Marek Kimmel

Alveolar soft-part sarcoma. A clinico-pathologic study of half a century

In the period from 1923 to 1986 our pathologists examined pathologic material from 102 patients with alveolar soft‐part sarcoma (ASPS). Followup clinical data is available for 91. Median followup is 7 years (range 1 month to 27 years). Local recurrence was only found if residual disease was left at the time of the original excision. Survival in those patients who presented without metastases was 77% at 2 years, 60% at 5 years, 38% at 10 years and 15% at 20 years (median 6 years). No survival advantage could be demonstrated for patients who received chemo and/or radiotherapy, although numbers are small and staging not uniform. An evaluation by electron microscopy and immunohistochemistry cannot confirm recent claims that ASPS is a muscle tumor. ASPS is an unusual neoplasm; the primary therapeutic option is aggressive surgical excision. Survival even with the development of metastases can be long.

simuPOP: a forward-time population genetics simulation environment

SUMMARY simuPOP is a forward-time population genetics simulation environment. The core of simuPOP is a scripting language (Python) that provides a large number of objects and functions to manipulate populations, and a mechanism to evolve populations forward in time. Using this R/Splus-like environment, users can create, manipulate and evolve populations interactively, or write a script and run it as a batch file. Owing to its flexible and extensible design, simuPOP can simulate large and complex evolutionary processes with ease. At a more user-friendly level, simuPOP provides an increasing number of built-in scripts that perform simulations ranging from implementation of basic population genetics models to generating datasets under complex evolutionary scenarios. AVAILABILITY simuPOP is freely available at http://simupop.sourceforge.net, distributed under GPL license.

The sensitivity of bladder wash flow cytometry, bladder wash cytology, and voided cytology in the detection of bladder carcinoma

The sensitivity of voided urinary cytology (VUC), bladder wash cytology (BWC), and bladder wash flow cytometry (BWFCM) in detecting cancer was studied in 70 patients with biopsy‐proven bladder tumors. There were 11 Grade I papillomas, 14 Grade II TA, 18 Grade II‐III TIS, 19 Grade II‐III T1, and eight Grade II‐III T2 carcinomas. One to five VUCs per patient (mean, 2.63) were obtained within the 24 hours preceding biopsy. At endoscopy a bladder wash specimen was obtained and divided for cytologic and flow cytometric examinations. For all tumor categories combined, the sensitivity for one, two, and three voided cytology examinations per patient was 41%, 41%, and 60%, respectively. The sensitivity of a single BWC was 61%, of a single BWFCM, 83%. Thus, one BWFCM is more sensitive than three VUC (binomial test; P = 0.006); one BWC is more sensitive than two VUC (P = 0.01); and one BWFCM is more sensitive than one BWC (P = 0.003). These findings remain significant when papillomas are excluded from the analysis (P ≤ 0.03) and when papillomas and T2 tumors are jointly excluded (P ≤ 0.02). Only four of 70 patients (6%) had their cancers detected by VUC and/or BWC rather than BWFCM. In summary, irrigation cytology specimens are more sensitive than voided urinary cytology, and bladder wash flow cytometry is more sensitive than either in diagnosing bladder cancer. Flow cytometry is more sensitive because of the better sampling of bladder irrigation compared with voided urine and because of the measurement technique itself.

Mammary angiosarcoma: the prognostic significance of tumor differentiation

Mammary angiosarcoma appears to be a heterogeneous group of neoplasms morphologically, in which growth pattern or grade is an important prognostic factor. In this report, 63 patients whose slides were seen in consultation and/or who were treated at Memorial Sloan‐Kettering Cancer Center (MSKCC) are described. Included are 32 MSKCC patients from an earlier study (with additional follow‐up for 15 who are alive) and 31 new cases. Twenty‐five (40%) patients had low‐grade (Type I) lesions (including the only man in the series), 12 (19%) patients had intermediate‐grade (Type II) tumors, and 26 (41%) patients had high‐grade (Type III) angiosarcomas. Because prognosis is significantly related to the type of angiosarcoma, the lesion should be thoroughly studied microscopically to establish tumor type. Estimated probabilities of disease‐free survival 5 years after initial treatment were as follows: Type I: 76%; Type II: 70%; and Type III: 15%. The median length of disease‐free survival also was related to tumor type (Type I: >15 years; Type II: >12 years; and Type III: 15 months). Pretreatment duration of the lesion and primary tumor size were not significantly related to the risk of recurrence or to survival. Total mastectomy is recommended for most mammary angiosarcomas. Adjuvant chemotherapy was used in 31 of 63 (49%) patients and, in this group, recurrences developed in 14 (45%) patients. Among 32 (51%) patients not treated with adjuvant chemotherapy, 18 (56%) had recurrences. Whereas the few long‐term survivors with Type III tumors received adjuvant chemotherapy, recurrences developed in most patients with comparable lesions who were given this treatment. Because Type III angiosarcoma has a poor prognosis, such treatment may be appropriate for these patients. We were unable to demonstrate that adjuvant chemotherapy significantly improved prognosis for patients with Type I and Type II tumors, although recurrences tended to be less frequent among treated patients.

Prediction of missense mutation functionality depends on both the algorithm and sequence alignment employed

Multiple algorithms are used to predict the impact of missense mutations on protein structure and function using algorithm‐generated sequence alignments or manually curated alignments. We compared the accuracy with native alignment of SIFT, Align‐GVGD, PolyPhen‐2, and Xvar when generating functionality predictions of well‐characterized missense mutations (n = 267) within the BRCA1, MSH2, MLH1, and TP53 genes. We also evaluated the impact of the alignment employed on predictions from these algorithms (except Xvar) when supplied the same four alignments including alignments automatically generated by (1) SIFT, (2) Polyphen‐2, (3) Uniprot, and (4) a manually curated alignment tuned for Align‐GVGD. Alignments differ in sequence composition and evolutionary depth. Data‐based receiver operating characteristic curves employing the native alignment for each algorithm result in area under the curve of 78–79% for all four algorithms. Predictions from the PolyPhen‐2 algorithm were least dependent on the alignment employed. In contrast, Align‐GVGD predicts all variants neutral when provided alignments with a large number of sequences. Of note, algorithms make different predictions of variants even when provided the same alignment and do not necessarily perform best using their own alignment. Thus, researchers should consider optimizing both the algorithm and sequence alignment employed in missense prediction. Hum Mutat 32:1–8, 2011.

Impact of Reduced Tobacco Smoking on Lung Cancer Mortality in the United States During 1975–2000

Background Considerable effort has been expended on tobacco control strategies in the United States since the mid-1950s. However, we have little quantitative information on how changes in smoking behaviors have impacted lung cancer mortality. We quantified the cumulative impact of changes in smoking behaviors that started in the mid-1950s on lung cancer mortality in the United States over the period 1975–2000. Methods A consortium of six groups of investigators used common inputs consisting of simulated cohort-wise smoking histories for the birth cohorts of 1890 through 1970 and independent models to estimate the number of US lung cancer deaths averted during 1975–2000 as a result of changes in smoking behavior that began in the mid-1950s. We also estimated the number of deaths that could have been averted had tobacco control been completely effective in eliminating smoking after the Surgeon General’s first report on Smoking and Health in 1964. Results Approximately 795 851 US lung cancer deaths were averted during the period 1975–2000: 552 574 among men and 243 277 among women. In the year 2000 alone, approximately 70 218 lung cancer deaths were averted: 44 135 among men and 26 083 among women. However, these numbers are estimated to represent approximately 32% of lung cancer deaths that could have potentially been averted during the period 1975–2000, 38% of the lung cancer deaths that could have been averted in 1991–2000, and 44% of lung cancer deaths that could have been averted in 2000. Conclusions Our results reflect the cumulative impact of changes in smoking behavior since the 1950s. Despite a large impact of changing smoking behaviors on lung cancer deaths, lung cancer remains a major public health problem. Continued efforts at tobacco control are critical to further reduce the burden of this disease.

Screening for lung cancer: The Mayo lung project revisited

Background. The Mayo Lung Project (MLP) reported lung cancer incidence and mortality in a population offered chest radiographs and sputum cytologic screening examinations every 4 months and a population offered only the Mayo Clinic advice to undergo annual examination. No mortality benefit attributable to screening was observed after 6 years of observation and at least 1 year of follow‐up.

The sensitivity of flow cytometry compared with conventional cytology in the detection of superficial bladder carcinoma

Three groups of patients with superficial bladder carcinoma were studied: 110 patients had carcinoma in situ (TIS), 54 had noninvasive papillary transitional cell carcinoma (TA), and 64 had transitional cell carcinoma infiltrating the lamina propria (T1). One to six conventional cytologic examinations per patient (mean 2.8) were obtained during the 24 hour period before biopsy. For all tumor categories combined, the sensitivity was 49%, 54%, 62%, and 66% for one, two, three, and four cytologic examinations per patient, respectively. Cytologic sensitivity varied according to tumor category; it was greater in the TIS and T1 categories than in the TA category.

Optimal control problems arising in cell‐cycle‐specific cancer chemotherapy

We explore mathematical properties of models of cancer chemotherapy including cell‐cycle dependence. Using the mathematical methods of control theory, we demonstrate two assertions of interest for the biomedical community: 1 Periodic chemotherapy protocols are close to the optimum for a wide class of models and have additional favourable properties. 2 Two possible approaches, (a) to minimize the final count of malignant cells and the cumulative effect of the drug on normal cells, or (b) to maximize the final count of normal cells and the cumulative effect of the drug on malignant cells, lead to similar principles of optimization.

Prediction of enzyme function based on 3D templates of evolutionarily important amino acids

BackgroundStructural genomics projects such as the Protein Structure Initiative (PSI) yield many new structures, but often these have no known molecular functions. One approach to recover this information is to use 3D templates – structure-function motifs that consist of a few functionally critical amino acids and may suggest functional similarity when geometrically matched to other structures. Since experimentally determined functional sites are not common enough to define 3D templates on a large scale, this work tests a computational strategy to select relevant residues for 3D templates.ResultsBased on evolutionary information and heuristics, an Evolutionary Trace Annotation (ETA) pipeline built templates for 98 enzymes, half taken from the PSI, and sought matches in a non-redundant structure database. On average each template matched 2.7 distinct proteins, of which 2.0 share the first three Enzyme Commission digits as the templates enzyme of origin. In many cases (61%) a single most likely function could be predicted as the annotation with the most matches, and in these cases such a plurality vote identified the correct function with 87% accuracy. ETA was also found to be complementary to sequence homology-based annotations. When matches are required to both geometrically match the 3D template and to be sequence homologs found by BLAST or PSI-BLAST, the annotation accuracy is greater than either method alone, especially in the region of lower sequence identity where homology-based annotations are least reliable.ConclusionThese data suggest that knowledge of evolutionarily important residues improves functional annotation among distant enzyme homologs. Since, unlike other 3D template approaches, the ETA method bypasses the need for experimental knowledge of the catalytic mechanism, it should prove a useful, large scale, and general adjunct to combine with other methods to decipher protein function in the structural proteome.