This paper examines how knowledge created by firm experience (learning economies) and scale and scope economies affect performance in firms' development activities. The empirical results suggest that ...each factor has a significant effect on development performance. Moreover, knowledge that results from greater experience within a particular technological area, when combined with knowledge spillovers from greater scope in other technological areas, significantly improves development performance. The results suggest that experience shapes and facilitates firms' abilities to absorb knowledge spillovers. Our empirical findings thus provide a more nuanced examination of the drivers of performance and have implications for the management of firms' development activities.
In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points ...of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.
Objective
Fine needle aspiration (FNA) is widely used in the diagnosis of metastatic melanoma, both at initial presentation and in the setting of recurrent disease. The purpose of this study was to ...evaluate the performance of confirmatory immunohistochemistry (IHC) and molecular analysis of the BRAF mutation in cytological preparations of metastatic melanoma.
Methods
A 2‐year retrospective review of pathology reports was performed on cytological samples of metastatic melanoma at the University Health Network (Toronto, Canada) and the Santa Casa Medical School (Sao Paulo, Brazil). IHC was performed on cell block sections prepared from formalin‐fixed, fresh samples or residuum of CytoLyt/PreservCyt post‐fixed in formalin. BRAF V600E/K mutations were assessed by amplification refractory mutation system (ARMS) analysis.
Results
A total of 104 samples (94 FNAs and 10 fluids) from 83 patients (20 women, 63 men) were included. IHC was attempted in 43 cases (41.3%) and successful in 41 (95.3%). The panel number of antibodies ranged from 1 to 15 (median 3). The most frequently used melanoma markers included HMB‐45, melanoma cocktail and S100 protein, used in 25 (58.1%), 23 (53.5%) and 18 samples (41.9%). Thirty cases (69.8%) used three or fewer markers. The BRAF V600E/K mutation was tested in eight samples, being successful in seven (87.5%) and positive in three (37.5%).
Conclusions
Cytological samples are a reliable and sufficient source for IHC and subsequent molecular analysis, allowing a reduced diagnostic time and rapid, appropriate treatment options in patients with advanced melanoma.
The present study evaluated the performance of IHC and BRAF mutation analysis applied on cytological preparations of metastatic melanomas and the findings endorse the use of cytology for a rapid and complete diagnostic workup of metastatic melanomas.
To date, the primary objective of phase I trials has been to safely select the maximum tolerated dose (MTD) of a drug or drug combination for utilization in subsequent trials. Although conventional ...cytotoxic chemotherapy is generally more effective at the MTD than molecularly targeted agents (MTAs), recent single-institution data suggest that molecularly targeted agent may not require an MTD for efficacy. We analyzed patient outcome results in MTA phase I trials at multiple institutions throughout North America sponsored by the National Cancer Institute's Cancer Therapy Evaluation Program.
We retrospectively collected and analyzed data on patients treated on monotherapy phase I trials investigating novel MTAs with a defined MTD from 2000 to 2009. Logistic regression analysis was used to test whether there was an increase in the probability of a response as dose increased. A Cox proportional hazards model was used to determine if overall survival increased with increasing dose. All statistical tests were two-sided.
We analyzed 1908 patients treated on 55 eligible clinical trials. The probability of both overall response (complete response plus partial response) and overall survival increased with increasing dose (odds ratio for increased response = 1.56, P = .10; hazard ratio for death = 0.37, P = .008) when controlling for study as a covariate.
Patients treated in the context of phase I trials with MTAs continue to derive reasonable clinical benefit. Contrary to other single institution data, our data suggest clinical benefit in terms of increasing response and overall survival with increasing dose.
Cutaneous metastases from thyroid carcinoma are rare. This report describes four cases of thyroid carcinoma metastatic to the skin. Two cases were medullary carcinoma and two were papillary thyroid ...carcinoma. In two cases, skin metastases were the presenting feature of the underlying thyroid carcinoma. Examination of the skin lesions by conventional light microscopy suggested the possibility of metastatic carcinoma and immunohistochemical tests confirmed the diagnosis. Subsequent investigations identified primary thyroid lesions. In two cases, the skin metastasis was the first evidence of the recurrence of known thyroid carcinoma. These cases identify a novel presentation of thyroid carcinoma.
Objective
Detection of Epstein–Barr virus (EBV) status might help in the diagnosis of EBV‐related neoplasms. The rate of successful assays for the detection of EBV‐infected cells in cytological ...preparations has not been fully explored. Our aims were to examine the rate of successful in situ hybridization (ISH) assays for EBV‐encoded RNA (EBER) in cytological specimens and to explore reasons for failure.
Methods
An electronic search selected cases with ISH‐EBER assays performed on cytological preparations during a 10‐year period. Data regarding patient age, gender and immune status, sample type and site, type of preparation, ISH‐EBER results, immunophenotyping and immunohistochemistry results, final diagnosis and correspondent histopathological samples were retrieved.
Results
Sixty specimens from 58 patients with diagnoses of lymphoproliferative disorder (n = 35), carcinoma (n = 24) and sarcoma (n = 1) were identified. ISH‐EBER assays were performed on 50 cell block sections and on 10 cytospin preparations, with 22 positive and 32 negative results. Six tests (four cytospins and two cell block sections) failed owing to loss of material during the assay and background staining, with an overall failure rate of 10% and 4% if cytospins were excluded. Assays were performed on 13 cytology and surgical specimens from the same site, with only one discrepant result.
Conclusions
Cell block sections had more successful ISH‐EBER assays when compared with cytospins. Reasons for failure were loss of material on the slide and background staining. A high concordance rate with surgical specimens emphasizes the usefulness of cytological samples for determining EBV status in patients with exhausted or no histological material available.
Objective
To review cytomorphological criteria and clinicopathological findings in combination with ancillary tests for the specific diagnosis of pulmonary marginal zone lymphoma (MZL) in fine needle ...aspiration (FNA) specimens.
Methods
Cases of pulmonary MZL diagnosed using cytological specimens from 2005 to 2012 were retrieved and reviewed by three cytopathologists. Results of immunophenotypic analysis, interphase fluorescence in situ hybridization (FISH) and molecular assays were collated, together with clinical information and imaging data. Concurrent surgical biopsies were also retrieved.
Results
Fifteen lung FNA specimens were identified. The smears consisted predominantly of small centrocyte‐like cells. Marked plasma cell differentiation was evident in 11 cases. All cases with slides available showed tissue fragments with lymphoid tangles (TFLTs). Multinucleated giant cells were present in nine cases, two of which showed granulomas. Immunophenotyping confirmed B‐cell clonality in all cases. B‐cell clonality was detected by polymerase chain reaction (PCR) in two samples. FISH identified MALT1 translocation in four of 10 cases tested and trisomy 3 in three of four cases. Concurrent surgical biopsies were diagnosed independently as MZL in seven cases.
Conclusions
Cytology smears from lung FNA samples consisting of small lymphoid cells with a relative abundance of plasma cells or plasmacytoid cells and large TFLTs should prompt immunophenotyping and other ancillary studies, even if multinucleated giant cells and poorly formed granulomas are also identified. Specific diagnosis of pulmonary MZL in FNA samples can be rendered on the basis of morphological features coupled with the demonstration of B‐cell clonality by immunophenotyping or PCR and cytogenetic abnormalities by FISH.
Fine-needle aspiration (FNA) is a procedure that is increasingly being performed. Artefacts occurring after FNA are reported to complicate the histological analysis of the tissue, mainly in the ...thyroid; WHAFFT (worrisome histologic alterations following FNA of thyroid) is well documented in the literature. The case of a male patient with hypercalcaemia who was subsequently found to have a nodule in the thyroid gland is reported here. He underwent FNA, followed by a total thyroidectomy and parathyroidectomy. The abnormality in the parathyroid gland showed worrisome histological changes that were suspicious of a malignant lesion, resembling the changes seen in the thyroid gland after FNA. Parathyroid cells were identified by a review of the previous FNA. The concept of WHAFFT, which can mimic the features of malignancy in the parathyroid gland, is therefore introduced.
Because the activities of HER family members are elevated and/or aberrant in a variety of human neoplasms, these cell surface receptors are receiving increasing attention as potential therapeutic ...targets. In the present study, we examined the effect of combining the HER family tyrosine kinase inhibitor CI1033 (PD 183805) with the topoisomerase (topo) I poison 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, in a number of different cell lines. Colony-forming assays revealed that the antiproliferative effects of simultaneous treatment with CI1033 and SN-38 were synergistic in T98G glioblastoma cells and HCT8 colorectal carcinoma cells, whereas sequential treatments were additive at best. In additional studies examining the mechanistic basis for these findings in T98G cells, immunoblotting revealed that the inhibitory effects of CI1033 on epidermal growth factor receptor autophosphorylation were unaffected by SN-38. Likewise, CI1033 had no effect on topo I polypeptide levels, localization, or activity. Nonetheless, CI1033 markedly enhanced the number of covalent topo I-DNA complexes stabilized by SN-38 or the related agent topotecan (TPT). Analysis of intracellular SN-38 levels by high-performance liquid chromatography and intracellular TPT levels by flow microfluorometry revealed that CI1033 increased the steady-state accumulation of SN-38 and TPT by 9.4 +/- 1.9- and 1.8 +/- 0.2-fold, respectively. Further evaluation revealed that the initial rate of TPT uptake was unaffected by CI1033, whereas the rate of efflux was markedly diminished. Additional studies demonstrated that T98G and HCT8 cells express the breast cancer resistance protein (BCRP), a recently cloned ATP binding cassette transporter. Moreover, CI1033 enhanced the uptake and cytotoxicity of SN-38 and TPT in cells transfected with BCRP but not empty vector. Conversely, CI1033 accumulation was diminished in cells expressing BCRP, suggesting that CI1033 is a substrate for this efflux pump. These results indicate that CI1033 can modulate the accumulation and subsequent cytotoxicity of two widely used topo I poisons in cells that have no history of previous exposure to these agents.
Hyalinizing trabecular tumors of the thyroid are interesting but uncommon neoplasms. They have been classified as benign hyalinizing trabecular adenomas or malignant hyalinizing trabecular ...carcinomas. They share both epidemiologic and morphologic features with papillary carcinoma, and there has been much speculation about the relationship between these two entities. Because RET/PTC gene rearrangements are specific to papillary thyroid carcinoma, the authors examined the presence of RET/PTC-1, -2, and -3 in eight hyalinizing trabecular tumors using reverse transcription-polymerase chain reaction with Southern hybridization and immunohistochemistry. They detected the presence of a RET/PTC gene rearrangement in six of the eight hyalinizing trabecular tumors. This confirms the long-standing suspicion that hyalinizing trabecular tumors do indeed represent a morphologic variant of papillary carcinoma.
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