Bone Marrow Atlas

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Role of Evidence Based Medicine in Diagnostic Surgical Pathology

Evidence-based medicine (EBM) has been defined as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients” or as “the integration of best research evidence with clinical expertise and patient values”. It is an evolving discipline that applies analytical and quantitative methods to evaluate the validity of available medical information, with the overall goal of identifying scientifically-sound data or “best evidence”. This evidence is integrated to improve medical practice through clinical guidelines and other tools that are used for education, standardization of care, quality initiatives and coverage decisions. The ideas of EBM have spread rapidly through medicine during the past decade and are recently eliciting a growing interest in Anatomic Pathology and Laboratory Medicine.

Basic Concepts of Evidence-Based Medicine

EBM investigators attempt to identify the best current and relevant research information available for a particular problem and to integrate the “evidence” into guidelines, rules or other tools that will assist medical practitioners in their daily practice.
Basic Process for the identification of best evidence and its integration into guidelines, rules or other protocols.

1. Formulate specific questions regarding the diagnosis, prognosis, causation and/or treatment of individual patients with a particular clinical problem
2. Search for specific information in the scientific literature
3. Appraise the internal and external validity of the available evidence, and its impact, applicability and usefulness in daily practice
4. Incorporate “best evidence” from several reliable sources along with personal clinical exexperience into” guidelines, rules or other protocols
5. Evaluate the effectiveness and efficiency of those “Evidence-based” recommendations

Bayesian approach to the analysis of data : influence of the prior probability of findings of interest.

Descriptive statistical tests offer limited information about other features that can influence the outcome of observational studies, such as the prevalence of a disease within the population study and in the control group and the prior probability of a finding. For example, it is well known that lymph node status has a statistically significant prognostic significance in most patients with cancer. However, in patients with Stage IV neoplasms who have a high “prior probability” of dying from their disease, the prognostic value of the feature lymph node status is probably rather limited. These considerations are intuitively used in daily practice by most pathologists, but there are few, if any, available evidence-based guidelines or other protocols that take into consideration the prevalence and prior probability of various findings into the selection and/or interpretation of diagnostic features, immunostains or other ancillary tests in Surgical Pathology. Another consideration that has not been addressed in most observational studies in Pathology is the need to divide the data into “training” or “testing” sets (“study” and “holdout” cases) in research projects attempting to derive classification or prognostic models. Most clinico-pathological categorization has been based on data derived from analyzing 100% of the data from study groups and control groups with descriptive univariate, and less often multivariate statistical methods. However, multiple studies using Bayesian methods have shown that models derived by the use of 100% of a dataset usually have limited external validity as there is a certain element of “circular reasoning” in the modeling methodology.

Evaluating the Quality of Published Studies in the Medical Literature.
Ebell has proposed a system for classifying published medical evidence into 4 levels, with “grade I” being the best (most reliable). Grade I studies are those that include data validated with a “test” group that is from a different and distinct population from the “training” cohort. Grade II studies report data that are obtained from the same population, the members of which are divided into independent “training” and “validation” subsets and evaluated prospectively. Grade III analysis also include “training” and “validation” subsets from the same population, but data are collected contemporaneously rather than prospectively. Grade IV studies are those in which the “training” group is also used as the “validation group”. According to this scheme, most studies in the pathology literature would probably be classified as Grade IV, the most vulnerable to external validity problems.

Integration of “best evidence” from the literature with personal clinical experience into “evidence-based” guidelines, rules or other protocols.

Advocates of EBM have attempted to organize “best evidence” from the scientific literature and their own experience into algorithms, protocols, guidelines or “rules” that guide individual patient care by practitioners. Pathologists may benefit from emulating this approach, in future efforts at constructing “patient-based” prognostic and predictive models. For example, immunostains are most often used to distinguish between various neoplasms in a descriptive manner. Studies using immunostains in the pathology literature usually list the percentage of lesions that label for particular epitopes, as well as the sensitivity, specificity and predictive values of such markers in narrow morphological contexts. However, few studies have assessed these data with meta-analysis or calculated likelihood ratios (LR) or other probabilistic measures as applied to panels of markers in selected differential diagnoses. At an even more basic level, the relative statistical values attending particular morphological findings has seldom been analyzed in the same fashion. In contrast, several prognostic scoring models or “rules” that integrate multivariate pathological, clinical, imaging and other information are being developed by other specialists. For example, Kattan and associates have developed pretreatment nomograms that combine clinical and pathological data from prostate cancer patients and predict 5-year probability of metastasis.

Data collected from surgical pathology specimens can also be integrated with the use of “tools for reasoning with uncertainty” such as rule-based expert systems, multivariate statistics, Bayesian belief networks and neural networks.

Evolving Role of Immunohistochemistry in Surgical Pathology

Immunohistochemistry has far surpassed it’s initial expectation as an invaluable tool in the correct recognition of tumours. It is now being increasingly sought after for prognostication of tumours and as a justification for initiaton of expensive targeted therapy in oncology practice. The wider application of IHC has increased the demands from a surgical pathologist who no longer restricts to giving a correct label but also actively participates in the subsequent clinical decision making process.

However many physicians have this notion that IHC is akin to a biochemical test. The IHC result is considered as representing enough “evidence” to neatly categorise disease entities and resolve messy diagnostic dilemmas. In fact clinicians often demand “IHC confirmation” of surgical pathology reports (even where IHC may not be needed and is unlikely to add any value) and ever so often pathologists who lack access to IHC facilities often end their reports stating “IHC confirmation necessary” (almost as a disclaimer) for every possible lesion.

This situation has risen partly due to the belief (more aptly misbelief ) that the “IHC test” can be translated into “a” particular diagnosis. The “IHC test” is looked upon as a tool to usher in the much needed objectivity in routine surgical pathology practice and this is accompanied with an underlying perception that IHC can make-up for lack of diagnostic skill and experience in the complex task of giving a correct histological diagnosis.

The moot point , therefore, is : “ How good is IHC evidence ?” This issue will be addressed under the following headings :

A. Generation of the IHC result
B. Search engines for information
C. Application of IHC result to resolve frequent diagnostic dilemmas
D. Clinical Decision support from IHC result
E. Data warehousing
F. Quality control in IHC

A. Generation of IHC result : Several factors influence the final IHC result and no two tissue specimens will react in the same way even though they could be representing the same anatomic site and could also be matched for stage and grade. The factors responsible for this variation can be Pre-analytical, Analytical, and Post-analytical.

The pre-analytical factors : Optimal preservation of the antigenic epitope is vital. IHC can be affected by the duration of anoxia at surgery, time gap between resection to fixation, the type of fixative, the duration in the fixative, the size of the tissue, the thickness, and whether freezing was done. Finally, the quality of reagents such as the company, the batch, and the shelf-life of antibodies can affect the kind of result obtained. Of these optimal fixation is of special interest because it is a critical yet manageable step.

The analytical factors : include the various techniques used for antigen retrieval namely heat, Microwaving, Pressure cooking, trypsin digestion, autoclaving with different buffers etc. Proper endogenous peroxidase blocking is vital to prevent background staining. Further, whether an autostainer is being used or the staining is done by hand will influence the end result. The biochemical process involved is important, for example the relatively recent “catalyzed signal amplification” method is considered more sensitive than avidin-biotin or extraavidin methods.

The postanalytical (interpretative) factors : Finally, a very much underrated factor is the actual interpretation of the IHC result by the surgical pathologist. Several large studies have addressed the issue of inter and intra-observer errors .The positive or the negative interpretation has several subtle nuances which only a busy practitioner of IHC will realise. Suffice it to say a combination of several observations such as intensity, quantity and localisation of the IHC reaction and visualization of the immunostain in the lesional cells - as opposed to the immuno reaction seen in normal tissues, reactive tissues and other ‘bystanders’ (often referred to as “background” staining) – are features vital to the the final interpretation. Nevertheless the lack of a prescribed threshold level for interpreting a reaction as positive leaves immense scope for inter and intra observer errors. Finally, whatever the interpretation – it is the integration of the information obtained from the IHC test in the histopathologic picture is what matters most in the final interpretion.

B. Search engines : There is burgeoning literature on new antibodies, and newer application of old antibodies. Sharing of epitopes and significant immunoreactivity as an epiphomena rather than a common trait (eg. bcl2, CD34, c-kit), is well-recognized.
Hence, it is necessary to refer to sites which give information of the possible range of reactivity and some of these are as follows :

http://immunoquery.com, http://immunohypermart.net,
http://www.ncbi.nlm.nih.gov/prow

as also the various journals on Immunohistochemistry.

C. Application of IHC to resolve some diagnostic dilemmas in surgical pathology :
Several vexatious diagnostic dilemmas are well-known in surgical pathology practice.
To mention some of the frequent queries include distinguishing mesothelioma vs adenocarcinoma, the subtype of the malignant round cell tumour and poorly differentiated malignancies, the possible primary in case of metastasis from unknown primary (MCUO), neuroendocrine vs neuroectodermal lesions, and many others. Lineage identification by IHC is particularly helpful in lymphomas, melanomas, astrocytomas and pecomas. Algorithms constructed on the basis of previously demonstrated immunoreactivity on a large number of test cases have proved to be accurate in identifying the primary in 67% of MCUO. The IHC approach to find the possible primary is much more cost-effective as opposed to extensive work-up with radiological studies and various endoscopy procedures.

D. Clinical Decision support : 
Several immunohistological markers which influence tumour behaviour and help tumour prognostication for microstaging, predicting response to therapy, monitoring drug resistance, detecting growth factors and receptors, evaluating tumour angiogenesis etc. have been described in the literature. Most of these have not as yet been incorporated in a routine diagnostic setting. There are other markers such as CD20, C-kit and HER-2/NEU which are increasingly requested to clinically justify targeted therapy. The application of this information for the Indian patients could be guided by the general guidelines for evidence based medicine with the following considerations: a) will the IHC result make a difference in the management or will the patient benefit from the information given by the IHC result; b) what about the cost to the patient and the delay in the report? c) is the treatment feasible in our socioeconomic setting? Generating IHC results which are not going to affect patient management or are not applicable to an individual patient only burden the IHC laboratory with no value added to an individual patient although they make the typed report look more impressive.

E. Importance of data warehousing : 
Unlike blood chemistry results there are no readily available reference ranges for the several IHC antibodies with respect to age, normal tissue, physiological alterations, benign tumours and malignant tumours. In the Indian context IHC is in its infancy and there is a lack of information on Indian co-horts. Geographic variation could influence IHC results such as percentage of ER/PR positivity in breast tumours, ALK1 & CD30 in ALCL, and ALK-1 in B- cell NHL. This highlights the importance of data warehousing to obtain information on Indian patients

F. Quality control / assurance in Immunohistochemistry :
Qualitive assurance is easily applicable to results which are quantifiable and objective. Attempts at quality assurance in IHC comprise establishment of standardized procedures to ensure technical reproducibility, uniformity in interpretation and evaluation and quantification of extent of immunoreaction by the use of a scoring system to bring in objectivity. An interlaboratory trial involving 172 pathologists and 3526 immunostains brought out some unexpected findings. There is a general belief that the staining quality is a major problem in the application of IHC; however a multivariate model in which each step of the diagnostic pathway, beginning with a pre IHC tentative diagnosis, was introduced, revealed that only (i) the correct tentative diagnosis, (ii) the interpretation of the IHC stain and (iii) the conclusions drawn from the IHC stain were independently predictive of the correct final diagnosis. Neither antibody selection nor quality of immunostain correlated independently to the correct final diagnosis. A definitive diagnosis could not be rendered if the morphological tentative diagnosis was incorrect or not included in the differential diagnosis. The results of another large study, evaluating interlaboratory and interobserver agreement for semiquantitative assessment of estrogen receptor (ER) using Tissue array technology wherein 172 laboratories participated, suggested that neither the pH of the formalin buffer or the duration in the fixative greatly influenced the detection of ER. Variability in subsequent IHC practices (such as antigen retrieval) and interpretation of results was a greater source of diagnostic error. The antibody which has been subjected to a lot of scrutiny with respect to overall evaluation of accuracy, specificity, sensitivity and reproducibility is HER 2/neu overexpression to identify the 20%-30% of breast cancer women who could benefit from Herceptin therapy (which is a humanized monoclonal antibody). A comparative study involving results from 94 Laboratories in 21 countries (predominantly European) participating in the National External Quality Assessment scheme for Immunocytochemistry (UK NEQAS-ICC) concluded that the reliability of the Her-2 assay could be greatly improved by stringent quality control and an ongoing quality assurance program using a standard reference obtained from cell lines.

To conclude, standardization in IHC is a daunting task. The multiple variables which affect the final result are not easy to control but standardization of technical steps, and hopefully availability of a reference for most lesions in future (such as in HER-2/neu assays) will bring in uniformity in IHC results regardless of where they are generated.

As of now it will be difficult to find a pathologist who has not, at some point or other, decided to neglect the IHC result.

Application of Molecular Diagnostics in Surgical Pathology

The growing momentum of molecular analysis has enormous promise for diagnostics and numerous research applications. The vast arsenal of newer modalities in the field of molecular pathology available today is bewildering and ever expanding. They provide opportunities to study etiopathogenesis, to aid diagnosis, to prognosticate tumours and to devise targeted therapy.

Molecular diagnostics
Immunohistochemistry helps classify soft tissue and bone tumors, but a proportion of pediatric tumors defy such attempts at classification. Specific translocation based molecular “signatures” of these tumors have the potential to resolve such diagnostic dilemmas.

Ewing sarcoma family of tumors (ESFTs) are being characterized by non-random gene rearrangements between the EWS gene on chromosome 22q12 and various members of the ETS gene family such as FLI1 (chromosome 11), ERG (chromosome 21), ETV1 (chromosome 7), E1AF (chromosome 17) and FEV (chromosome 2). Accurate diagnosis of ESFT is crucial for the most appropriate clinical management of patients. Desmoplastic small round cell tumor is characterized by t(11;22) (p13;q12) resulting in EWS-WT1 fusion. Alveolar rhabdomyosarcoma demonstrates PAX3-FKHR and PAX7-FKHR fusion. t(X;18) (p11;q11) is associated with > 90% of both monophasic and biphasic synovial sarcomas; SYT-SSX1 and SYT-SSX2 fusion transcripts correlate with biphasic and monophasic morphology respectively.

Sensitive technique like RT-PCR has made it possible to evaluate tiny biopsies, archived paraffin blocks and needle aspiration cytology material for the presence of specific translocations and arrive at a definitive diagnosis. The use of Fluorescence in Situ Hybridization, FISH, on interphase nuclei, allows the detection of nucleic acid targets while preserving the morphology of the tissue. Many chromosomal abnormalities such as duplication, deletion or translocation, are diagnosable using FISH. This technique requires less tissue, can be performed on archival tissue, and there is visual control of the tumour. Investigating aneuploidy at chromosomes 3, 7, 17, and 9p21 (e.g. loss at 9p21) using a multitarget FISH performed on urine specimens is a promising approach and useful adjunct to urine cytology and cystoscopy for the non-invasive detection of recurrent urothelial tumours.

Molecular diagnostics, however, are generally viewed as expensive and labor intensive, which means that advances to improve automation, throughput, scalability, and reliability are critical.

Prognostic uses
– The fusion transcript type in the evaluation of ESFT may be prognostically useful with the presence of EWS-FLI1 type1 transcript being associated with improved outcome compared with that in patients with other fusion transcript types.

– Alveolar rhabdomyosarcoma with PAX3-FKHR fusion is associated with poor prognosis as compared to those with PAX7-FKHR translocation.

– SYT/SSX1 variant of synovial sarcoma might be less favorable, associated with higher tumor proliferating rate and reduced overall survival as compared to SYT/SSX2.

– N-myc amplification is a major prognostic factor connoting poor prognosis in neuroblastoma.

– HER-2/neu, ERBB2, a proto-oncogene located on chromosome 17 has become an important prognostic indicator in breast cancer. FISH based assay uses probes for chromosome 17 centromere and HER-2 gene simultaneously, and HER-2 gene amplification is defined as a ratio of HER-2 gene copies per chromosome 17 copy equal to or greater than 2.0. Amplification and /or overexpression of HER-2 occurs in 15% to 25% of human breast cancers and is associated with a poor clinical outcome. Over expression of the HER-2 protein on FISH is closely correlated with amplification of the HER-2 gene in tumours scored immunohistochemically as 3+, but not in tumours scored as 2+. It has been documented in the literature that HER-2 gene amplification determined by FISH is a better predictor of response to trastuzumab-based therapy than HER-2 overexpression determined by immunohistochemical scores of 2+ to 3+. The accurate assessment of HER-2 gene amplification is critical in the management of these tumours.

Diagnosis of Recurrent Disease
Urinary cytology has been the reference test for the evaluation of symptomatic patients, for the detection of lesions in high-risk patients, and for the follow-up of patients with a prior history of urothelial carcinoma. Although routine cytology has a relatively high level of specificity for the detection of high-grade in situ and invasive lesions, the sensitivity for patients with low-grade TCC is low. Urine cytology is further limited by poor specificity for clinically significant lesions in cases that are classified as atypical on the basis of cells with equivocal cytologic features. Therefore, the clinical outcomes for individual cases cannot be accurately determined by cytologic examination alone. As a result, many patients undergo unnecessary procedures to rule out malignancy based on limited specificity for clinically significant lesions. The U.S. Food and Drug Administration (FDA) recently approved the UroVysionTM Bladder Recurrence Cancer Test (Vysis; Downers Grove, IL) for the detection of urothelial carcinoma in urine. The UroVysionTM test has been designed for interphase cell quantification of chromosomes 3, 7, 17, and 9p21 region (p16/CDKN2A gene), which are recognized as frequently involved in numerical anomalies in bladder cancer. Interestingly, the UroVysionTM test also was proven to be effective in detecting tumor recurrence before evidence of urothelial carcinoma was found on biopsy, likely due to the ability of voided urine to represent the entire urothelium versus the regional evaluation of the biopsy. Patients with atypical/suspicious findings on urine cytology and negative FISH may be subjected to longer intervals of cystoscopic surveillance. Thus negative FISH is also considered a valuable negative finding. The assay also holds hope for a group of patients with hematuria and dysuria with negative cystoscopic findings and urine cytologic findings. Patients with positive FISH but negative biopsy should be carefully followed, as they are at risk of harboring occult disease. Anticipatory positive cases (FISH pos/CYSTO neg/HISTO neg) recur at twice the rate and in half the time as true negative cases.

Molecular Therapeutics
The emergence of molecularly targeted therapeutics in oncology has placed increased importance on molecular diagnostic tests in guiding therapeutic intervention.

EGFR Activity in Cancer
The EGFR is a member of a family of four receptors [EGFR (HER1 or ErbB1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4)].

These receptors are large proteins which reside in the cell membrane. When a ligand, for example EGF or TGF-a, binds to the EGFR, it causes receptor dimerisation and autophosphorylation of the internal receptor domain.

This initiates a cascade of cellular reactions that result in increased cell division and influences other aspects of malignant progression of the tumor - angiogenesis, metastasis and an inhibition of apoptosis.
Inhibition of the EGFR thus provides a rational target for anticancer therapy. Currently, two approaches are in clinical development: monoclonal antibodies and small molecule inhibitors of the EGFR tyrosine kinase enzyme.

A monoclonal antibody to HER2/neu (trastuzumab) has proved successful in limiting the growth of tumors and has been licensed for the treatment of advanced breast cancers that overexpress this receptor. The measurement of p185HER-2/neu expression has gained new importance based on the approval of trastuzumab for the treatment of patients with metastatic breast cancer. Treatment with Trastuzumab alone or in combination with chemotherapy is indicated only for patients whose tumours over express p185HER-2/neu or demonstrate HER-2/neu gene amplification based on FISH.

The combination of trastuzumab with cytotoxic chemotherapy is also considered to improve other clinical endpoints, including response duration, time to tumour progression, and overall survival, compared with the chemotherapy-only treatment option.

Recent studies have shown promising results with tyrosine kinase inhibitors of EGFR (ZD1839 and OSI-774) in patients with esophageal and lung carcinomas. In non-small-cell lung carcinomas, ZD1839 (Iressa®; AstraZeneca; London, UK) produced objective responses in about 15%-20% of patients with advanced disease who had failed one or two chemotherapy regimens (at least one platinum based) and in 10% of patients who had failed two or more prior chemotherapy regimens containing platinum and docetaxel, with a favorable adverse event profile. These findings raised considerable excitement regarding the potential role of such therapies for lung cancer patients with less advanced disease and their potential to improve survival.

Genomics
A major leap in functional genomic investigations would be the ability to perform global gene expression analysis with in vivo-derived genetic material originating from morphologically distinct cellular populations that constitute the various stages of cancer progression. The recent advent of high-density DNA microarray technology, with its capacity for simultaneous monitoring of thousands of genes, provides a unique opportunity for high-throughput genetic analysis of tumours.

Proteomics
Molecular diagnostics, however, are generally viewed as expensive and labor intensive, which means that advances to improve automation, throughput, scalability, and reliability are critical.

Prognostic uses
– The fusion transcript type in the evaluation of ESFT may be prognostically useful with the presence of EWS-FLI1 type1 transcript being associated with improved outcome compared with that in patients with other fusion transcript types.

– Alveolar rhabdomyosarcoma with PAX3-FKHR fusion is associated with poor prognosis as compared to those with PAX7-FKHR translocation.

– SYT/SSX1 variant of synovial sarcoma might be less favorable, associated with higher tumor proliferating rate and reduced overall survival as compared to SYT/SSX2.

– N-myc amplification is a major prognostic factor connoting poor prognosis in neuroblastoma.

– HER-2/neu, ERBB2, a proto-oncogene located on chromosome 17 has become an important prognostic indicator in breast cancer. FISH based assay uses probes for chromosome 17 centromere and HER-2 gene simultaneously, and HER-2 gene amplification is defined as a ratio of HER-2 gene copies per chromosome 17 copy equal to or greater than 2.0. Amplification and /or overexpression of HER-2 occurs in 15% to 25% of human breast cancers and is associated with a poor clinical outcome. Over expression of the HER-2 protein on FISH is closely correlated with amplification of the HER-2 gene in tumours scored immunohistochemically as 3+, but not in tumours scored as 2+. It has been documented in the literature that HER-2 gene amplification determined by FISH is a better predictor of response to trastuzumab-based therapy than HER-2 overexpression determined by immunohistochemical scores of 2+ to 3+. The accurate assessment of HER-2 gene amplification is critical in the management of these tumours.

Current status of understanding of the genetic etiology of coronary heart disease Pranavchand R, Reddy B M - J Postgrad Med

Current status of understanding of the genetic etiology of coronary heart disease Pranavchand R, Reddy B M - J Postgrad Med

Urinalysis: A Comprehensive Review

JEFF A. SIMERVILLE, M.D., WILLIAM C. MAXTED, M.D., and JOHN J. PAHIRA, M.D., Georgetown University School of Medicine, Washington, D.C

Am Fam Physician. 2005 Mar 15;71(6):1153-1162.

A complete urinalysis includes physical, chemical, and microscopic examinations. Midstream clean collection is acceptable in most situations, but the specimen should be examined within two hours of collection. Cloudy urine often is a result of precipitated phosphate crystals in alkaline urine, but pyuria also can be the cause. A strong odor may be the result of a concentrated specimen rather than a urinary tract infection. Dipstick urinalysis is convenient, but false-positive and false-negative results can occur. Specific gravity provides a reliable assessment of the patient’s hydration status. Microhematuria has a range of causes, from benign to life threatening. Glomerular, renal, and urologic causes of microhematuria often can be differentiated by other elements of the urinalysis. Although transient proteinuria typically is a benign condition, persistent proteinuria requires further work-up. Uncomplicated urinary tract infections diagnosed by positive leukocyte esterase and nitrite tests can be treated without culture.

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Sacrococcygeal Masses Other Than Meningomyelocele--- Akhilesh Agarwal, Sukanta Das, Dipak Ghosh,and Anshu Agarwal

Abstract

This series comprises of a variety of sacrococcygeal masses other than meningomyelocele that presented to the department of pediatric surgery of Medical College Kolkata over last 10 years. In this series, 23 cases of sacrococcygeal masses are included. Barring meningomyelocele, teratoma constitutes a major group of cases. It also includes few other interesting and atypical masses such as presacral dermoid, degenerated nerve fiber, fibrofatty tissue, rhabdomyosarcoma, etc. This is an endeavor to enlighten ourselves so that the diagnosis and management of unfamiliar sacrococcygeal masses can be done.

Keywords: Sacrococcygeal masses

PMC FREE PAPER

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Circulating nucleic acids in plasma and serum: diagnosis and prognosis in cancer Peter Brian Gahan

Abstract

The presence of DNA and RNA circulating in human plasma and serum is described. The known sources of the DNA/RNA in blood, the ability of these nucleic acids to enter other cells and to express in the recipient cells are considered along with their relationship to metastases. The possible role(s) of the DNA/RNA in personalized clinical diagnosis, monitoring of treatment and prognosis in oncology are discussed.

Keywords: Circulating DNA/RNA, Plasma/serum, Cancer, Diagnosis, Nucleic acid uptake/expression, Personalized medicine

PubMed Link >>HERE<<

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Sputum examination for early detection of lung cancer (REVIEW 2003) F B J M Thunnissen

Abstract

Conventional sputum cytology can be used for the detection of lung cancer, but has shown a low yield in prospective screening trials. This review focuses on the technical aspects relevant to the outcome of DNA and image analysis in sputum. Published articles are discussed in the light of the technical background. Recent developments in DNA analysis and nuclear image analysis show a clear potential to improve or refine diagnosis beyond that achieved with conventional sputum cytology examination. The challenge for future studies in DNA and nuclear analysis of sputum is to ensure high levels of quality control and to confirm these initial encouraging results.

Keywords: Sputum samples, lung cancer, early diagnosis, cytology, molecular markers

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Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review (2007) S. R. Mase, et. al

Abstract:

Current international tuberculosis (TB) guidelines recommend the microscopic examination of three sputum specimens for acid-fast bacilli in the evaluation of persons suspected of having pulmonary TB. We conducted a systematic review of studies that quantified the diagnostic yield of each of three sputum specimens. By searching multiple databases and sources, we identified a total of 37 eligible studies. The incremental yield in smear-positive results (in studies using all smear-positive cases as the denominator) and the increase in sensitivity (in studies that used all culture-positive cases as the denominator) of the third specimen were the main outcomes of interest. Although heterogeneity in study methods and results presented challenges for data synthesis, subgroup analyses suggest that the average incremental yield and/or the increase in sensitivity of examining a third specimen ranged between 2% and 5%. Reducing the recommended number of specimens examined from three to two (particularly to two specimens collected on the same day) could benefit TB control programs, and potentially increase case detection for several reasons. A number of operational research issues need to be addressed. Studies examining the most effective and efficient means to utilize current technologies for microscopic examination of sputum would be most useful if they followed an internationally coordinated and standardized approach, both to strengthen the country-specific evidence base and to permit comparison among studies.

Keywords: tuberculosis; smear microscopy; incremental yield; acid-fast bacillus; serial sputum specimens

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Guidelines on diagnosis and management of malignant lymphoma 2008

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Concise Review: Cord Blood Banking, Transplantation and Induced Pluripotent Stem Cell: Success and Opportunities

Rao M, Ahrlund-Richter L, Kaufman DS.

Source

National Center for Regenerative Medicine, NIH, Bethesda, Maryland, USA. mahendra.rao@nih.gov

Abstract

Hematopoietic cell transplantation (HCT) has become a standard practice to treat a number of malignant and nonmalignant hematologic diseases. Bone marrow, mobilized peripheral blood, and umbilical cord blood can all serve as primary sources of cells for HCT. The number of cord blood units currently stored is large, although it represents only a fraction of potential collections. With much of the collection being sequestered in private banks for possible autologous use, there is a reason to expect that public banks may not be able to provide for the demand in coming years as use of cord blood for treatment of patients with diseases such as leukemia and lymphoma continues to increase. We suggest that a possible solution to encourage private banks to share their valuable units is to apply recent methodologies to generate induced pluripotent stem cells from cord cells and to optimize techniques to generate hematopoietic lineages from them. This strategy would allow us to take advantage of the units already collected under appropriate regulatory guidelines, to access a pristine cell that can be converted to a pluripotent cell at a much higher efficiency and in a shorter time period than other cells. The ability to potentially replenish a used cord unit with new cells, as well as extend the potential utility of cord blood for additional therapeutic applications, should allow banks to develop an appropriate business model for both private and public cord blood banks to flourish.

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Semen analysis and Sperm function Testing -- Review

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Premalignant lesions of the lower female genital tract: cervix, vagina and vulva McCluggage, W. Glenn Pathology . 45(3):214–228, April 2013. doi: 10.1097/PAT.0b013e32835f21b1

Abstract

Summary: Premalignant lesions of the lower female genital tract encompassing the cervix, vagina and vulva are variably common and many, but by no means all, are related to infection by human papillomavirus (HPV). In this review, pathological aspects of the various premalignant lesions are discussed, mainly concentrating on new developments. The value of ancillary studies, mainly immunohistochemical, is discussed at the appropriate points. In the cervix, the terminology and morphological features of premalignant glandular lesions is covered, as is the distinction between adenocarcinoma in situ (AIS) and early invasive adenocarcinoma, which may be very problematic. A spectrum of benign, premalignant and malignant cervical glandular lesions exhibiting gastric differentiation is emerging with lobular endocervical glandular hyperplasia (LEGH), including so-called atypical LEGH, representing a possible precursor of non HPV-related cervical adenocarcinomas exhibiting gastric differentiation; these include the cytologically bland adenoma malignum and the morphologically malignant gastric type adenocarcinoma. Stratified mucin producing intraepithelial lesion (SMILE) is a premalignant cervical lesion with morphological overlap between cervical intraepithelial neoplasia (CIN) and AIS and which is variably regarded as a form of reserve cell dysplasia or stratified AIS. It is now firmly established that there are two distinct types of vulval intraepithelial neoplasia (VIN) with a different pathogenesis, molecular events, morphological features and risk of progression to squamous carcinoma. These comprise a more common HPV-related usual type VIN (also referred to as classic, undifferentiated, basaloid, warty, Bowenoid type) and a more uncommon differentiated (simplex) type which is non-HPV related and which is sometimes associated with lichen sclerosus. The former has a relatively low risk of progression to HPV-related vulval squamous carcinoma and the latter a high risk of progression to non-HPV related vulval squamous carcinoma. Various aspects of vulval Paget's disease are also discussed.

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CNS Tumors : DD based on site, age, cytological features

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Salt in Health and Disease — A Delicate Balance — NEJM

Salt in Health and Disease — A Delicate Balance — NEJM

Application of Immunohistochemistry to the Genitourinary System (Prostate, Urinary Bladder, Testis, and Kidney)

http://rpatologiahfmp.org/descargas/articulos/ApImmunohistochemistryGenitourinarySystem.pdf