Efficacy/prognosis of antiviral therapy on hepatitis C following treatment of lymphoma in HCV-positive diffuse large-cell lymphoma

Annals of HematologyDecember 2017, Volume 96, Issue 12, pp 2057–2061 |

Efficacy and prognosis of antiviral therapy on hepatitis C following treatment of lymphoma in HCV-positive diffuse large-cell lymphoma

Yutaka Tsutsumi, Chie Nakayama, Koki Kamada, Ryo Kikuchi, Daiki Kudo, Shinichi Ito, Satomi Matsuoka, Souichi Shiratori, Yoshiya Yamamoto, Hirohito Naruse, Takanori Teshima

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Discussion
It was recently reported that performing antiviral therapy against HCV in the treatment of HCV-positive lymphoma has had positive effects including improvement of the lymphoma, and that antiviral therapy including interferon against low-grade lymphoma may be able to improve the prognosis when performed following chemotherapy for low-grade lymphoma [9, 10]. In our report, since HCV is often stained in tissue samples, and since cases where there is a drop in HCV viral RNA are less likely to recur [7], it is suggested that HCV is directly or indirectly associated with the occurrence and progression of lymphoma. However, the main causes of the transition to lymphoma are still unclear. Furthermore, it has been reported that improvements can be obtained with antiviral therapy alone (e.g., in cases of splenic marginal zone lymphoma), and it is expected that the use of antiviral therapy against HCV-positive lymphoma yields an improved prognosis [11, 12, 13].

On the other hand, studies of whether treatment of HCV with antiviral drugs after treatment for diffuse large-cell lymphoma contributes to the prognosis are being conducted either retrospectively or through a combination of retrospective and prospective methods [14, 15]. It has been reported that the 5-year OS and PFS can both be improved [14, 15]. Also, a report by Michot et al. pointed out the possibility of including cases where diffuse large B cell lymphoma is thought to have transformed from splenic marginal zone lymphoma [14], but in this case, cases that have transformed from splenic marginal zone lymphoma are not included. In Europe and the USA, there are many cases where splenic marginal zone lymphoma is associated with HCV. These cases are highly responsive to HCV antiviral therapy, suggesting the possibility of an improved prognosis. On the other hand, in a report by Michot et al., there were cases in which SVR could not be obtained in the antiviral therapy group, while in a report by Hosry et al., there were many cirrhosis cases among the analysis subjects, and it is thought that these factors may have acted on OS and PFS in a negative direction [14, 15]. In our analysis, genotype 2 was more common in the DAA group, while genotype 1 was more common in the control 1 group, and the difference in genotype may also have affected the outcome of treatment. It is thought that this affected the OS and PFS analysis of this report and earlier reports [14, 15].

Since DAA was used after obtaining confirmation of chronic HCV-positive hepatitis by liver biopsy in the cases analyzed here, DAA therapy was performed about 6 weeks after treatment with anticancer drugs. However, there are no clear guidelines on the appropriate timing for DAA treatment, such as whether antiviral therapy should be performed after or during lymphoma treatment, or before anticancer treatment of the lymphoma. A recent report investigated the interactions of DAA administered simultaneously with various anticancer drugs in cancer cases complicated by HCV infection. In this report, although blood toxicity and gastrointestinal toxicity were found, the change brought about by DAA therapy was only 10%, and the SVR was also 95%, and it was reported that it may be possible to use DAA therapy simultaneously with anticancer treatment [16, 17]. On the other hand, in this analysis, there were no problems arising from the continued use of DAA therapy, or complications requiring a change of medication regime, but this could be because there were no cases where DAA therapy was performed at the same time as the anticancer treatment.

In this study, we are conducting a prospective examination of five cases, and so far, 2 years has elapsed since the start of treatment, but in all five cases, the patients have survived without any recurrence, and it seems that following chemotherapy with antiviral therapy may contribute to the prognosis in cases of HCV-positive diffuse large-cell lymphoma. Furthermore, although analysis has only been performed in a few cases, it seems that HCV-RNA-positive cases may have a poorer prognosis than non-HCV-infected diffuse large-cell lymphoma cases, and although there are signs that the prognosis is improved for DAA treatment cases, it may be recommended that DAA treatment is performed after remission in HCV-RNA-positive diffuse large-cell lymphoma. However, since we have only examined a few cases for a short period of time, we are hopeful that the usefulness of antiHCV therapy will be demonstrated more clearly by a prospective study involving a larger number of people.

https://link.springer.com/article/10.1007%2Fs00277-017-3129-0

From hepatitis C virus infection to B-cell lymphoma

Accepted Manuscript
From hepatitis C virus infection to B-cell lymphoma
L Couronné E Bachy S Roulland B Nadel F Davi M Armand D Canioni J M Michot C Visco L Arcaini C Besson O Hermine

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Annals of Oncology, mdx635, https://doi.org/10.1093/annonc/mdx635
Published:
10 October 2017

Abstract

In addition to liver disorders, Hepatitis C virus (HCV) is also associated with extrahepatic immune manifestations and B-cell non-Hodgkin lymphoma (NHL), especially marginal zone lymphoma, de novo or transformed diffuse large B-cell lymphoma and to a lesser extent, follicular lymphoma. Epidemiological data and clinical observations argue for an association between HCV and lymphoproliferative disorders. The causative role of HCV in NHL has been further supported by the response to anti-viral therapy. Pathophysiological processes at stake leading from HCV infection to overt lymphoma still need to be further elucidated. Based on reported biological studies, several mechanisms of transformation seem however to emerge. A strong body of evidence supports the hypothesis of an indirect transformation mechanism by which sustained antigenic stimulation leads from oligoclonal to monoclonal expansion and sometimes to frank lymphoma, mostly of marginal zone subtype. By infecting lymphocytes, HCV could play a direct role in cellular transformation, particularly in de novo large B cell lymphoma. Finally, HCV is associated with follicular lymphoma in a subset of patients. In this setting, it may be hypothesized that inflammatory cytokines stimulate proliferation and transformation of IgH-BCL2 clones that are increased during chronic HCV infection.

Unraveling the pathogenesis of HCV-related B-cell lymphoproliferation is of prime importance to optimize therapeutic strategies, especially with the recent development of new direct-acting antiviral drugs.

Continue to accepted manuscript

Extrahepatic manifestations of HCV & Treatment

Found On This Blog
A collection of research articles on ailments related to HCV

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Latest Tweets By @HenryEChang on the extrahepatic manifestations of HCV.

July 14, 2017

Extrahepatic manifestations of HCV: The role of direct acting antivirals

María Laura Polo and *Natalia Laufer
Expert Review of Anti-infective Therapy DOI: 10.1080/14787210.2017.1354697

Introduction:

Hepatitis C virus (HCV) represents a major health concern, as nearly 3 million people become newly infected by this pathogen annually. The majority of infected individuals fail to clear the virus, and chronicity is established. Chronic HCV patients are at high risk for liver disease, ranging from mild fibrosis to cirrhosis and severe hepatocellular carcinoma. Over the last few years, the development of multiple direct acting antivirals (DAA) have revolutionized the HCV infection treatment, demonstrating cure rates higher than 90%, and showing less side effects than previous interferon-based regimens. Areas covered: Besides liver, HCV infection affects a variety of organs, therefore inducing diverse extrahepatic manifestations.

This review covers clinical, experimental, and epidemiological publications regarding systemic manifestations of HCV, as well as recent studies focused on the effect of DAA in such conditions.  Expert commentary: Though further research is needed; available data suggest that HCV eradication is often associated with the improvement of extrahepatic symptoms. Therefore, the emergence of DAA would offer the opportunity to treat both HCV infection and its systemic manifestations, requiring shorter treatment duration and driving minor adverse effects.
Link - Download Full Text Article.......

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Clinics in Liver Disease, Volume 21, Issue 3

Chronic Hepatitis C Virus Infection and Depression
Luigi Elio Adinolfi, Riccardo Nevola, Luca Rinaldi, Ciro Romano, Mauro Giordano

KEYWORDS
HCV Depression Quality of life

KEY POINTS
Depression is an extrahepatic manifestation of chronic hepatitis C virus (HCV) infection reported in one-third of patients.

The prevalence of depression in patients with HCV has been estimated to be 1.5 to 4.0 times higher than that observed in the general population.

Direct HCV neuro-invasion, induction of local and systemic inflammation, neurotransmission, and metabolic derangements are the hypothesized pathogenic mechanisms of depression.

Depression considerably impacts health-related quality of life of HCV-positive patients.

Clearance of HCV by antiviral treatments is associated with an improvement of both depression and quality of life.
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Metabolic Manifestations of Hepatitis C Virus
Lawrence Serfaty

KEYWORDS
Hepatitis C Steatosis Hypobetalipoproteinemia Microsomal triglyceride transfer protein Insulin resistance. Tumor necrosis factor

KEY POINTS
Out of excessive alcohol consumption, steatosis should be classified into 2 types according to hepatitis C virus (HCV) genotypes: metabolic steatosis, which is associated with features of metabolic syndrome and insulin resistance in patients infected with nongenotype 3, and viral steatosis, which is correlated with viral load and hyperlipemia in patients infected with genotype 3.

HCV interacts with host lipid metabolism by several mechanisms, such as promotion of lipogenesis, reduction of fatty acid oxidation, and decreases of lipids export, leading to hepatic steatosis and hypolipidemia.

A strong link between HCV infection and diabetes mellitus has been found in subjectbased studies and, to a lesser degree, in population-based studies.

HCV-mediated insulin resistance may be promoted through multiple pathogenic mechanisms, such as direct inhibition of insulin signaling pathway by HCV core protein in the liver, overproduction of tumor necrosis factor-alpha, oxidative stress, modulation of incretins, or pancreatic ß-cells dysfunction.
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Neurologic manifestations of hepatitis C virus infection
Sentia Iriana, MD, Michael P. Curry, MD, Nezam H. Afdhal, MD, DSc

KEYWORDS
Hepatitis C Fatigue Neurocognition MR spectroscopy Interferon Ledipasvir/sofosbuvir Cerebrovascular disease

KEY POINTS
The extrahepatic manifestations of hepatitis C virus (HCV) in the brain include neurocognitive dysfunction, which is manifested by subtle changes in memory, attention, and processing speed.

Neurocognitive defects are independent of the histologic stage of disease and may be induced by a direct effect of HCV on microglial cells or mediated by systemic cytokines crossing the blood-brain barrier.

Magnetic resonance spectroscopy demonstrates abnormal metabolism in basal ganglia and prefrontal and frontal cortex, which has been associated with fatigue and abnormal neurocognitive testing. Interferon and direct-acting antiviral therapy can improve cerebral metabolism and neurocognition if a sustained virologic response is obtained.

Cerebrovascular events and mortality are increased in patients with HCV and may be through an increased risk of carotid artery disease and plaque formation.
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Rheumatologic manifestations of hepatitis C virus

Patrice Cacoub, Cloé Comarmond, Anne Claire Desbois, David Saadoun

KEYWORDS
Hepatitis C (HCV) Rheumatic disorders Arthritis Vasculitis Arthralgia Sicca syndrome

KEY POINTS
Main rheumatologic manifestations reported with hepatitis C virus (HCV) chronic infection include arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome.

Immunologic factors predisposing to developsuch manifestations include stimulation of B cells, expansion of B-cell–producing immunoglobulin M with rheumatoid factor activity and of clonal marginal zone, like B cells, and a decrease of regulatory T cells.

The treatment of HCV infection with interferon alpha has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders.

New oral interferon-free combinations now offer an opportunity for patients with HCV extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a high efficacy rate and a low risk of side effects.

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Other EHM of HCV infection (pulmonary, idiopathic thrombocytopenic purpura, nondiabetes endocrine disorders

Daniel Segna, Jean-François DuFour

KEYWORDS
Hepatitis C Extrahepatic manifestations Pulmonary Endocrine Idiopathic thrombocytopenic purpura

KEY POINTS
Hepatitis C Virus (HCV) infection may increase the risk for obstructive, interstitial, and vascular lung disease, lung cancer, and mortality in HCV-infected lung transplant recipients.

HCV infection may increase the risk of idiopathic thrombocytopenic purpura, nonresponse to corticosteroids during the treatment, and higher rates of splenectomy.

HCV infection may increase the risk of autoimmune thyroiditis, infertility, growth hormone and adrenal deficiency, osteoporosis, and low-trauma fractures.

Targeted prospective cohorts may confirm these results mostly obtained from small casecontrol studies with different study populations and low level of evidence.

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Hepatitis C Virus–Associated Non-Hodgkin Lymphomas
Gabriele Pozzato, Cesare Mazzaro, Valter Gattei

KEYWORDS
Hepatitis C virus Marginal zone lymphoma Non-Hodgkin lymphoma Direct antiviral agents

KEY POINTS
Eradication of hepatitis C virus (HCV) in indolent non-Hodgkin lymphomas (NHLs), especially in marginal zone lymphomas(MZLs), determines the regression of the hematological disorder in a significant fraction of cases.

Because direct antiviral agents (DAAs) show an excellent profile in terms of efficacy, safety, and rapid onset of action, these drugs can be used in any clinical situation and the presence of any comorbidities.

To avoid the progression of the NHL, despite HCV eradication, antiviral therapy should be provided as soon as the viral infection is discovered; before that, the chronic antigenic stimulation determines the irreversible proliferation of neoplastic B cells.
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Dermatologic manifestations of chronic hepatitis C
Mehmet Sayiner, Pegah Golabi, Freba Farhat, Zobair M. Younossi

KEYWORDS
Hepatitis C Extrahepatic manifestation Dermatologic manifestation Cryoglobulinemia Porphyria Lichen planus

KEY POINTS
HCV infection is associated with several dermatologic diseases, such as symptomatic mixed cryoglobulinemia, lichen planus, porphyria cutanea tarda, and necrolytic acral erythema.

Most of the dermatologic manifestations may be caused by immune complexes. In the interferon and ribavirin era, treatment was associated with dermatologic side effects.

The new generation of interferon-free and ribavirin-free anti-HCV regimens is devoid of dermatologic side effects.
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Hepatitis C Infection - A systematic disease
Zobair M. Younossi
KEYWORDS
Hepatitis C virus Hepatic complications Extrahepatic complications

KEY POINTS
It is critical to recognize that hepatitis C virus (HCV) infection is a multifaceted systemic disease with both hepatic and extrahepatic complications.

The comprehensive burden of HCV should not only include its clinical burden, but also its burden on the economic and patient-reported outcomes.

It is only through this comprehensive approach to HCV infection that we can fully appreciate its true burden, and understand the full benefit of curing HCV for the patient and the society.
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Thank you Henry E. Chang

HCV Weekend Reading: Hepatitis C and non-Hodgkin lymphoma

Hello everyone, welcome to another edition of "Weekend Reading." Sit back, grab a cup of coffee and let's talk about what's new, and what you didn't catch last week.

We begin with a study presented at the annual meeting of the American College of Preventive Medicine in New Orleans last week.

The results were alarming, according to the study not only do people with HCV have a 30 times higher risk of death from liver cancer, compared to those without the virus, but people infected with hepatitis C also have a higher mortality rate from non-Hodgkin lymphoma, pancreatic, rectal, and oral or pharyngeal cancers.

Researchers reported; "persons with chronic hepatitis C died an average of 12 years earlier than the general population from 12 different cancers - i.e., bladder, breast, colon, esophagus, leukemia, liver, lung, non-Hodgkin lymphoma, oral, pancreatic, prostate, and rectal cancers."

Excerpt; 
Hepatitis C Infection Tied to Higher Risk of Death From Non-liver Cancers

Study author Dr. Robert D. Allison from Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland, said it is important to point out that "chronic hepatitis C infection is a known risk factor for developing non-Hodgkin lymphoma (NHL). But to our knowledge, this is the first U.S. study to investigate and show that persons with chronic hepatitis C have a higher risk of death from NHL."

He said there are multiple possible explanations for the other cancers. "The HCV group had a higher rate of smoking and alcohol use than the general population. So, it's hard to say for sure if the increased risk of death from the three smoking-related cancers (oral, pancreatic, and rectal) was related to HCV infection. However, NHL is not associated with either smoking or alcohol use."

 Read more @ Medscape

This study serves as a reminder that chronic hepatitis C not only affects the liver, but is also associated with a risk for other cancers, syndromes and conditions outside the liver, as well as cirrhosis and liver cancer. The good news is treating HCV remains the cornerstone of preventing liver damage, serious complications and long-term health problems caused by the virus.

New In March - To Treat Or Not To Treat

Deciding to treat hepatitis C is an enormous decision to make, an impossible decision without a basic understanding of the disease, and its treatments. Over the years, I have aspired to help bring easy to understand information to people newly diagnosed with hepatitis C.  Recently, I put together a collection of slides for people considering treatment. The project is close to my heart, and I hope to achieve what I set out to do, which is to offer a point of reference for anyone faced with this difficult and complicated decision.  The slides begin with my own diagnosis, and offer a glance at other conditions related to HCV, terminology used to define treatment response, detailed SVR (cure rates) for both FDA approved and investigational interferon-free regimens, along with links to clinical trials, news and updates. If you haven't seen it, click here to begin.

New At HCV Advocate

New in March over at HCV Advocate is this months HCV Newsletter, one of my favorite publications. A few topics include Gilead's one pill combination of sofosbuvir (Sovaldi) and ledipasvir, and a update reviewing the latest HCV drug developments, written by Alan Franciscus, Editor-in-Chief. In addition, liver health and nutrition is always an important topic at HCV Advocate, advice for healthy food strategies and sleep disturbances in people living with hepatitis C round out this months newsletter.

The Big Commercial

Thank goodness, the topic of HCV has remained in the headlines over the last few months. A commercial, of sorts, brought to you by Gilead made its debut last week. Did you see it? You did? Did you notice what I noticed?

People with HCV are gorgeous!

Yep, both the men and the women in the commercial are beautiful. Although, for some reason, HCV never had that affect on me.

A Disappointment?

To be fair, the commercial addressed how serious this disease is, and mentioned that left untreated, it can lead to serious liver damage and liver cancer.

Obviously, any seasoned HCV patient, could not help but notice the commercial was targeting "baby boomers" without ever addressing the fact they were baby boomers.  Sadly, Gilead missed an opportunity to bring important awareness to the disease.

Flash Of Statistics

Some thirty seconds into the ad, a quick flash of text appears across the bottom of the screen, reading: Over 3 million people have hepatitis C. What a shame it didn't read; Over 3 million US citizens have hepatitis C, more than 75 percent of the estimated 3 million infected are baby boomers. If you were born between 1945 and 1965 - Get tested.

However, I guess that might be misconstrued as a advertising ploy, generally regarded in the field as "shockvertising."

The only thing is........ it is shocking.

In the end, we take what we can get. One commercial addressing treating this disease, is better then none. Gilead is one of a few drug companies that has, and will be - saving thousands of precious lives



This commercial (and campaign) is designed to get diagnosed patients to rethink treating their hepatitis C. And through empathy and understanding, we connect with hepatitis C patients and encourage them to take action by registering online at HepcHope.com and to talk to their gastroenterologist about scientific advances that may help them move on from hepatitis C.

Enjoy the rest of your weekend and the Oscars tonight!

Tina

Patients with hepatitis at greater risk for non-Hodgkin's lymphoma

 Martin Moehlen, MD

December 3, 2012

BOSTON — Patients with hepatitis, particularly hepatitis B, may be at increased risk for developing non-Hodgkin’s lymphoma, according to data presented at The Liver Meeting.

Researchers performed a cross-sectional study incorporating information on 1,055,912 patients in the National Inpatient Sample database between 2005 and 2009. The cohort included 479,661 patients with HCV and 48,295 with HBV. Incidence of non-Hodgkin’s lymphoma (NHL) was observed among patients with hepatitis and compared against patients without hepatitis.

“In the literature for hepatitis C and NHL, there’s been some conflicting information about whether there’s a connection between these two diseases,” researcher Martin Moehlen, MD, MPH, gastroenterology fellow at Tulane University in New Orleans, told Healio.com. “Here we have a very large database where we were able to ask [whether] there is an association between hepatitis B and hepatitis C and NHL.”

Univariate analysis indicated that NHL was most common among patients with HBV (2.1% of patients compared with 0.82% of HCV patients and 0.65% among patients without hepatitis, P<.001 for difference).

Multivariate analysis identified an independent association between hepatitis and risk for NHL, with the association more pronounced among those with HBV (OR=3.32 for HBV and OR=1.23 for HCV, P<.001 for both). Advanced age also was associated with NHL risk (OR=1.45 for patients aged 44-53 years; OR=1.86 for those aged 54-65, and OR=2.07 for those aged older than 65 years). Inverse associations were observed between NHL and female sex (OR=0.57) and black race (OR=0.75) (P<.001 for all).

“When you have somebody with NHL, you want to be thinking about testing [that] individual for hepatitis B and C,” Moehlen said. “Usually people are looking for HBV, because of the concern that if you treat with chemotherapy, HBV can flare. HCV though, sometimes, is underneath the radar, but it is something that’s important to look at.”

Moehlen said the increased risk in patients with HBV vs. those with HCV was a curiosity in the study and called for further investigation.

Disclosure: Researcher Luis Balart reported numerous financial disclosures.

For more information:
Moehlen M. #907: Hepatitis B and C are associated with Non-Hodgkin’s Lymphoma: cross-sectional study of the National Inpatient Sample database. Presented at: The Liver Meeting 2012; Nov. 9-13, Boston.

http://www.healio.com/hepatology/chronic-hepatitis/news/online/%7B397BBDE0-9A30-4A58-BBD8-B8A89E420065%7D/Patients-with-hepatitis-at-greater-risk-for-non-Hodgkins-lymphoma

Hepatitis C Virus Infection In Non-Hodgkin’s Lymphoma: A Case Control Study

Hepatitis C Virus Infection In Non-Hodgkin’s Lymphoma: A Case Control Study

[ID:1491, in press, available in 2012][DOI: 10.5812/kowsar.1735143X.801]
Authors: Muhammad SK,Chandio MA, Soomro MA, Shaikh BA
Correspondence:
Shaikh Khalid Muhammad

Abstract:

Background:
Hepatitis C virus (HCV) is the most common cause of chronic liver disease in Pakistan{%1%} Globally an estimated 170 million persons are infected with HCV and around 3-4 million are newly infected each year with HCV {%2%}{%3%} Currently the prevalence of HCV in Pakistan is 4-7%.{%4%}{%5%}{%6%}HCV is a hepatotropic virus, causing chronic hepatitis in at least 80% of infected with it. If left untreated, 20-30% will eventually develop Cirrhosis with average latency of 15-25 years and Hepato-Cellular Carcinoma at rate of 1-5% per year with average latency of 20-30 years. {%3%}{%7%}.

Objectives: To determine the association between hepatitis C virus (HCV) infection and Non-Hodgkin's Lymphoma (NHL).

Methods & Materials: This 2 year case control study was started on 1st January 2009. 292 cases of NHL underwent staging according to Ann Arbor staging and were graded according to working formulation classification. Blood samples from 292 NHL cases and 1168 age and sex matched controls (2 groups) meeting our selection criteria, were sent for detection of anti-HCV Ab on ELISA. Chi-square test was applied to compare anti-HCV Ab seropositivity in cases and controls and odd ratios were computed. NHL cases were divided in anti-HCV Ab seronegative and seropositive groups to compare the effect of anti-HCV Ab seropositivity on stage and grades of NHL. P value of 0.05 was taken as statistically significant.

Results: 52 (17.8%) cases, 45 (7.7%) controls in group 1(10 Relatives) and 50 (8.6%) controls in group 2 (Non Hematological Malignancy) were anti-HCV Ab positive, with odd ratios of 2.59 (95%CI: 1.69 - 3.97) for group 1 and 2.31 (95%CI: 1.52 - 3.50) for group 2 with P value of 0.000 for both. Anti-HCV Ab positive NHL cases were more likely to be in middle age (40-60years) with odds of 3.68 (95%CI: 2.07 - 6.50). There was no significant effect of anti-HCV Ab seropositivity on grades and stages of NHL.

Conclusion: NHL is strongly associated with Anti-HCV Ab seropositivity, with 2 to 2.5 odd risk and seropositive cases tend to be in middle and young age.

Keywords: Hepatitis C Virus (HCV); Hepatitis C Antibodies; Association; Lymphoma, Non-Hodgkin (NHL).

Discussion Only
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This was first study conducted in Pakistan to observe the association between HCV and NHL and to observe the impact of anti-HCV Ab seropositivity on the stages and grades of NHL. In our study, we excluded NHL patients who had experienced exposure to any known risk factor for lymphoma development such as irradiation exposure, HIV infection, HBV infection, exposure to cytotoxic or immunosuppressive drugs, autoimmune disorders, and connective tissue disorders. We also excluded patients with a history of transfusion or parenteral medication or surgical procedures in the last 6 months as well as known patients with hemophilia or thalassemias since these disorders may falsely elevate the number of patients in the anti-HCV Ab-positive group. After exclusion, a total of 292 patients were enrolled in our study. For the cases, we used age- and sex-matched controls.
Advantages in selecting 1st degree relatives as control group 1 were that the relative belonged to the same locality of origin, experienced the same environmental factors, and had a genetic makeup similar to that of the patient.

Control group 2 consisted of patients with non-hematological malignancy and was used to compute the odds of NHL n HCV, as compared to other non-hematological malignancies. In our study, we identified statistically significant (P <0.000) odds ratio values for HCV in NHL patients. The HCV-infected NHL patients were younger (P < 0.000) than the non-infected individuals, but the risk was higher in young (< 20 years) and middle-aged (40–60 years) patients. There was no significant impact of HCV seropositivity on the stages and grades of NHL. Similar results were reported by researchers in Egypt and Saudi Arabia. In Egypt, Cowgill et al. (30) observed a significant association between NHL and HCV, but they did not evaluate the impact of HCV infection on the stages and grades of NHL. HCV infection in NHL patients is reportedly independent of age. Polymerase chain reaction, which was used in a previous study, was better than ELISA for the detection of HCV infection. In Saudi Arabia, Harakati et al. (31) reported that HCV-infected NHL patients were more likely to have intermediate-grade NHL than non-infected patients. Researchers in Europe also documented a similar association between NHL and HCV infection, but few studies have been conducted to evaluate the impact of the stages and grades of NHL in detail. Mele et al. (32) documented a strong association and concluded that in Italy, 1 of 20 instances of B-NHL may be attributable to HCV infection, and thus, the patients may benefit from antiviral treatment. In Turkey, Isikdogan et al. (33) observed that HCV-seropositive NHL patients were more likely to have intermediate-grade NHL. In France, Seve et al. (34) documented a positive but non-significant trend
towards an association between NHL and HCV infection (odds ratio, 1.31; 95% CI, 0.51–3.36). In Spain, De Sanjose et al. (35) found no significant difference in HCV seropositivity between nodal and extranodal NHL cases.

Similar to our study, all these studies reported a positive association between NHL and HCV. A Spanish study reported results similar to those of our study regarding the impact on the grades of NHL, but a Turkish study reported contradictory results. Studies performed in other countries have also reported a strong association between HCV and NHL. Spinelli et al. (36) in Canada, Takeshita et al. (37) in Japan, Masami et al. (38) and Nieters et al. (39) in a European multicenter case-control study (EPILYMPH), and El-Sayed et al. (40) in Egypt also reported similar results.


Most of these studies did not examine the impact of HCV seropositivity on the stages, grades, and B symptoms of NHL. Our study not only studied the association between NHL and HCV but also examined its impact on the stages and grades of NHL. In addition, this was the first study performed in Pakistan on this issue. The literature supports the concept that hepatitis C and NHL are associated.
However, limited studies have been conducted in Pakistan to explore this issue. The incidences of these disorders are currently increasing. The primary reasons for increase in HCV infections in developing countries such as Pakistan include poverty, lack of public awareness, non-availability of vaccines, and lack of health care facilities. Furthermore, the incidence of NHL is also increasing
at a rate of 1–4% per year. This association of HCV with NHL may put the public at risk of an NHL epidemic, particularly in developing countries such as Pakistan. This may ultimately result in decreased life expectancy and loss of young people in developing nations.

In conclusion, HCV infection is strongly associated with NHL. HCV was 2–3 times more prevalent in NHL patients than in the controls. HCV infection in NHL patients was more frequently observed in young and middle-aged subjects. No statistically significant impact was observed regarding anti-HCV Ab seropositivity on the stages and grades of NHL.

On the basis of our results, larger epidemiological studies can be conducted. Our study results also provide information for health policy and decision makers that can be used to control a combined epidemic.

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Hepatitis:How many stages are there in non-Hodgkin's lymphoma?

How many stages are there in non-Hodgkin's lymphoma?
Every weekday, a CNNHealth expert doctor answers a viewer question. On Wednesdays, it's Dr. Otis Brawley, chief medical officer at theAmerican Cancer Society.
Question asked by Paula Holman-Yorba of San Bernardino, California

How many stages are there in non-Hodgkin's lymphoma?

Expert answer
Two weeks ago, Paula asked about staging of non-Hodgkin's lymphoma. We discussed cancer staging in general. This week, we discuss lymphoma and its staging and prognosis.
Lymphoma is cancer of the lymphatic system, which is an important part of the immune system. The lymphatic system consists of conduits or tubes throughout the body with filters called lymph nodes along the path. The system carries a clear fluid with immune fighting cells such as lymphocytes.
Lymphoma is a disease that is increasing in incidence in the Western world. Common risk factors include exposure to:
• ionizing radiation;
• certain chemicals such as benzene, insecticides, or herbicides; and
• some viruses such as HIV, HTLV 1 and 2.

There is also evidence that people with immune diseases such as rheumatoid arthritis, systemic lupus erythematosus (SLE, or lupus), or celiac sprue are at higher risk of developing lymphoma. Patients with immune hyperstimulation from H. pylori infection of the stomach or hepatitis C are also at increased risk of certain types of lymphoma.

The appropriate treatment and the prognosis for a lymphoma patient are related to a combination of the type of lymphoma and stage of disease. The type of tumor is determined by a pathologist's microscopic examination of a biopsy of the tumor.

There are two major types of lymphoma: the Hodgkin's lymphomas and the non-Hodgkins lymphomas. HL spreads primarily through the ducts of the lymph system. NHL spreads more through blood vessels. There are five subtypes of HD and more than two dozen types of NHL. These NHL are categorized into three groups: the indolent, intermediate and aggressive.
The stage or degree of spread of the disease is determined by the physical examination and radiologic imaging.

A TNM stage, discussed last week, is determined and usually translated into what is known as the Ann Arbor staging system with Cotswolds modifications. This is the overall or summary stage, in brief:
• Stage I - Lymphoma involving a single lymph node region (I) or a single node and the organ next to it.
• Stage II - Involvement of two or more lymph node regions in the chest or two or more in the abdomen or the area of the retroperitoneum (low back). There can be direct extension of lymphoma from the lymph node chain into an adjacent organ.
• Stage III - Involvement of lymph node in the abdomen and the chest or the retroperitoneum and the chest. Involvement of the spleen, which is located in the left upper abdomen, is stage III disease.
• Stage IV - Diffuse or disseminated lymphoma involving one or more organs or tissues without associated lymphatic involvement.

Patients with stage I or stage II disease are then further stratified for treatment purposes into favorable and unfavorable prognosis disease, based upon the presence or absence of certain clinical features, such as age and B symptoms (weight loss, fevers, night sweats, and large volume of disease in the chest).

Laboratory studies are done to determine the type of cancerous cells. There are drugs specific to the treatment of what are known as B cell lymphomas. B cell positive versus T cell positive or other laboratory markers can also be used to predict patterns of spread and patterns of invasion of a lymphoma.
The appropriate treatment of a lymphoma varies by the type of tumor and by the stage. Stage I and II lymphomas can often be treated with radiation alone. They are of limited size and spread, such that they can be illuminated by one radiation beam. Stage III and IV lymphomas generally must be treated with a series of chemotherapy drugs active in lymphoma. Type of tumor is very important, as indolent lymphoma usually presents as widely spread or stage IV disease, but can often be appropriately watched, and treatment can sometimes be deferred for a decade or more. On the other hand, the aggressive lymphomas can be a medical emergency requiring immediate treatment.

The international prognostic index (IPI) is used to determine prognosis for patients with lymphoma. The index takes into account the the type of lymphoma, stage of disease, and what markers or genes are expressed in the tumor. As a whole, lymphoma is one of the most treatable of malignancies. While the prognosis for many of the lymphomas can be very good, there are some lymphomas that are very difficult to treat.
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