Reversibility of cirrhosis in chronic hepatitis B

Malekzadeh R, Mohamadnejad M, Rakhshani N et al

Hepatic fibrosis and cirrhosis are the consequences of many types of chronic liver disease, and, at its final stage when liver nodule and scarring develop, they are generally considered to be irreversible.

Methods: Here authors describe 3 patients with chronic hepatitis B with clinical, biochemical, and histologic evidence of cirrhosis. They underwent treatment with interferon-or lamivudine and had follow-up liver biopsy while in clinical, biochemical, and virologic remission. Biopsy specimens were randomly coded in unpaired manner according to patient, and they were read independently by 2 pathologists using the modified hepatitis activity index (with a maximum stage of 6). The mean interval between biopsies was 5.5 years.

Results: The mean ALT level decreased from 113.7 to 28.3 U/L. The mean bilirubin level decreased from 2.4 to 0.9 mg/dL, and the mean prothrombin time decreased from 16.3 to 12.3 seconds. The mean Child-Pugh score decreased from 8 to 5. The mean fibrosis score decreased from 5.8 to 0.5 (P = 0.004), and the mean grading score decreased from 10.8 to 3.2 (P = 0.017).

Conclusions: Cirrhosis due to chronic hepatitis B might be reversible in some patients who respond to antiviral therapy.

Clinical Gastroenterology and Hepatology, April 2004, Volume 2, Number 4

Pathophysiology, clinical consequences, and treatment of tumor lysis syndrome

Davidson MB,, Thakkar S , John K., Bhandarkar ND et al

Tumor lysis syndrome is an oncologic emergency that is characterized by severe electrolyte abnormalities and, frequently, by acute renal failure. The syndrome typically occurs in patients with lymphoproliferative malignancies, most often after initiation of treatment. The pathophysiology involves massive tumor cell lysis resulting in the release of large amounts of potassium, phosphate, and uric acid. Deposition of uric acid and calcium phosphate crystals in the renal tubules may lead to acute renal failure, which is often exacerbated by concomitant intravascular volume depletion. The kidney normally excretes these products, and consequently preexisting renal failure exacerbates the metabolic derangements of tumor lysis syndrome. Standard treatment aims to clear high plasma levels of potassium, uric acid, and phosphorus; correct acidosis; and prevent acute renal failure by way of aggressive intravenous hydration; lowering serum potassium levels; use of allopurinol; urinary alkalinization; or renal replacement therapy (if necessary). Allopurinol is the standard of care for treating hyperuricemia of malignancy, but is associated with drawbacks. Recombinant urate oxidase (rasburicase), which recently became available in the United States, provides a safe and effective alternative to allopurinol for lowering uric acid levels and preventing uric acid nephropathy.

The American Journal of Medicine, 116: 546-554, 2004

CYTOPATHOLOGY

Fine Needle Aspiration Biopsy of Soft Tissue Sarcomas: Utility and Diagnostic Challenges

(Review Article)

Singh, Harsharan K; Kilpatrick, Scott E; Silverman, Jan F.

The role of fine needle aspiration biopsy (FNAB) as the primary modality for the initial diagnosis of previously undiagnosed soft tissue sarcomas presents several important challenges. Most practicing pathologists are inexperienced with the wide array of soft tissue neoplasms and their morphologic heterogeneity, making them susceptible to misdiagnosis. However, in the hands of experienced cytopathologists, FNAB in conjunction with ancillary techniques has a diagnostic accuracy approaching 95% for the diagnosis of malignancy. FNAB has been shown to have a diagnostic yield nearly identical with core needle biopsy while avoiding significant clinical complications. Nevertheless, FNAB has certain limitations related to the accurate histologic grading and subtyping of certain subgroups of sarcomas. It may also be difficult to accurately distinguish between low-grade sarcomas and benign or borderline cellular lesions, especially in the spindle cell sarcoma subgroup. The aim of this review is to highlight the utility and limitations of FNAB in the primary diagnosis of soft tissue sarcomas, highlight diagnostically challenging lesions, and comment on the limitations of FNAB in providing a definitive diagnosis.

Soft tissue sarcomas are a heterogeneous group of uncommon neoplasms.. In children as compared with adults, the incidence of soft tissue sarcomas is higher as an overall percentage of childhood neoplasms.1 Fine needle aspiration biopsy (FNAB) has become an important and widely used diagnostic procedure for the evaluation and documentation of local recurrences, as well as metastases from previously diagnosed soft tissue sarcomas and for diagnosing benign nonneoplastic lesions and metastatic carcinomas in soft tissue. But its role as the primary modality for the initial diagnosis of soft tissue sarcomas is not as widely accepted by all clinicians and pathologists. In childhood sarcomas, FNAB is even more underutilized because many of these patients are eligible for enrollment only in histogenetic-specific treatment protocols [ie, Pediatric Oncology Group (POG)], which require accurate histologic subtyping. The two major factors contributing to the lack of widespread usage of FNAB as the diagnostic procedure of choice have been the inexperience of cytopathologists with the wide spectrum of soft tissue neoplasms, coupled with overlapping morphologic appearances of reactive and neoplastic lesions, making them susceptible to misdiagnosis.

Moreover, interpreting soft tissue FNAB material requires considerable expertise, and a diagnosis of malignancy may result in debilitating surgery (ie, limb amputation), causing pathologists to potentially be hesitant in rendering a definitive diagnosis. However, in the hands of experienced cytopathologists, FNAB in conjunction with ancillary techniques (immunohistochemistry, cytogenetics, flow cytometry, and/ or electron microscopy) can afford a diagnostic sensitivity and specificity approaching 95% for the diagnosis of a malignancy and reported false-positive and false-negative rates ranging from less than 1% to 4% for adequate specimens. The selection of a biopsy technique should take into account whether it can reliably provide pertinent diagnostic and prognostic information on which therapeutic decisions can be based while avoiding complications such as disruption of the tumor bed.

In this regard, FNAB compares favorably with core needle biopsy having roughly the same diagnostic accuracy in separating benign from malignant soft tissue lesions. Several studies have shown that diagnostic FNAB had an identical yield to core needle biopsy, and when both were performed, the information from the needle core did not contribute to further patient management.

In a large study of FNAB of primary bone and soft tissue sarcomas from 140 patients, of which 91 patients had FNAB of previously undiagnosed soft tissue sarcomas, Kilpatrick and colleagues showed no complications resulting from the FNAB procedure and no recurrences in the FNAB needle track. In this study, no false-positive diagnoses were made (benign tumor diagnosed as malignant cytologically), and there was only one true false-negative case (malignant tumor diagnosed as cytologically benign), which had no adverse consequences for the patient. It must be emphasized that in the cited studies, an experienced cytopathologist was available on site for immediate interpretation and for determining the need for additional material for ancillary studies (more FNAB passes for cell block preparation, immunohistochemical staining, cytogenetics, flow cytometry, and electron microscopy). It is our opinion that if an on-site cytopathologist experienced at evaluating soft tissue lesions is not available, then the advantages and diagnostic accuracy of FNAB can be compromised, and tissue biopsy may be better to insure that adequate material would be available for ancillary studies. Alternatively, the patient can be referred to an institution where all diagnostic modalities and options are available.

Histologic grading of soft tissue sarcomas is important for management and prognosis. Recent studies have shown that histologic grade is valuable in predicting metastases. Except for pediatric small round cell tumors, therapy is based mainly on anatomic location and stage, the latter incorporating histologic grade. Of the several reported grading systems, the National Cancer Institute (NCI) system as proposed by Costa and later modified by Guillou and the Fdration Nationale des Centers de Lutte Contr le Cancer (FNCLCC) system are the most widely used and reproducible systems in the United States and Europe. For pediatric small round cell tumors, the POG system proposed by Parham and colleagues and the similar NCI system incorporate the histologic subtype and grade while integrating the unique clinical and morphologic features of pediatric sarcomas. These systems are, however, less applicable to FNAB specimens because they require assessment of the percentage of tumor necrosis and mitotic rates. Accurate assessment of these parameters is not possible on cytologic specimens. For FNAB specimens, several studies recommend a classification approach that divides soft tissue sarcomas into five major cytomorphologic subgroups or subtypes based on the predominant cytologic appearance of the specimen on aspiration smears: myxoid, spindle cell, pleomorphic, polygonal/epithelioid cell, and round cell. This system has been shown to be applicable to FNAB specimens. In most cases, once a cytomorphologic subtype has been determined (ie, round cell, pleomorphic sarcoma), the corresponding histologic grade in many cases is definitional.

Recent guidelines published by the Association of Directors of Anatomic and Surgical Pathology (ADASP) for the reporting of soft tissue sarcomas commented on the use of needle biopsy in soft tissue tumor diagnosis, highlighting concerns that precise typing and grading are not possible, prone to sampling error and might not provide enough material for diagnosis (ie, ancillary studies). They also raised concerns about potential sampling problems caused by the heterogeneity of soft tissue tumors, potentially leading to an underestimation of the true histologic grade. However, there are only a few studies documenting how well FNAB can subtype previously undiagnosed soft tissue sarcomas, and the results vary widely, with an average 50-70% success rate. In one of the largest series, Kilpatrick and colleagues found the accuracy of FNAB for histologic subtyping to be greater for pediatric sarcomas (92%) (with the use of ancillary studies) than for adult sarcomas (52%).13 In this study, cytogenetic analysis was accurately performed using FNAB material to confirm the t(11;22) translocation in two cases of Ewing sarcoma and the t(x;18) translocation in three synovial sarcomas supporting the FNAB morphologic impression. The authors further showed that if one is able to subtype or at the least, place the sarcoma into the proper cytomorphologic group using the approach therapy at most institutions can proceed appropriately. A crucial point that was raised in this study related to the proper evaluation of the role of FNAB in the diagnosis and management of sarcomas: the accuracy of the technique for histologic subtyping is less important than the percentage of cases in which an FNAB diagnosis was sufficient for definitive therapy. In their series, the FNAB diagnosis was sufficient to begin definitive therapy in 83% of patients with soft tissue sarcomas. For most sarcomas, if the subtype (synovial sarcoma, etc) or cytomorpologic group (pleomorphic sarcoma, etc.) could be ascertained by cytologic examination, then a specific grade was not needed for the initiation of treatment because in most cases, the histologic grade is either readily apparent or is definitional for certain histologic subtypes. There were also no sampling problems caused by morphologic heterogeneity in the overwhelming majority of the cases, largely because of a multidisciplinary approach of reviewing imaging studies before FNAB to increase diagnostic yield. More recently, Jones et al have shown similar results supporting the opinion that FNAB can accurately subtype and grade soft tissue sarcomas in most cases. In their series of 107 FNAB (77 with corresponding surgical material available), only low-grade sarcomas were undergraded in a significant minority of cases, reducing the utility of FNAB when this group of neoplasms is encountered. Grading spindle cell sarcomas is often challenging, and separating some nonneoplastic spindle cell proliferations from low-grade spindle cell sarcomas may also be difficult. Others have found similar difficulties when sampling lipomatous tumors and recommend that deeply seated soft tissue lesions that appear predominantly fatty by current imaging techniques should be evaluated by incisional or excisional biopsy techniques.

Advances in Anatomic Pathology, 11:24-37, 2004

MOLECULAR PATHOLOGY

Diabetes Susceptibility Gene Discovered

Nancy Touchette

Researchers have known for decades that diabetes runs in families and that that environmental factors, such as obesity and physical inactivity, also play a big role. But the specific genes that may cause or predispose a person to diabetes have long eluded researchers.

Several lines of research are coming together and point to a common culprit. Many cases of type 2, or adult onset, diabetes can now be traced, at least in part, to common variations near the same gene. This gene, known as HNF4a, serves as a master switch that controls many genes that are active in both the pancreas and liver.

The genetic studies have nailed down HNF4a as a diabetes susceptibility gene, says Duncan Odom of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts , lead author of one of three recent studies. Our study suggests a mechanism for why variations in this gene might cause diabetes.

Two research teams used a traditional approach to look for genetic variations among families affected by the disease. Although the teams studied different ethnic groups, they found common variations near the same gene that are more prevalent in people with diabetes.

Michael Boehnke of the University of Michigan in Ann Arbor, and colleagues including Francis Collins, director of the National Human Genome Research Institute, looked at variations in a region of chromosome 20 in people from Finland. They identified four variants near the HNF4a gene that occurred more frequently in people with type 2 diabetes than in those without the disease.

In a similar study, M. Alan Permutt of Washington University in St. Louis, Missouri, found two additional variations near the same gene that were associated with diabetes in an Ashkenazi Jewish population.

Several years ago, researchers discovered that a rare mutation in the same gene could cause a simpler, more severe form of diabetes called Mature-Onset Diabetes of the Young, or MODY. While most forms of type 2 diabetes occur in older, overweight individuals, MODY tends to develop in younger individuals who are not necessarily overweight or sedentary.

Although a single severe mutation in the HNF4a gene is enough to cause MODY, less severe, more common variations in the same gene do not in themselves cause diabetes. Rather, these variations, which occur in about 20 percent of the general population, appear to predispose individuals to type 2 diabetes. Other environmental or genetic factors, such as obesity or other genetic variations, are needed to trigger the disease.

Just why changes in the HNF4a gene predispose individuals to diabetes is unknown, but researchers studying the function of the normal gene now have some clues. It now appears that this gene codes for a protein that in turn regulates the activity of other important genes in the cell.

In a third study, Odom and his colleagues at the Whitehead Institute looked at the genes in different tissues that are controlled by the HNFa protein. They found that the protein binds to a whopping 40 percent of all liver and pancreas genes they examined. By contrast, most other known gene regulators bind to only two percent or less of all genes in a given cell or tissue.

The big surprise was that HNF4a is so widely acting, Odom says. Almost half of all active genes in the liver and pancreas are bound to this protein.

This suggests that the protein plays a key role in both the liver and the pancreas. With so many genes under its control, it is possible that variations in the protein could alter the activity of many genes and gene networks and cause disease.

But the finding also raises another question.

If this protein is important for both liver and pancreas genes, why do we only see problems in the pancreas? asks Odom.

The variations associated with diabetes found in the Fins and Ashkenazi Jews occur in the region of the gene required to make one of two different versions of the protein, which is only produced in the pancreas. Both forms of the protein are produced in the liver.

Next, researchers would like to find out whether diabetes in other population groups is also linked to variations in HNF4a. And they would like to understand better what genes it regulates.

Variations in this protein could cause differences in 30 or 40 pathways in the cell, says Rohit Kulkarni, of the Joslin Diabetes Center in Boston, Massachusetts . There are a lot of permutations in these pathways that could lead to disease. Thats what makes this work so exciting.

Although variations in HNF4a most severely affects the pancreas, which produces only one form of the protein, Kulkarni says there may be more subtle effects in the liver. The liver plays a big role in fat and carbohydrate metabolism and its the accumulation of fat in the body that is thought to trigger the resistance to insulin that occurs in obese and sedentary individuals.

In the past we have only looked at individual genes and proteins, says Kulkarni. Now we have to look at the whole picture.

Genome News Network, April 2, 2004

NF-B: Emerging transcription factor in inflammation, immunity and cancer

Karin M, Cao Y, Greten FR et al

There is increasing evidence that NF-B is a major, if not themajor transcription nuclear factor regulating inflammation and immunity.While this implies that blocking NF-B might be therapeuticallybeneficial, it raises clear questions regarding the balancebetween efficacy and safety. In this brief review authors discussthe effects of NF-B blockade in rheumatoid arthritis, inflammationand immunity, and consider possible therapeutic targets withinthe NF-B family.

NF-B is a family of transcription factors central to immunityand inflammation. NF-B molecules exist as homo- or heterodimericcomplexes formed by combinations of five distinct DNA bindingsubunits, p65/RelA, RelB, c-Rel, p50, and p52, and are, undermost circumstances, found in the cytosol bound to IB proteins.However, in response to various stimuli that include physicaland chemical stress, viral and microbial products (for example,lipopolysaccharide (LPS)), and inflammatory cytokines (for example,interleukin (IL)1 and tumour necrosis factor (TNF)), IB proteinsare rapidly phosphorylated, ubiquitinated, and degraded, freeingNF-B to translocate rapidly into the nucleus to regulate geneexpression . IB kinases are central to that processas they regulate IB phosphorylation.

Effects of NF-B inhibition on the immune response

NF-B was first described as its name suggests, in B lymphocytes.Thus its importance on the immune system is not unexpected.We have used the adenoviral system to probe the function ofhuman dendritic cells, the cells that initiate immune responses,and then confirmed the results using the drug PSI (proteosomeinhibitor), which covalently binds to and hence blocks proteosomefunction and subsequently blocks dendritic cell function. There are reports that blocking NF-B predisposes certain cellsto apoptosis. Recent data favors atherosclerosis to involve an increase rather than a decrease in apoptosis

Atherosclerosis

Atherosclerosis is now recognized as an inflammation of the arterial wall and the action of nuclear factor kappa B (NF-kB) is now considered central to atherosclerosis since it induces the trasscription of pro-inflammatory molecules. NF-_kB is known to be activated in the atherosclerotic plaques.

NF-kappaB in cancer: from innocent bystander to major culprit

Nuclear factor of kappaB (NF-kappaB) is a sequence-specific transcription factor that is known to be involved in the inflammatory and innate immune responses. Although the importance of NF-KB in immunity is undisputed, recent evidence indicates that NF-kappaB and the signalling pathways that are involvedNF-KB in immunity is undisputed, recent evidence indicates that NF-kappaB and the signalling pathways that are involved in its activation are also important for tumour development. NF-kappaB should therefore receive as much attention from cancer researchers as it has already from immunologists.

Nat Rev Cancer. 2002 Apr; 2(4): 301-10.

BOTTOM LINE

How to write a case report

Anwar R, Kabir H, Botchu R et al

Research has become an integral part of medical careers. A case report is a way of communicating information to the medical world about a rare or unreported feature, condition, complication, or intervention by publishing it in a medical journal.

When to start

Be on the look out for a case report from the start of your basic surgical or medical training. This will introduce you to the research world, and if your report is published it will be an asset to your CV. Any kind of research entails a lot of hard work and persistence. Your thought processes should be geared towards research in your postgraduate career, and you should use every opportunity you get for writing a report. So if you come across something unusual, discuss it with a consultant, particularly one who is keen on research.

Many consultants have huge amounts of material in the top drawers of their desks, waiting to be published. All they want is an enthusiastic medic who will help share their load in writing and getting it published. They are usually helpful if you ask them about this.

How to start

A senior doctor's help is a must from the beginning. He or she may know from their experience what cases are suitable for publication. Do an extensive literature search--PubMed, Medline, Ovid, Embase, and even search engines like Google will give you a vast amount of information related to the condition or feature you are after. Narrow down the search to your actual topic. If this comes up with very few search results, it means (assuming your search method is correct) that the case is rare and the report is therefore more likely to be published.

Your hospital library staff can help (especially in the beginning) by doing your searches for you and then getting relevant literature from other sources, if necessary. So don't be afraid to ask them. It is always useful to read in a standard textbook or appropriate journal everything about the topic that your case report relates to. Note down or photocopy important references at the end of the chapter or article and follow them up.

Obtaining consent from the patient is not only good medical practice but also mandatory for some journals. If there is no standard form, make up your own. It is useful to have the patient's contact details on the form just in case you want to trace him or her later. It is also polite to ask permission from the doctor in charge of the patient's management.

How to collect information related to the case

After you have done the groundwork, collect all the material for the case report. Use the patient's notes to record the details of all the events in the patient's care--that is, history, examination findings, results of investigations with dates, and operative findings, if any, together with the details of the actual intervention and follow ups. Get copies--do not take the originals (they are the patient's only records for future reference). You are allowed to have copies only of radiographs, slides, photographs, and so on, but in this electronic age it is better to use a digital camera for your personal copies of radiographs and clinical photographs. This avoids many potential problems and saves a lot of time. Make sure you return the notes and radiographs to their original source. You should also visit the patient again and make sure you have got the facts right.

Which journal to choose

Again, the advice of your supervising consultant is useful. Select a journal that you think would be the most appropriate for your case report. For example, unusual injury presentations are more likely to be accepted in the journals such as Trauma rather than more mainstream, general interest journal.

Download or copy the information for authors for that particular journal and keep the hard copy safely in a folder with all the other information about the case. It is also useful to have a copy of any case report from a previous issue of the journal to get an idea of the presentation. It is extremely important to understand the basic format required by the journal. Your case report may be rejected because it does not conform to the standard format, no matter how good the content is. Margins, spacing, figure numbering, and style of references (Vancouver, Harvard, and so on), all are important aspects.

How many colleagues should be included?

The honest answer is not many: the supervising consultant and maybe one or two other colleagues, depending on how sincere and helpful they have been in collecting information or literature. You or your consultant (discuss with him or her) must be the first author. Do not ever give photographs or any other material related to your case report to anyone who you think might misplace them.

How do I write it?

It is best to write everything in one stretch. Piecemeal writing consumes time because you have to go over everything repeatedly. The following format is the most common way of writing a case report.

Introduction

Describe your case report in one sentence. Also mention how rare it is.

Case report

You have to summarise the information that you have gathered: a brief history and important and relevant positive and negative findings with details of investigations, treatment, and the condition of the patient after treatment. Don't include unnecessary details. Remember, this part should read like an interesting story, which your reader should enjoy.

One common form of presentation is to divide it into separate paragraphs with history, examination, investigation, treatment, and outcome in separate paragraphs--a textbook style of presentation without the headings.

Discussion

Remember that the probability of getting any research work published in a reputable journal is determined primarily by how well your arguments are presented scientifically --that is, how your report is supported or discussed. The first paragraph may explain the objective of reporting the case.

You must subsequently describe what others have written before about the condition or any related feature. Be generous in quoting the literature but don't go into unnecessary details.

The third and most important stage in the discussion is to substantiate the message you are trying to convey. Your reviewers want proof of the rarity of the condition and the scientific explanations for it. If you don't do this, they are likely to reject your report immediately. So you must be able to describe the cause of the condition or why a particular procedure or feature was chosen. How did it influence the outcome? How does it differ from usual and what are your recommendations? Are there any lessons to be learnt? All (or at least, most) of these questions need to be answered in the discussion.

Conclusion

This is not always necessary in a case report but if it is, summarise your message in a few sentences.

References

The reference section is boring and time consuming but extremely important. Keep to the style ( Vancouver , Harvard, etc) that your journal requires. The references should be in the form of numbers as you go along (usually 1, 2, 3, etc, as superscripts or in brackets in the order of appearance, as required by your journal). It is useful to put the same number on your hard copy of the reference.

Finishing touches

Expect to have to edit and revise the report about three times. Make sure you use the spell and grammar checks on your computer. Every section of the case report--discussion, reference, etc--should start on a new page. Get the senior author (usually supervising consultant) to review the finished report and then write a covering letter. All the other documents, including photographs, copyright, and so on, as required by the journal, should be attached to the final copy of the report before sending it to the journal.

You are allowed to have a party once you have put your completed case report in the mailbox. Not for celebration but for preparation. Your search for the next case report should start the next day.

Student BMJ 12: 60-61,2004

Microcystic tubulopapillary carcinoma of the pancreas: a new tumor entity?
Esposito I, Bauer A, Hoheisel JD et al

Virchows Arch. 441: Mar 11, 2004

Malekzadeh R, Mohamadnejad M, Rakhshani N et al

CYTOPATHOLOGY

Fine Needle Aspiration Biopsy of Soft Tissue Sarcomas: Utility and Diagnostic Challenges

(Review Article)

Microcystic tubulopapillary carcinoma of the pancreas: a new tumor entity? Esposito I, Bauer A, Hoheisel JD et al

Virchows Arch. 441: Mar 11, 2004

Malekzadeh R, Mohamadnejad M, Rakhshani N et al

CYTOPATHOLOGY

Fine Needle Aspiration Biopsy of Soft Tissue Sarcomas: Utility and Diagnostic Challenges

(Review Article)

Microcystic tubulopapillary carcinoma of the pancreas: a new tumor entity?
Esposito I, Bauer A, Hoheisel JD et al