Dental Public Health Education in Europe: a survey of European Dental Schools to determine current practice and inform a core undergraduate programme.

OBJECTIVE: Describe current Dental Public Health [DPH] curricula content and delivery across European dental schools and ascertain views on a core undergraduate curriculum for dental students. RESEARCH DESIGN: Survey of European dental schools, informed by professional and academic literature and European Association for Dental Public Health [EADPH] Special Interest Working Group discussions. Questionnaires were distributed electronically, by post, and via EADPH network members, to the Deans of 252 dental schools in Europe. E-mail reminders were sent to non-responders. SETTING: European Dental Schools. RESULTS: Around half (n=124, 49%) out of a possible 252 schools responded, all of which reported having some DPH education. Two-thirds reported having a dedicated DPH department. Education was delivered by a variety of staff including those trained in paediatric and preventive dentistry. There were differing degrees of integration within the undergraduate programme and substantial variability in topics, teaching methods and approaches to assessment. Key components of the curriculum supported by respondents were: DPH philosophy and approach, population demography and health, health promotion and disease prevention, health care systems, the dental workforce and planning for health and oral health. Respondents were generally in favour of improving current teaching and shaping a core DPH curriculum for Europe. CONCLUSIONS: Amongst those who completed the questionnaire, there was a general agreement on the need for a core Dental Public Health curriculum for European dentists. Given the variation across Europe, increased awareness and prioritisation of the subject is required, facilitated by collaborative support.

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial.

Background: Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. Patients and methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%. Clinical trial name and number: KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).

Understanding the context of male and transgender sex work using peer ethnography.

OBJECTIVES: To distinguish between three distinct groups of male and transgender sex workers in Pakistan and to demonstrate how members of these stigmatized groups need to be engaged in the research process to go beyond stated norms of behaviour. METHODS: A peer ethnography study was undertaken in a major city in Pakistan. 15 male and 15 transgender sex workers were trained as peer researchers to each interview three peers in their network. Analysis was based on interviews with peer researchers as well as observation of dynamics during training and analysis workshops. RESULTS: The research process revealed that, within the epidemiological category of biological males who sell sex, there are three sociologically different sexual identities: khusras (transgender), khotkis (feminized males) and banthas (mainstream male identity). Both khusras and khotkis are organised in strong social structures based on a shared identity. While these networks provide emotional and material support, they also come with rigid group norms based on expected "feminine" behaviours. In everyday reality, sex workers showed fluidity in both behaviour and identity according to the situational context, transgressing both wider societal and group norms. The informal observational component in peer ethnography was crucial for the accurate interpretation of interview data. Participant accounts of behaviour and relationships are shaped by the research contexts including who interviews them, at what stage of familiarity and who may overhear the conversation. CONCLUSIONS: To avoid imposing a "false clarity" on categorisation of identity and assumed behaviour, it is necessary to go beyond verbal accounts to document the fluidity of everyday reality.

HIV and other sexually transmitted infections among men, transgenders and women selling sex in two cities in Pakistan: a cross-sectional prevalence survey.

OBJECTIVES: The extent and possibilities of spread of the HIV epidemic are not fully understood in Pakistan. A survey was conducted among men, women and transgender populations selling sex in Rawalpindi (Punjab) and Abbottabad (North West Frontier Province) in order to inform evidence-based programme planning. METHODS: A cross-sectional survey was performed with participants recruited through respondent-driven sampling. Male and transgender sex workers were analysed in three gender groups; women were analysed as one group. Behavioural surveys were conducted and clinical specimens collected. Laboratory tests looked for evidence of acute infection (gonorrhoea, Chlamydia, syphilis, Trichomonas) and infection over the lifetime (HIV, herpes simplex virus-2, syphilis). Predictors of infection were explored using univariable and multivariable logistic regression. RESULTS: The prevalence of HIV was low in 917 male and transgender sex workers and absent in 533 female sex workers in the study. High levels of current sexually transmitted infections were found, predominantly among transgender sex workers. Risk behaviours were common and knowledge of HIV was extremely low. Multivariable analysis found a large number of factors associated with higher levels of infection, including experience of forced first sex. Protection against risk was low, but those sex workers who reported using condoms at last sex had lower rates of infection. CONCLUSIONS: The HIV epidemic is currently in its early stages among people who sell sex, but there may be potential for a much greater spread given the levels of other sexually transmitted infections found and the concomitant low levels of both protective knowledge and risk-reducing behaviours. Action is needed now to avert an epidemic. Framing interventions by upholding the recognition and protection of human rights is vital.

Diagnostic yield of sputum induction in patients with pleural tuberculosis at a tertiary care hospital in Karachi.

OBJECTIVE: To evaluate the diagnostic yield of acid-fast bacilli (AFB) smear, culture for Mycobacterium tuberculosis and Xpert® MTB/RIF assay in induced sputum (IS) specimens in patients with pleural tuberculosis (TB).DESIGN: A total of 156 patients were evaluated at Jinnah Postgraduate Medical Centre, Karachi, Pakistan, from April 2016 to December 2017. Patients with exudative lymphocytic pleural effusions with normal lung parenchyma on chest radiography were included in the study: 102 were due to tuberculous and 54 due to non-tuberculous infections as diagnosed using thoracoscopic pleural biopsy. IS samples were sent for acid-fast bacilli (AFB) smear, AFB culture and Xpert assay.RESULT: In patients with a clinical diagnosis of TB, mycobacteria were detected in IS AFB smear in 7.8%, AFB culture in 21.6% and Xpert assay in 34.3% of cases. All sputum samples collected from patients with non-tuberculous aetiology were negative.CONCLUSION: Testing IS samples for M. tuberculosis provides another approach to diagnosing pleural TB, especially in settings in which invasive procedures are less accessible. Our study also emphasises the contagiousness of pleural TB, and the need to screen the household contacts of these patients and possible isolation of patients with pleural TB admitted to hospital.

Prevalence of primary multidrug resistance to anti-tuberculosis drugs in Pakistan.

SETTING: Pakistan ranks sixth in the world in terms of tuberculosis (TB) burden, with a World Health Organization estimated incidence of 181 per 100000, or 286000 new cases annually. Hospital-based data indicate a significant problem of multidrug-resistant TB (MDR-TB) in the country and highlight the need to assess its extent at community level. In this cross-sectional study, sputum samples from 742 untreated newly diagnosed pulmonary TB patients from all over the country were used. OBJECTIVE: To assess the prevalence of primary drug resistance in Pakistan. RESULTS: Of 672 culture-positive patients, 76 (11.3%) showed resistance to one or more drugs. Resistance to streptomycin (10 microg/ml) was found in 36 (5.4%) patients, isoniazid (INH) (1 microg/ml) in 51 (7.6%), rifampicin (RMP) (5 microg/ml) in 15 (2.2%), ethambutol (10 microg/ml) in 12 (1.8%) and pyrazinamide in 22 (3.3%) samples. Forty-six (6.8%) of the isolates tested were resistant to a single drug, 10 (1.5%) to two drugs, 12 (1.8%) to three drugs, and 6 (0.9%) to four drugs, while 2 (0.3%) isolates were resistant to all five first-line agents. Primary MDR-TB was 1.8% (n=12) (INH 1 microg/ml, RMP 5 microg/ml). CONCLUSION: The results of this study show a prevalence of primary MDR-TB in Pakistan of <2%, which needs to be addressed through an effective DOTS strategy.

Perspectives on domestic violence: case study from Karachi, Pakistan.

There is no adequate profile of domestic violence in Pakistan although this issue is frequently highlighted by the media. This case study used qualitative and quantitative methods to explore the nature and forms of domestic violence, circumstances, impact and coping mechanisms amongst selected women victims in Karachi. Violence was a continuum: all the women reported verbal abuse, often escalating into physical, emotional, sexual and economic abuse. The husband was the most common perpetrator. Women suffered in silence due to sociocultural norms, misinterpretation of religious beliefs, subordinate status, economic dependence and lack of legal redress. Besides short-term local measures, public policy informed by correct interpretation of religion can bring about a change in prevailing societal norms.

Pattern of first- and second-line drug resistance among pulmonary tuberculosis retreatment cases in Pakistan.

BACKGROUND: Drug resistance in general, and multidrug-resistant tuberculosis (MDR-TB) in particular, threatens global tuberculosis (TB) control efforts. Population-based estimates of drug resistance are needed to develop strategies for controlling drug-resistant TB in Pakistan. OBJECTIVE: To obtain population-based data on Mycobacterium tuberculosis drug resistance in Pakistan. METHODS: To obtain drug resistance data, we conducted a population-based study of TB cases in all provinces of Pakistan. We performed culture and drug susceptibility testing on M. tuberculosis isolates from patients with a prior history of anti-tuberculosis treatment (retreatment cases) from all over the country. RESULTS: Of 544 isolates from previously treated cases, 289 (53.1%) were susceptible to all first-line drugs, 255 (46.9%) were resistant to at least one anti-tuberculosis drug and 132 (24.3%) were MDR-TB. Among MDR-TB isolates, 47.0% were ofloxacin (OFX) resistant. Extensively drug-resistant TB was found in two (0.4%) isolates. CONCLUSION: Prevalence of drug resistance in retreatment isolates was high. The alarmingly high prevalence of OFX resistance among MDR-TB isolates may threaten the success of efforts to control and treat MDR-TB.

DNA topoisomerase II alpha expression is associated with alkylating agent resistance.

Increased expression of DNA topoisomerase II alpha has been associated with resistance to certain DNA-damaging alkylating agents, but no causal relationship or mechanism has been established. To investigate this observation, we developed a model of topoisomerase II overexpression by transfecting a full-length Chinese hamster ovary topoisomerase II alpha into EMT6 mouse mammary carcinoma. Topoisomerase II alpha-transfected cell lines demonstrated continued topoisomerase II alpha mRNA and protein expression, which were undetectable in vector-only lines, in stationary phase (G0-G1). The topoisomerase II transfectants were approximately 5-10-fold resistant to the alkylating agents cisplatin and mechlorethamine. Upon release from G0-G1, the topoisomerase II transfectants demonstrated more rapid thymidine incorporation and shorter cell-doubling times than control cells. Purified topoisomerase II and nuclear extracts with topoisomerase II-decatenating activity bound to cisplatin-treated DNA with significantly greater affinity than to untreated DNA in a cisplatin concentration-dependent manner. These observations suggest that expression of topoisomerase II alpha may have a role in cellular resistance to antineoplastic alkylating agents. The mechanism for this may involve increased binding of topoisomerase II alpha to alkylating agent-damaged DNA.

A safety and pharmacokinetic study of a mixed-backbone oligonucleotide (GEM231) targeting the type I protein kinase A by two-hour infusions in patients with refractory solid tumors.

GEM231 is a mixed-backbone oligonucleotide targeting the regulatory subunit alpha of type I protein kinase A, which plays an important role in growth and maintenance of malignancies. Preclinically, GEM231 inhibited human cancer xenografts either alone or synergistically with chemotherapeutic agents and has demonstrated an improved metabolic stability and safety profile compared to the first-generation compounds. Objectives of this study were to define the safety profile and pharmacokinetics of GEM231 administered as 2-h IV infusions twice weekly in patients with refractory solid tumors. Fourteen patients (13 evaluable for safety) received escalating doses of GEM231 at 20-360 mg/m2 (2.5-9 mg/kg). Tumor histologies included non-small cell lung cancer, renal cell cancer, sarcoma, and others. The plasma pharmacokinetics of GEM231 were linear and predictable. Maximum plasma concentration (Cmax) reached 50-70 microg/ml (8-13 microM) at dose 360 mg/m2 and 27-32 microg/ml at dose 240 mg/m2. The plasma half-life was about 1.5 h. The only clinical toxicities were transient grade I-II fever and fatigue at doses > or = 240 mg/m2. There was no treatment-related complement activation or thrombocytopenia at any dose level, except with the first dose in one patient who had pre-existing borderline thrombocytopenia. Transient activated partial thrombin time prolongation occurred at doses > or =160 mg/m2. Dose-limiting toxicities included transient activated partial thrombin time prolongation (one of three patients at 360 mg/m2) and cumulative reversible transaminase elevation (three of three patients at 360 mg/m2 and three of six patients at 240 mg/m2 during weeks 3-10). One patient with colon cancer had stabilization of a previously rising carcinoembryonic antigen. Thus, in this first clinical evaluation of a mixed-backbone oligonucleotide in cancer patients, high plasma concentrations of GEM231 were well tolerated without significant acute toxicities, but prolonged treatment was associated with reversible transaminitis. Although 240 mg/m2 by 2-h infusion twice weekly was safe for a 4-week treatment duration, alternative dosing schedules are being tested to minimize the cumulative toxicity, which will be essential to extend the duration of therapy at the highest GEM231 dose tested.

A Phase I and pharmacokinetic study of TNP-470 administered weekly to patients with advanced cancer.

A Phase I study of angiogenesis inhibitor TNP-470 was conducted in patients with advanced cancer. TNP-470 (25-235 mg/m2) was administered i.v. over 4 h once a week to patients who had solid tumors refractory to the best available treatment or with a high risk of recurrence and who had normal renal, hepatic, and hematological function and no evidence of coagulopathy. The aims of the study were to determine the maximum tolerated dose, dose-limiting toxicities (DLTs), and the pharmacokinetics of TNP-470 given on a once-weekly schedule. Thirty-six patients, ages 23-75 (median, 54 years), with an Eastern Cooperative Oncology Group performance status of 0-2 were treated. The number of patients at each dose level (mg/m2) were 6 (25), 3 (50), 3 (75), 3 (100), 3 (133), 12 (177), and 6 (235). The principal toxicities of TNP-470 were dizziness, lightheadedness, vertigo, ataxia, decrease in concentration and short-term memory, confusion, anxiety, and depression, which occurred at doses of 133, 177, and 235 mg/m2. Two patients treated at 235 mg/m2 experienced DLT in the form of grade III cerebellar neurotoxicity after 6 weeks of treatment. Overall, these neurological symptoms were dose-related, had an insidious onset, progressively worsened with treatment, and resolved completely within 2 weeks of stopping the drug. One patient with malignant melanoma had stabilization of the previously growing disease for 27 weeks while on the treatment. Two patients, one with adenocarcinoma of the colon and the other with a soft tissue sarcoma, had no clinically detectable disease but were at high risk for recurrence at the initiation of treatment and received 13 months and > 3 years of treatment, respectively, with no evidence of disease recurrence. The remaining patients had progression of their disease after 1-6 months of treatment. The mean plasma half-life (t(1/2)) of TNP-470 and its principal metabolite, AGM-1883, were extremely short (harmonic mean, t(1/2) of 2 and 6 min, respectively) with practically no drug detectable in the plasma by 60 min after the end of the infusion. MII, an inactive metabolite, had a considerably longer t(1/2) of approximately 2.6 h. Mean peak TNP-470 concentrations were > or = 400 ng/ml at doses > or = 177 mg/m2. On the basis of this study, the maximum tolerated dose of TNP-470 administered on a weekly schedule was 177 mg/m2 given i.v over 4 h. The principal DLT was neurotoxicity, which appeared to be dose-related and was completely reversible. On the basis of the short plasma t(1/2) of TNP-470, exploration of a prolonged i.v. infusion schedule is warranted.

A phase I and pharmacokinetic study of squalamine, a novel antiangiogenic agent, in patients with advanced cancers.

PURPOSE: A Phase I study of squalamine, a novel antiangiogenic agent originally isolated from the dogfish shark Squalus acanthias, was conducted in patients with advanced cancers to: (a) determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT) and pharmacokinetics of squalamine lactate when given as a 120-h continuous i.v. infusion every two weeks; and (b) to obtain information on prolonged (>120-h) continuous i.v. infusions in patients who have tolerated 120-h infusions. EXPERIMENTAL DESIGN: A rapid dose escalation scheme was used that permitted intrapatient dose escalation. Three or more patients were treated at each dose, of which at least one patient started treatment de novo at that dose. Once DLT was encountered, the dose was decreased by one dose level, and the duration of infusion was prolonged from 10 up to 30 days in 5-day increments. RESULTS: Nineteen patients were treated at eight squalamine dose levels; the number of patients/dose level who received 120-h infusions were [expressed as dose in mg/m(2)/day (number of patients initiated de novo at that dose/total number of patients treated at that dose)]: 6 (3/3), 12 (3/6), 24 (1/5), 48 (2/6), 96 (4/10), 192 (2/6), 384 (3/8), and 538 (1/5). DLT was encountered at 384 mg/m(2)/day (1/3 de novo patients, 5/8 total patients) and 538 mg/m(2)/day (1/1 de novo patients, 4/5 total patients) and consisted of hepatotoxicity, characterized by grade 3 transaminase elevations that resolved 3-11 days after ceasing squalamine infusion. Three patients did not experience hepatotoxicity when first treated at 384 mg/m(2)/day but developed DLT at the same dose when de-escalated from 538 mg/m(2)/day. Other toxicities included grade 1-3 fatigue, grade 1-2 nausea, anorexia, and neuromuscular symptoms. The maximum duration of continuous i.v. infusion was 20 days at a dose rate of 192 mg/m(2)/day in one patient without adverse effects. Pharmacokinetic calculations revealed a linear relationship between area under the curve or Cmax and squalamine dose rate up to 384 mg/m(2)/day, with a prolonged terminal squalamine persistence in patient plasma (median t(1/2) = 18 h; range, 8-48 h). Transient tumor responses were observed in a patient with synovial cell sarcoma and a patient with breast carcinoma with cutaneous metastases. CONCLUSIONS: The best tolerated dose rate of squalamine when administered as a 120-h continuous i.v. infusion was 192 mg/m(2)/day; however, patients without prior exposure to squalamine appeared to tolerate a dose rate of 384 mg/m(2)/day without DLT. On the basis of preclinical evidence of synergy with cytotoxic agents and demonstration of human safety from this trial, additional clinical trials have been initiated with squalamine in combination with chemotherapy for patients with late stage lung cancer and ovarian cancer.

A Phase I study of LGD1069 in adults with advanced cancer.

LGD1069 [Targretin; 4-[1-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphtalenyl) propenyl] benzoic acid] is a novel synthetic retinoid X receptor-selective retinoid that has been recently identified. The goals of this study were to determine the safety, toxicity, pharmacokinetics (PKs), and metabolic profile of LGD1069 in advanced cancer patients. Sixty patients received oral LGD1069 at doses ranging from 5-1000 mg/m2/day with PK sampling performed on days 1 and 15. No dose-limiting toxicities (DLTs) were observed up to the 500 mg/m2/day dose level. DLT observed at and above 650 mg/m2/day included skin desquamation, hyperbilirubinemia, transaminase elevation, leukopenia, and diarrhea. Asymptomatic, dose-related alterations in lipid and thyroid metabolism were also observed. DLTs frequently observed with retinoic acid receptor-selective retinoids and pan agonists, including headache, mucocutaneous toxicity, and hypercalcemia, were not dose-limiting with LGD1069. Day 1 LGD1069 Cmax and area under the curve values increased dose-proportionately up to 800 mg/m2/day. Repeat-dose (day 15) area under the curve values varied between 25 and 105% of day 1 values. Although no objective tumor responses were observed, tumor progression may have been substantially arrested or delayed in non-small cell lung cancer (5 of 16) and in head and neck cancer (1 of 5), as well as other tumor types. At the higher dose levels, the molar concentration of LGD1069 was up to 10-fold higher than observed with other retinoids, yet toxicity was minimal. LGD1069 is an retinoid X receptor-selective retinoid agonist with a more favorable PK and toxicity profile than previously studied retinoids and merits further investigation as a chemopreventive and anticancer agent. On the basis of this Phase I trial, the recommended Phase II dose is 500 mg/m2/day.

Phase I study of 9-cis-retinoic acid (ALRT1057 capsules) in adults with advanced cancer.

9-cis-Retinoic acid (9-cis-RA) and all-trans-RA (ATRA) are naturally occurring hormones. The nuclear receptors that mediate the effects of retinoids are the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs). ATRA binds RAR with high affinity but does not bind to RXR, whereas 9-cis-RA, an isomer of ATRA, is a ligand that binds and transactivates both RARs and RXRs. The goals of this study were to determine the safety, tolerability, pharmacokinetics, and metabolic profile of 9-cis-RA in advanced cancer patients. Forty-one patients received oral 9-cis-RA (ALRT1057; Panretin capsules) at doses ranging from 5-140 mg/m2/day. Twenty-six patients were treated once daily with up to 140 mg/m2; a subsequent cohort of 15 patients were treated twice daily (b.i.d.) at 100-140 mg/m2/day (50, 60, and 70 mg/m2 b.i.d.) to evaluate a b.i.d. dosing regimen. Headache was the most frequent adverse event and was dose limiting in 3 of 41 patients. Skin toxicity was the next most common toxicity and was seen in 11 of 41 patients; it was typically mild and limited to skin dryness and erythema. Other toxicities included conjunctivitis, flushing, diarrhea, transaminitis, hypercalcemia, and asymptomatic hypertryglyceridemia. Toxicities were typically dose related, occurred primarily above 83 mg/m2/day, and were not ameliorated by b.i.d. dosing. No tumor responses were observed. The mean day 1 area under the plasma concentration-time curve and peak plasma concentration values were dose-proportional over all dose levels, whereas day 15 area under the plasma concentration-time curve and peak plasma concentration values were nonlinear above 83 mg/m2/day, suggesting that 9-cis-RA induced its own metabolism at doses equal to and above 140 mg/m2/day. 9-cis-RA is a retinoid receptor pan agonist with a more favorable pharmacokinetic and toxicity profile than that observed with previously studied retinoids and merits further investigation.

Medical interns knowledge of TB in Pakistan.

Of 460 interns from five Pakistani teaching hospitals surveyed, only 22% correctly identified the estimated number of new TB cases in Pakistan. The majority (96%) knew that droplet infection was the usual mode of transmission. Only 38% considered sputum smears for acid-fast bacilli as the best test for diagnosis of pulmonary TB and 43.5% for follow-up during TB treatment. The recommended four-drug anti-TB regimen was prescribed by 56.5% in the initiation phase and the recommended two-drug combination in the continuation phase by 52%. Most interns (82%) were unable to identify a single component of directly observed treatment short course (DOTS) strategy. Our study reflects poor awareness of and low compliance to the World Health Organization/National Tuberculosis Programme guidelines among interns. For effective control of TB, immediate action to improve undergraduate and continuing medical education is essential, with special emphasis on national guidelines.

Docetaxel (Taxotere) and gemcitabine in combination therapy.

In patients with advanced cancers, gemcitabine and docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) can be administered together at 80% to 100% of their single-agent doses on days 1 and 8 of an every-3-week cycle without undue toxicity. In phase 1/11 studies, this combination has demonstrated activity against a range of tumors, including non-small cell lung cancer, and may represent an alternative to cisplatin-based chemotherapy. In advanced cancer, benefits in quality of life are likely to result. The fact that the combination of gemcitabine and docetaxel is generally well tolerated also suggests that the regimen should be assessed in the adjuvant and neoadjuvant settings.

Docetaxel and gemcitabine combinations in non-small cell lung cancer.

Docetaxel and gemcitabine have been shown to be active as single agents in a variety of solid tumors. These two agents have been studied in combination with several different treatment schedules. Two phase I studies used a novel 2-week administration schedule that involved a 1-hour infusion of 35 mg/m2 to 65 mg/m2 docetaxel and gemcitabine administered as either a 30-minute infusion (2,000 to 4,000 mg/m2) or a 10 mg/m2/min infusion (1,000 to 1,200 mg/m2 total dose). Another novel phase I study evaluated the effect of drug sequence on toxicities. Patients received 30 to 40 mg/m2 docetaxel and 800 to 1,250 mg/m2 gemcitabine on days 1 and 8 every 21 days. Two phase I studies of a monthly docetaxel regimen have been conducted. Patients received 800 mg/m2 gemcitabine on days 1, 8, and 15 and 100 mg/m2 docetaxel on day 1 of a 28-day cycle. Finally, in a phase II study, patients received 900 mg/m2 gemcitabine on days 1 and 8 and 100 mg/m2 docetaxel on day 8, with granulocyte colony-stimulating factor administered on days 9 through 15. In these studies, antitumor responses were observed in lung cancer as well as a number of other histologies. Neutropenia was the most frequent dose-limiting toxicity and no difference in clinical toxicity was observed with either sequence of administration. The emerging evidence suggests, therefore, that the combination of gemcitabine and docetaxel is active in a variety of solid tumors and is well tolerated.

Sequence effect of irinotecan (CPT-11) and topoisomerase II inhibitors in vivo.

UNLABELLED: The DNA topoisomerases I and II are the target of several clinically important antineoplastic agents which produce DNA cleavage by stabilization of the covalent DNA-protein bond with resultant cell death after DNA synthesis is attempted. Depletion of the target topoisomerase and reciprocal changes in the other occur with drug treatment. PURPOSE AND METHODS: To develop empiric treatment regimens of combinations and sequences of agents directed against topoisomerase I (irinotecan/CPT-11) and II (etoposide and doxorubicin), in vivo studies were performed in mice bearing the EMT-6 mammary tumor to assess efficacy, host tolerance and the resultant biochemical changes in topoisomerase mRNA and protein. RESULTS: At 24 h after therapy, depletion of the target topoisomerase mRNA and protein with reciprocal increases in the alternate topoisomerase mRNA and, to a lesser extent, protein were noted. No therapeutic antagonism was found with any combination or sequence of agents, and therapeutic antagonism was noted with concurrent irinotecan/etoposide and sequential doxorubicin/irinotecan. Depletion of target topoisomerases by combined therapy beyond a threshold necessary for therapeutic efficacy produced no additional benefit. CONCLUSIONS: Antineoplastic therapy with combinations of topoisomerase I and II agents is feasible and may produce therapeutic synergy. The appropriate sequence may depend on the particular agents used. The rationale for such therapy, that topoisomerases I and II may have reciprocal and compensatory interactions, is supported by the biochemical data.

Phase I and pharmacokinetic study of two sequences of gemcitabine and docetaxel administered weekly to patients with advanced cancer.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and effect of drug sequence on toxicities and pharmacokinetics of the combination of gemcitabine and docetaxel. METHODS: A total of 34 patients with advanced cancers were treated with gemcitabine and docetaxel on days 1 and 8 of each 21-day cycle according to the following dose escalation schedule: level 1, 800 and 30 mg/m2, respectively; level 2, 800 and 40 mg/m2; level 3, 1,000 and 40 mg/m2; and level 4, 1,250 and 40 mg/m2. At each dose level, at least three patients were assigned to one of the two sequences of drug administration: gemcitabine-->docetaxel or docetaxel-->gemcitabine. Once the MTD had been reached, six additional patients, who had received no more than one chemotherapy regimen, were enrolled to dose levels 3 and 4 (gemcitabine-->docetaxel) to determine the MTD in minimally pretreated patients. RESULTS: Neutropenia was the most frequent DLT with an overall incidence of 23.5%. Grade 3/4 neutropenia occurred in 62% of patients (8/13) who had received two or more prior chemotherapy regimens, but not at all (0/15) in patients who had received no more than one prior chemotherapy regimens (P< 0.001). Additional DLTs included grade 4 diarrhea and grade 4 stomatitis in one patient each. The MTD was determined to be gemcitabine 800 mg/m2 and docetaxel 40 mg/m2 in patients who had received two or more prior chemotherapy regimens. However, minimally pretreated patients (no more than one prior chemotherapy regimen) were able to tolerate higher doses with an MTD of gemcitabine 1,250 mg/m2 and docetaxel 40 mg/m2. There were no significant differences in toxicities or pharmacokinetics between the two sequences of administration. Partial and minor responses were observed in 23.5% of patients: non-small-cell lung (two of eight), gastric (two of three), head and neck (one of two), bladder (two of four) and hepatocellular cancer (one of one). CONCLUSIONS: The combination of gemcitabine and docetaxel administered on days 1 and 8 every 21 days was feasible and well tolerated in patients with advanced malignancies. The sequence of administration had no significant effect on the toxicity or pharmacokinetics of either drug. Minimally pretreated patients tolerated higher doses of this combination without significant toxicities. This schedule and combination demonstrated activity in a variety of solid tumors, and merits further evaluation.

Yield of gastric lavage and bronchial wash in pulmonary tuberculosis.

OBJECTIVE: To determine the yield of acid-fast bacilli (AFB) in gastric lavage and bronchial washing in adult patients clinically and radiologically suspected of pulmonary tuberculosis but who cannot produce sputum. METHODS: Selected adult patients were admitted to the ward; gastric lavage was done for 3 consecutive days after an overnight fast followed by bronchial wash. Specimens were immediately sent to laboratory for AFB direct smear and culture. RESULTS: The yield of AFB in gastric lavage on direct smear was 16/20 (80%) and 12/20 (60%) in the first and second samples, respectively. When combined, 18/20 (90%) were direct smear positive, while the third sample did not increase the yield. The yield of AFB culture in gastric lavage was 6/20 (30%) in both the first and second samples, while the combined results of the first and second samples were 8/20 (40%). The third sample did not increase the yield. In bronchial wash, AFB direct smear was positive in 18/20 (90%), while culture was positive in 14/20 (70%). CONCLUSION: Gastric lavage and bronchial washing are useful methods for the diagnosis of pulmonary tuberculosis in patients who cannot produce sputum. Two gastric lavage specimens are adequate. On comparison, bronchial wash is superior to gastric lavage in culture, but their yield on direct smear is equal.