Median Development Time Research Articles

Susceptibility of different types of sorghums during storage to Sitophilus zeamais Motschulsky

Caryopses belonging to twelve different sorghum cultivars (two red, one brown or high-tannin, two white heterowaxy, two white waxy, two white high-digestible protein and three white with regular endosperm) were selected to study their resistance to Sitophilus zeamais during storage. Five resistance parameters were evaluated: Dobie Index, Total Emerged Insects, Median Development Time, Ratio final/initial insects and Weight Loss. Biophysical characteristics (test weight, 1000 kernel weight, endosperm texture, flotation index, true density, percentage of kernel removed with TADD, anatomical parts, color index and kernel size), chemical composition (starch, amylose, protein, free amino nitrogen and ash), and nutraceutical traits (free and bound phenolics and antioxidant capacity for the free and bound fractions) were obtained. The most resistant cultivars were both red sorghums (RR1 and RR2) and a white cultivar with regular endosperm (WR1) whereas the most susceptible were the brown high-tannin (Sumac), a white waxy (Waxy1) and a white high digestible (HD1). Correlation coefficients among resistance parameters and physicochemical characteristics were calculated, yielding a clear relationship amongst different endosperm texture indicators, endosperm, ash, amylose and free amino nitrogen content, and susceptibility traits. The harder kernels (in terms of vitrousness), higher endosperm percentage, low ash, increased amylose content and reduced free amino nitrogen concentration had more resistance to S. zeamais. Significant relationships among nutraceutical profiles and resistance were not detected, despite the wide range of phenolics in the array of kernels. These results indicated that endosperm structure is predominant in sorghum resistance to S. zeamais.

GVHD-associated chronic kidney disease after allogeneic haematopoietic cell transplantation

Chronic kidney disease (CKD) has been related to allogeneic haematopoietic cell transplantation (HCT) as a late effect caused by a variety of factors. We retrospectively evaluated the development of CKD in 230 patients, aged 34 (5-65) years, who had undergone allogeneic HCT for haematological disease, using sibling or unrelated donors and myeloablative or reduced conditioning regimens. Pre-HCT glomerular filtration rate (GFR) was within normal limits (108±28 mL/min/1.73 m(2)) in patients who did not develop CKD and 95±24 mL/min/1.73 m(2) in those with CKD postHCT, while the GFR 12 months post transplant declined to 104±26 and 69±19 mL/min/1.73 m(2), respectively. CKD incidence was 20.4%, with a median time of development of 6 (3-18) months post transplant. On multivariate analysis, risk factors for CKD were the presence of chronic GVHD (cGVHD; P=0.001), unrelated donor transplantation (P=0.008), post-transplant event of acute kidney injury (AKI) (P=0.002) and older age (P=0.002). In long-term survivors stable significant predictors for CKD were older age at transplantation, cGVHD and AKI. CKD did not influence non-relapse mortality. In our study, cGVHD emerges as an important cause of kidney injury in HCT survivors, regardless of administration of nephrotoxic agents.

Yield and agronomic performance of maize hybrids resistant to the maize weevil Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae)

This study evaluated improved maize hybrids (Zea mays L.) with varying level of resistance to the maize weevil, Sitophilus zeamais Motschulsky, for yield and agronomic traits for two seasons. A total of 22 improved maize hybrids and three commercial standards were tested. Out of the 22 tested, two hybrids CKPH08035 (7.4–9.9 t ha−1) and CKPH08039 (7.3–9.8 t ha−1) significantly out yielded the commercial standards WH505 (8.8 t ha−1) and BH140 (5.5 t ha−1). In addition to yield, the improved hybrids also possess desirable traits including good plant height, good plant and ear aspects and good husk cover. The hybrid CKPH08004 had the lowest Dobie index of susceptibility and was regarded as resistant to S. zeamais. Weevils fed with the resistant hybrids produced low numbers of F1 generation weevils, had a high median developmental time and a low percentage of grain damage and grain weight loss. An increasing number of F1 generation resulted in an increasing grain damage and grain weight loss. We found an inverse relationship between the susceptibility index and percent mortality. However, the numbers of F1 generation, percent grain damage and grain weight loss were positively correlated with the susceptibility index. The use of resistant maize hybrids should be promoted in managing S. zeamais in stored maize under subsistence farming conditions in Africa.

Clinical outcomes in patients who received lapatinib plus capecitabine combination therapy for HER2-positive breast cancer with brain metastasis and a comparison of survival with those who received trastuzumab-based therapy: a study by the Anatolian Society of Medical Oncology

In this study, we investigated the effect of lapatinib plus capecitabine treatment in HER2-positive breast cancer patients with brain metastasis. Of 405 metastatic breast cancer patients with brain metastases at referral centers in Turkey, 46 were treated with lapatinib plus capecitabine only after the development of brain metastasis. Patients who only received trastuzumab-based therapy after the development of brain metastases were accepted as the historic control group for survival analyses (n = 65). Patients who received both drugs consecutively or sequentially were excluded from the analyses (n = 34). Median age among 46 patients who received lapatinib plus capecitabine therapy was 45 years (27-76), and median time for development of brain metastases was 11.9 months (0-69 months). Twenty-six out of 38 patients who received lapatinib plus capecitabine and had extracranial metastasis showed partial response or stable diseases (68.4 %). Grade 3-4 toxicity was observed in eight patients (17.3 %). Median overall survival (OS) in patients treated with lapatinib plus capecitabine was significantly increased compared to that in patients treated with trastuzumab-based therapy (19.1 vs. 12 months, respectively, p = 0.039). The incidence of cerebral death was slightly decreased in patients who received lapatinib plus capecitabine compared to those who received trastuzumab-based therapy (32 vs. 43.4 %, p = 0.332). In the multivariate analysis, lapatinib plus capecitabine therapy remained an independent positive predictor for survival [odds ratio (OR), 0.57; p = 0.02]. Although this retrospective multicenter study had several limitations, the results suggest that undergoing lapatinib plus capecitabine therapy after the diagnosis of brain metastasis may further improve survival compared to undergoing only trastuzumab-based therapy.

Tolerance of Hyas araneus zoea I larvae to elevated seawater PCO2 despite elevated metabolic costs

Early life stages of marine crustaceans respond sensitively to elevated seawater PCO2. However, the underlying physiological mechanisms have not been studied well. We therefore investigated the effects of elevated seawater PCO2 on oxygen consumption, dry weight, elemental composition, median developmental time (MDT) and mortality in zoea I larvae of the spider crab Hyas araneus (Svalbard 79°N/11°E; collection, May 2009; hatch, December 2009). At the time of moulting, oxygen consumption rate had reached a steady state level under control conditions. In contrast, elevated seawater PCO2 caused the metabolic rate to rise continuously leading to a maximum 1.5-fold increase beyond control level a few days before moulting into the second stage (zoea II), followed by a pronounced decrease. Dry weight of larvae reared under high CO2 conditions was lower than in control larvae at the beginning of the moult cycle, yet this difference had disappeared at the time of moulting. MDT of zoea I varied between 45 ± 1 days under control conditions and 42 ± 2 days under the highest seawater CO2 concentration. The present study indicates that larval development under elevated seawater PCO2 levels results in higher metabolic costs during premoulting events in zoea I. However, H. araneus zoea I larvae seem to be able to compensate for higher metabolic costs as larval MDT and survival was not affected by elevated PCO2 levels.

The effect of temperature on the development and life cycle regulation of the pine weevil Hylobius abietis and the potential impacts of climate change

The pine weevil Hylobius abietis is widely distributed in the Palaearctic region where it is a major pest. Although predominantly semi‐voltine, with a 2‐year life cycle, the generation time across its range can vary from 1 to 4 years. The duration of the life cycle and the seasonal timing of weevil activity affect the economic impact and management of this pest, all of which are likely to change in a warming climate. To determine the effect of temperature and tree species on weevil growth and development, laboratory experiments were performed with eggs, larvae, prepupae, pupae and adults, using, as appropriate, the host species Scots pine Pinus sylvestris L. and Sitka spruce Picea sitchensis (Bong.) Carr. under constant or alternating temperatures. The development rate was linearly related to temperature, with developmental thresholds for eggs, larvae and pupae of 8, 4.5 and 7.3 °C, respectively. Day‐degrees were estimated for each life stage. Larval development was affected by tree species, being slower on Sitka spruce than on Scots pine, and was faster under alternating than constant temperatures. The development time for prepupae was highly variable, with an apparent facultative prepupal diapause initiated by temperature. The temperature range 20–17.5 °C marked the transition between median prepupal development times of approximately 25 and 90 days. The prepupal stage may serve to minimize the risk of overwintering mortality in the pupal stage and help to synchronize the life cycle. Larval and adult mass was positively related to developmental temperature, demonstrating an inverse temperature size rule, and weevils were heavier when developing on Scots pine than Sitka spruce. Development in alternating temperatures reduced weevil mass on Scots pine. The influence of temperature on weevil mass is likely to have a positive effect on fecundity and overwintering survival. The effects of climate change on development, voltinism and weevil mass are discussed.

Skin toxicities and survival in advanced hepatocellular carcinoma patients treated with sorafenib

Sorafenib is the first small molecule with significant clinical activity for advanced hepatocellular carcinoma (HCC). However, intolerable adverse events are sometimes observed. On the other hand, it has been reported that some toxicities of molecular targeted drugs, such as skin toxicities and arterial hypertension, are correlated with good clinical outcomes in other cancers. We identified the correlations between adverse events and prognosis for sorafenib therapy in all patients with HCC treated at the institutions of the Saga Liver Cancer Study Group. The toxicities were assessed using the Common Terminology Criteria for Adverse Events version 4.0. Ninety-four patients received sorafenib until August 2010. The overall incidence of treatment-related adverse events was 98% of patients. Skin toxicities, including palmar-plantar erythrodysesthesia syndrome, rash, pruritus and alopecia, were the most common adverse events and were observed in 58 patients (62%). Hypertension was observed in 23 patients (24%). The median survival time was 12.5 months among the total patients. The patients with skin toxicities showed significantly longer survival than the patients without these toxicities (hazard ratio, 0.449; 95% confidence interval, 0.256-0.786; P = 0.005). Hypertension had no correlation with survival. Skin toxicities were also significant prognostic factors in a multivariate analysis (hazard ratio, 0.522; 95% confidence interval, 0.274-0.997; P = 0.049), along with Child-Pugh class and α-fetoprotein level. The median development time for skin toxicities was 21 days. Skin toxicities occur commonly at the early phase in patients treated with sorafenib, and could be a promising surrogate marker for the treatment outcome.

Development time of trial protocols in the Japan Clinical Oncology Group (JCOG).

e16568 Background: Protocol development process consists of multiple steps and takes considerable amount of time, and it is regarded as one of barriers for timely trial completion. Streamlining of protocol development has been one of the major concerns worldwide today. Dilts et al. reported that median calendar days to activate phase III trial are 784 in CALGB (JCO 2006), 808 in ECOG (Clin Cancer Res 2008), and 602 in all CTEP-sponsored trials (JCO 2009). We studied protocol development time of the trials conducted by JCOG and explored possible solutions for streamlining protocol development. Methods: An analysis for protocol development time was conducted on all JCOG trials activated between 2000 and 2010. Protocol development time was the calendar time from concept approval by JCOG Executive Committee to final protocol approval by JCOG Protocol Review Committee. Association between “fast/slow,” divided by median, and trial characteristics were investigated by both univariate comparison and multivariate logistic regression analysis. Results: The median protocol development time was 573 days in 69 trials (range: 222 to 2,413 days). The results of subset analyses are shown in the table. Variability was remarkable among disease subgroups and year of concept approval. Odds ratio (OR) in multivariate logistic regression model was significant only in disease subgroups (faster in gastrointestinal group). Conclusions: Unfavorably, it took longer time in phase II trials than in phase III trials, and more time may have been needed to reach agreement on protocol treatment among investigators in phase II. To reduce intergroup difference, more aggressive promotion of sharing know-how in faster disease group may be necessary. Protocol development time by trial characteristics. N Median (days) Year of concept approval 2000-2001 17 551 2002-2003 17 432 2004-2005 15 879 2006-2007 12 697 2008-2009 8 481 Phase II 18 690.5 III 32 533.5 Modality Chemotherapy alone 23 573 Radiotherapy included 14 481 Chemoradiotherapy included 7 752 Surgery included 28 578.5 Group Gastrointestinal groups 30 519.5 Lung groups 14 598.5 Other disease groups 25 653

A sense of urgency: Evaluating the link between clinical trial development time and the accrual performance of cancer therapy evaluation program (NCI-CTEP) sponsored studies.

Postactivation barriers to oncology clinical trial accruals are well documented; however, potential barriers prior to trial opening are not. We investigate one such barrier: trial development time. National Cancer Institute Cancer Therapy Evaluation Program (CTEP)-sponsored trials for all therapeutic, nonpediatric phase I, I/II, II, and III studies activated between 2000 and 2004 were investigated for an 8-year period (n = 419). Successful trials were those achieving 100% of minimum accrual goal. Time to open a study was the calendar time from initial CTEP submission to trial activation. Multivariate logistic regression analysis was used to calculate unadjusted and adjusted odds ratios (OR), controlling for study phase and size of expected accruals. Among the CTEP-approved oncology trials, 37.9% (n = 221) failed to attain the minimum accrual goals, with 70.8% (n = 14) of phase III trials resulting in poor accrual. A total of 16,474 patients (42.5% of accruals) accrued to those studies were unable to achieve the projected minimum accrual goal. Trials requiring less than 12 months of development were significantly more likely to achieve accrual goals (OR, 2.15; 95% confidence interval, 1.29-3.57, P = 0.003) than trials with the median development times of 12 to 18 months. Trials requiring a development time of greater than 24 months were significantly less likely to achieve accrual goals (OR, 0.40; 95% confidence interval, 0.20-0.78; P = 0.011) than trials with the median development time. A large percentage of oncology clinical trials do not achieve minimum projected accruals. Trial development time appears to be one important predictor of the likelihood of successfully achieving the minimum accrual goals.

Enhanced case detection and improved diagnosis of PKDL in a Kala-azar-endemic area of Bangladesh.

ObjectivesTo support the Bangladesh National Kala-azar Elimination Programme (NKEP), we investigated the feasibility of using trained village volunteers for detecting post-kala-azar dermal leishmaniasis (PKDL) cases, using polymerase chain reaction (PCR) for confirmation of diagnosis and treatment compliance by PKDL patients in Kanthal union of Trishal sub-district, Mymensingh, Bangladesh.MethodsIn this cross-sectional study, Field Research Assistants (FRAs) conducted census in the study area, and the research team trained village volunteers on how to look for PKDL suspects. The trained village volunteers (TVVs) visited each household in the study area for PKDL suspects and referred the suspected PKDL cases to the study clinic. The suspected cases underwent physical examinations by a qualified doctor and rK39 strip testing by the FRAs and, if positive, slit skin examination (SSE), culture, and PCR of skin specimens and peripheral buffy coat were done. Those with evidence of Leishmania donovani (LD) were referred for treatment. All the cases were followed for one year.ResultsThe total population of the study area was 29,226 from 6,566 households. The TVVs referred 52 PKDL suspects. Probable PKDL was diagnosed in 18 of the 52 PKDL suspect cases, and PKDL was confirmed in 9 of the 18 probable PKDL cases. The prevalence of probable PKDL was 6.2 per 10,000 people in the study area. Thirteen PKDL suspects self-reported from outside the study area, and probable and confirmed PKDL was diagnosed in 10 of the 13 suspects and in 5 of 10 probable PKDL cases respectively. All probable PKDL cases had hypopigmented macules. The median time for PKDL development was 36 months (IQR, 24–48). Evidence of the LD parasite was documented by SSE and PCR in 3.6% and 64.3% of the cases, respectively. PCR positivity was associated with gender and severity of disease. Those who were untreated had an increased risk (odds ratio = 3.33, 95%CI 1.29–8.59) of having persistent skin lesions compared to those who were treated. Patients' treatment-seeking behavior and treatment compliance were poor.ConclusionImproved detection of PKDL cases by TVVs is feasible and useful. The NKEP should promote PCR for the diagnosis of PKDL and should find ways for improving treatment compliance by patients.

Abstract A73: Multiple primary malignancies in early-stage breast cancer patients

Abstract Introduction: Early diagnosis and effective local and systemic therapy has reduced the risk of relapse and death from breast cancer; thus, patients are living longer but experience an increased risk for the development of multiple primary malignancies (MPM). Risk factors for MPM may be genetic, related to environmental or behavioral factors, or to breast cancer treatments such as radiotherapy, chemotherapy or hormone therapy. Controversy exists over the role of obesity and breast cancer outcomes and there is little information on long-term survivors. LSUHSC-Shreveport provides care for a predominantly indigent with high rates of obesity. This allows us to study the role of obesity in MPM before and after breast cancer diagnosis. In this study, we sought to determine the prevalence and risk factors for MPM in women with early stage breast cancer with emphasis in the role of obesity. Methods: We performed a retrospective analysis of all patients treated for invasive breast cancer from 1980 through 2006 at LSUHSC Shreveport. Patients with stage IV at diagnosis were excluded. Multiple primary malignancies (MPM) were defined as a different diagnosis of primary malignancy in patients with a history of breast cancer. MPM were divided in two categories depending on the interval between malignancy and breast cancer diagnosis. Tumors diagnosed before and within 3 months after breast cancer diagnosis were termed prior/synchronous tumors (PST). Tumors diagnosed ≥ 3 months after breast cancer diagnosis were termed secondary tumors (ST). We reviewed the demographics, smoking status, BMI at diagnosis of breast cancer, tumor characteristics, breast cancer treatments, site and date of MPM and last follow up. Descriptive statistics were performed to characterize the group of patients who developed MPM. Log rank test was used to estimate differences in overall survival between patients with MPM and without it. Results: Of the 1246 patients analyzed, 48% were obese and 29% were overweight. MPM was found in 164 patients (13%): 46 patients had PST and 118 had ST. The median time for development of PST was 6.9 years prior to breast cancer diagnosis with the most common cancers being endometrial cancer (26%), lymphoma (17%) and melanoma (6%). The median time for the development of ST was 7.6 years after breast cancer diagnosis with the most common cancers being breast cancer (54%), endometrial cancer (13%) and colon cancer (5%) The risk for development of ST increased with length of follow up: 2.3% at 5 years and 10% at 10 years. Patients with ST were more likely to be obese (59%, p=0.03) and to have received radiotherapy (60%, p=0.01) than patients without ST. No differences were observed with race, age at diagnosis, tumor characteristics or breast cancer treatments in patients with MPM. The median overall survival was 5.7 years with no difference in overall survival in patients with MPM (p=0.57). Conclusions: Our study has some limitations typical of retrospective studies and the generalization of the results may be limited. MPM does not affect the overall survival of breast cancer patients and both primary cancers should receive appropriate management with curative intent. We found that obesity at diagnosis of breast cancer is associated with a higher risk of ST. Further studies are needed to define the association of obesity and ST in women with early stage breast cancer. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):A73.

Reply to M.L. Lanthier et al

We appreciate comments by Lanthier et al 1 of the US Food and Drug Administration regarding whether accelerated approval (AA) has expedited approval of new molecular oncology entities. Based on nonpublicly available data, they report median development times of 6.3 years for AA versus 7.2 years for regular approval (RA). However, the US Food and Drug Administration reported to the General Accounting Office 2 that AA resulted in early approval for some cancer drugs “years before the drug would have been available under regular approval procedures” suggesting that the success metric should be years—not months. Ourcontentionisthatdrugsforrarecancershavedifferentchallenges than drugs approved for common cancers. The goals and mechanisms for marketing approval should reflect the particular circumstances. For drugs for common cancers, development times are similar for RA versus AA. The longer biologic licensing agreement development time for AA versus RA (median, 9.2 v 6.7 years) is explainedbyLanthieretalasbeingduetosmallnumbers.However,it is novel biologic agents for rare cancers that are the expected primary beneficiaries of AA. Lanthier et al 1 suggest that sponsors prefer RA versus AA. The reality is that over time, AA appears to be an increasingly difficult hurdle. Before 2003, AA supported 78% of new molecular oncology entities versus 33% since then. Another concern is lack of data transparency at US Food and Drug Administration. Despite extensive searching of public sources, we identified development times for only 75% of new molecular oncology entities. There have been several calls for improved data transparency and completeness including the General Accounting Office’s review of AA and of the US Food and Drug Administration’s nonpublicly available documents, Congressman Ed Markey’s review of the AA program, and a recent policy piece. 2-4 Some of these documents also point out that the US Food and Drug Administration has

Survival analysis approach to insect life table analysis and hypothesis testing: with particular reference to Russian wheat aphid (Diuraphis noxia(Mordvilko)) populations

The goal of this paper is to examine and demonstrate that survival analysis, which has been a de facto standard in biomedical research since the 1990s but has not been widely adopted in entomology yet, should possess similar potential in entomological research. The following three objectives are set to achieve this goal: (i) addressing a fundamental issue - censoring or incomplete observations; (ii) demonstrating the application of survival analysis to analyze insect life tables; and (iii) applying survival analysis for hypothesis testing. The data used to demonstrate the applications is from our laboratory experiments, which recorded the development, survival and reproduction of 1800 Russian wheat aphids (Diuraphis noxia (Mordvilko), RWA) under 25 treatments of temperature and plant-growth stage. With regard to the first two objectives, besides examining the near ubiquitous existence of censoring in insect population research, we constructed and analyzed life tables of 1800 RWA individuals with survival analysis. We further demonstrate that there could be very significant differences in life table parameters, such as median development times with and without considering censoring. To the best of our knowledge, this is the first recognition in entomology that censoring, which is hardly avoidable, can cause significant systematical bias (ranging between 4-25%; table 1) in insect development data analysis. As for the third objective, the study shows that four statistics from survival analysis can be applied to testing the effects of covariates, such as temperature and plant-growth stage, on development and survival of the Russian wheat aphid. The advantages of survival analysis include the handling of censored observations, survival probabilities in the form of rigorous survivor function vs. simple survival rates, dynamic modeling of covariates effects on development and survival with a unified model structure, etc. The methods demonstrated in this article should also be useful for entomological research beyond insect demography, such as bioassay, assessment of natural enemies, the studies of insect behaviors, etc.

English

  This study aimed at evaluating commonly used maize varieties, collected from Melkasa and Bako Agricultural Research Centers and Haramaya University, Ethiopia, against the maize weevil Sitophilus zeamais Motsch., one of the most important cosmopolitan stored product pests in maize. A total of 13 improved maize varieties were screened for their relative susceptibility to S. zeamais. The Dobie index of susceptibility was used to group the varieties. The variety, ‘BHQP-542’, had the least index of susceptibility and was regarded as resistant. The varieties, ‘Katumani’, ‘Melkasa-I’, ‘Melkasa-II’, ‘Melkasa-III’, ‘Coree’, ‘BH-541’, ‘BH-660’, ‘BH-540’, ‘Rare-I’, ‘Awasa-511’, ‘ACV3’ and ‘ACV6’, were moderately resistant. Weevils fed with the resistant variety produced low numbers of F1 progeny, had a high median developmental time and a low percentage of seed damage and seed weight loss. Maize varieties with a high F1 progeny tended to have a short median developmental time. An increasing number of F1 progeny resulted in an increasing seed damage and seed weight loss. We found an inverse relationship between the susceptibility index and percent mortality and median developmental time; however, the numbers of F1 progeny, percent seed damage and seed weight loss were positively related with the susceptibility index. The use of resistant varieties should be promoted in managing S. zeamais in stored maize under subsistence farming conditions in Africa.   Key words: Grain damage, maize; resistant variety, Sitophilus zeamais, susceptibility index.

Accelerated Approval of Cancer Drugs: Improved Access to Therapeutic Breakthroughs or Early Release of Unsafe and Ineffective Drugs?

Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

Acrocalanus gracilis (Copepoda: Calanoida) development and production in the Timor Sea

We investigated the juvenile development of the calanoid copepod Acrocalanus gracilis in the Timor Sea. The development was characterized by the calculation of stage-specific duration, median development time, moulting period duration, moult and growth rates. The morphometry of the experimental and wild populations were compared. Food concentrations in the experiment were lower than those in the field, and resulted in smaller animals than those in the field. Somatic growth (0.44 day21) was log-linear throughout the development, but moulting rates slowed with time. The development of A. gracilis was similar to other paracalanids, and conforms to the equiproportional model. Trophic resources seem to play an important role in controlling the developmental features and morphometry of Acrocalanus in tropical environments.

Metachronous multiple carcinomas arising at a colostomy site 18 years after abdominoperineal resection

Dear Editor: Metachronous multiple carcinomas at the site of stoma is rare condition after surgery. A median of 264 months interval from the initial operation was documented in 35 cases reported. In 1958, the following criteria for multiple carcinomas of the colon were defined by Mortel: (1) malignancy of a lesion, as indicated by histopathological examination; (2) synchronous carcinomas, with normal mucosa existing between the tumors; and (3) for metachronous carcinomas, a tumor, except for a tumor occurring at an anastomosis, which is not suspected of being an invasion, metastasis, or recurrence of another tumor. They reported that multiple carcinomas accounted for 4.3% of all colorectal carcinomas and for 12.9% of colorectal carcinomas and polypoid carcinoma of the colon. In 1996, the Cancer Registry of the Japanese Society for Cancer of the Colon and Rectum reported that multiple carcinomas occurred in 9.7% of patients (synchronous, 4.3%; metachronous, 5.4%). To our knowledge, 45 cases of stoma carcinomas that include both synchronous and metachronous carcinomas have been reported in Japan. Among them, 35 cases (25 men, median=68 years, range=38–88 years), including the present case, fulfilled the above criteria for metachronous multiple carcinomas arising at the site of colostomy. Thirty of the 35 cases underwent abdominoperineal resection for rectal carcinoma. The median time of development from initial operation to second tumor was 264 months (range= 19–504 months). In 24 of the 35 cases (68.6%), the second tumor was discovered more than 10 years after the initial surgery. As for the histology, adenocarcinoma was confirmed in 30 of the 35 cases (85.7%) and mucinous adenocarcinoma in three cases. These proportions were equivalent to common advanced cases in our series. In the present case, the patient did not recognize the possibility of carcinoma occurrence or growth more than 10 years. The fact suggests that most of the patients might not recognize the occurrence of a carcinoma in a stoma. Occurrence of carcinoma in the stoma site is a rare condition, but carcinoma can occur in a stoma. The refined observation of a stoma might be suggested for the ostomate for long period after stoma creation. Int J Colorectal Dis (2009) 24:1481 DOI 10.1007/s00384-009-0752-9

Intensified Case Finding for Tuberculosis in Prevention of Mother-to-Child Transmission Programs: A Simple and Potentially Vital Addition for Maternal and Child Health

The intersection of HIV and tuberculosis (TB) poses a serious threat to HIV-infected women and their children. The majority of patients with TB in sub-Saharan Africa are infected with HIV and together the overlapping epidemics synergistically accelerate illness and death. Escalating case rates increased mortality and the recent emergence of extensively drug-resistant TB highlights how catastrophic a once preventable and curable disease has become among people with HIV/AIDS. The HIV epidemic requires new strategies to control TB in high-burden areas especially as women of reproductive age are disproportionately affected by the epidemic. Intensified case finding for TB has the potential to reduce morbidity and mortality for people living with HIV especially pregnant women their families and infants. (excerpt)

Non-Melanoma Skin Cancer Incidence and Risk Factors After Kidney Transplantation: A Canadian Experience

Non-melanoma skin cancer (NMSC) after kidney transplantation is common and can result in significant morbidity and mortality. Incidence and risk factors for NMSC can vary between geographic locations and there is no literature describing the incidence or risk factors for NMSC in Canada. The purpose of this retrospective cohort study was to determine the incidence of NMSC, the time of development of NMSC, and risk factors (including sun exposure history) for NMSC in kidney transplant recipients between 1990 and 2003 in our center (n=926). We observed a 9.7% incidence of NMSC lesions after kidney transplant with a median time of development of a first NMSC lesion of 4 years. Risk factors for NMSC (multivariate analysis) include older men (>45 years), a history of posttransplant warts, and longer duration of residence in a northern climate. We conclude that NMSC is common after kidney transplantation in a northern climate and these individuals require disease prevention-specific education, more vigilant surveillance and early referral and treatment.

A simplified age-stage model for copepod population dynamics

MEPS Marine Ecology Progress Series Contact the journal Facebook Twitter RSS Mailing List Subscribe to our mailing list via Mailchimp HomeLatest VolumeAbout the JournalEditorsTheme Sections MEPS 360:179-187 (2008) - DOI: https://doi.org/10.3354/meps07314 A simplified age-stage model for copepod population dynamics Qiao Hu*, Cabell S. Davis, Colleen M. Petrik Biology Department, Woods Hole Oceanographic Institution, Woods Hole, Massachusetts 02543, USA *Email: qiao_hu@alum.mit.edu ABSTRACT: Complex 3D biological-physical models are becoming widely used in marine and freshwater ecology. These models are highly valued synthesizing tools because they provide insights into complex dynamics that are difficult to understand using purely empirical methods or theoretical analytical models. Of particular interest has been the incorporation of concentration-based copepod population dynamics into 3D physical transport models. These physical models typically have large numbers of grid points and therefore require a simplified biological model. However, concentration-based copepod models have used a fine resolution age-stage structure to prevent artificially short generation times, known as numerical ‘diffusion.’ This increased resolution has precluded use of age-stage structured copepod models in 3D physical models due to computational constraints. In this paper, we describe a new method, which tracks the mean age of each life stage instead of using age classes within each stage. We then compare this model to previous age-stage structured models. A probability model is developed with the molting rate derived from the mean age of the population and the probability density function (PDF) of molting. The effects of temperature and mortality on copepod population dynamics are also discussed. The mean-age method effectively removes the numerical diffusion problem and reproduces observed median development times (MDTs) without the need for a high-resolution age-stage structure. Thus, it is well-suited for finding solutions of concentration-based zooplankton models in complex biological-physical models. KEY WORDS: Plankton · Copepods · Modeling · Marine ecology · Oceanography · Limnology · Methodology · Mean age Full text in pdf format PreviousNextCite this article as: Hu Q, Davis CS, Petrik CM (2008) A simplified age-stage model for copepod population dynamics. Mar Ecol Prog Ser 360:179-187. https://doi.org/10.3354/meps07314 Export citation RSS - Facebook - Tweet - linkedIn Cited by Published in MEPS Vol. 360. Online publication date: May 22, 2008 Print ISSN: 0171-8630; Online ISSN: 1616-1599 Copyright © 2008 Inter-Research.