST rates. Thyroid cytology should be concentrated in high volume centres with specialist thyroid cytopathologists.

Melioidosis pneumonia and blast injury.

We present the case of a 24-year-old woman with acute septicemic melioidosis resulting from inhaled infective dust during a blast injury. With appropriate antibiotic treatment and supportive therapy in the ICU, the patient made an uneventful recovery.

Clinical pharmacokinetics of 9, 10-anthracenedicarboxaldehyde-bis [(4,5-dihydro-1 H-imidazol-2-yl)hydrazone]dihydrochloride.

We studied the clinical pharmacokinetics of the anthracene derivative bisantrene using high-performance liquid chromatographic analysis. We administered the drug to ten patients at 120-250 mg/m2 IV; one of these patients also received a second dose of 120 mg/m2 6 weeks later, and another received 150 mg/m2 weekly for three doses. Bisantrene disappeared from the plasma biphasically, with an initial t1/2 of 0.6 +/- 0.3 h and a terminal t1/2 of 24.7 +/- 6.9 h after single doses. The apparent volume of distribution according to the area under the curve was 42.1 +/- 5.9 l/kg, and the total clearance was 1045.5 +/- 51.0 ml/kg/h. The 96-h cumulative urinary excretion was 3.4% +/- 1.1% of dose; thus, renal excretion was a minor route of elimination for this agent. Bisantrene pharmacokinetics in the patient who received a second dose after 6 weeks showed insignificant changes. However, in the patient who was given this drug weekly for 3 weeks, the plasma t1/2 of the drug during the terminal phase became increasingly longer, while the total clearance was significantly reduced. These results suggest that bisantrene may accumulate in the body and that caution is essential in the event of frequent administration.

Clinical pharmacology of bruceantin by radioimmunoassay.

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.

AZQ therapy in patients with disseminated malignant melanoma.

Twenty-eight patients with disseminated malignant melanoma, who had failed prior therapy, were treated with aziridinylbenzoquinone (AZQ) administered on a 5-day I.V. schedule repeated every 4 weeks. The starting doses were 8 or 6 mg/m2/day x 5 days for good-and-poor-risk patients respectively. There were no complete or partial responses among 23 evaluable patients but four patients had stabilization of disease. The dose-limiting toxicity was thrombocytopenia. Other toxicities included weakness, nausea, vomiting, anorexia, dizziness, abdominal pain, and constipation. AZQ, given on a 5-day schedule, is ineffective in the treatment of patients with metastatic malignant melanoma.

A randomized study of continuous infusion vindesine versus vinblastine in adults with refractory metastatic sarcomas.

A randomized study was conducted in 33 adult patients with refractory metastatic sarcomas to compare the therapeutic efficacy of continuous vindesine versus continuous vinblastine. Of 30 evaluable patients, 15 patients received vindesine as a continuous 5-day infusion at 1.2 mg/m2 repeated every 3 weeks, and 15 patients received vinblastine at 1.5 mg/m2/day every 3 weeks. Ten patients had stable disease, while 20 patients showed progressive disease. No objective responses were observed. There was adequate myelosuppression and both drugs were well tolerated with few catheter-related problems. It does not appear that vindesine or vinblastine, given by continuous 5-day infusion, is active in the treatment of metastatic sarcomas in adults.

A phase II trial of PCNU in patients with malignant melanoma and central nervous system metastases.

Twelve patients with malignant melanoma metastatic to the central nervous system (CNS) were treated with PCNU. All patients had prior chemotherapy and/or radiation therapy and had progressive brain metastases, documented by computerized tomography. PCNU was given as a single intravenous infusion of 90-110 mg/m2 every 6-8 weeks. There was one partial response and four patients had stable disease. Although no episodes of sepsis or bleeding occurred, seven of 17 courses led to significant granulocytopenia or thrombocytopenia. Nonhematopoietic toxicities were mild. These results indicate that systemic PCNU is unlikely to be more effective than other currently used chemotherapy in patients with malignant melanoma and CNS metastases.

Phase II evaluation of PALA in patients with refractory metastatic sarcomas.

The efficacy of PALA was evaluated in 22 patients with metastatic soft tissue and bone sarcomas. The 20 evaluable patients had received a median of three prior chemotherapeutic regimens, including an adriamycin combination, to which eight had shown response. PALA was administered at 2-week intervals. Sixteen patients received 6 g/m2 over 1 hour intravenously as their initial dose, while six patients received 5 g/m2. The major side effects were skin rash, stomatitis, diarrhea, nausea, and vomiting. Significant myelosuppression was not seen. Two patients had stabilization of disease for periods of 10 and 13 weeks. At the dose and schedule used in this trial, PALA was not effective against advanced adult sarcoma.

Craniospinal radiotherapy for medulloblastoma in a man with severe kyphoscoliosis.

Medulloblastoma is an uncommon tumour in the adult population. Maximum surgical resection followed by craniospinal irradiation with a posterior fossa boost is the standard treatment. We report the case history of an adult with medulloblastoma and severe kyphoscoliosis. The unusual anatomy of the patient posed a technical challenge to the oncologist and the physicist in planning the craniospinal radiotherapy. A shaped spinal field matched to a parallel opposed pair of shaped head fields was used. The technique used in treating this patient was made possible with the use of a multileaf collimation and verification with an electronic portal imaging device. The patient remains well with no sign of relapse 4 years after treatment.

Glandular kallikrein gene expression in the human uterus.

1. Kallikrein enzyme activity has been previously reported in the uterus of several species and implicated in implantation and parturition. In order to provide further evidence for a local kallikrein-kinin system in this tissue, we wished to determine if the gene encoding kallikrein (KLK1) was expressed in the human uterus and determine the pattern of its expression across the menstrual cycle. 2. Reverse-transcriptase polymerase chain reaction (RT-PCR) of endometrial and myometrial total RNA coupled with Southern blot analysis showed that KLK1 was expressed in the human endometrium and myometrium. Endometrial expression of KLK1 was confirmed by DNA sequence analysis of the PCR products. Kallikrein was also localized by immunocytochemistry, primarily in the glandular epithelium of the endometrium. 3. Quantitative RT-PCR of 37 endometrial samples ranging from day 1 to 29 from across the menstrual cycle showed significantly higher KLK1 (kallikrein) expression from the mid proliferative to the early secretory phase compared with the late secretory and menstrual phases. 4. We have demonstrated for the first time that KLK1, the gene encoding glandular kallikrein, is expressed in the human uterus. The increase in endometrial KLK1 gene expression during the proliferative phase of the menstrual cycle suggests a role for kallikrein in the preparation of the endometrial lining for implantation.

Use of pressurised aerosol inhalers among patients attending the Chest Clinic and Primary Care Department of University Hospital, Kuala Lumpur.

Eighty consecutive patients who came to collect their prescriptions for pressurised aerosol inhalers at the Pharmacy of the University Hospital, Kuala Lumpur, were interviewed regarding their use of the pressurised inhaler. Their inhaler technique was also assessed. A significant proportion inhaled the steroid aerosol before the bronchodilator and 23.5% used the steroid inhaler for relief of acute dyspnoea. Only 28.8% of the 80 patients performed correctly all 6 steps necessary for the proper use of inhalers. The most common mistake was the failure to inhale slowly and deeply. Patients who had used the device for more than 5 years performed better, while correct inhaler technique was not dependent on the patient's sex, age or level of education.