Preventing Shingles

Shingles, also known as Herpes Zoster, usually occurs in elderly adults. It is characterized by painful eruption of vesicular lesions that follow a dermatomal distribution. The thoracic and lumbar roots are most commonly affected.

Pain precedes the appearance of the lesions and is severe and debilitating. The incidence and severity of herpes zoster increases with increasing age due to age related decline in immunity. Post herpetic neuralgia is a common complication of herpes zoster in the elderly. Facial nerve paralysis, herpes zoster ophthalmicus and bacterial superinfection are among other complications. Antiviral therapy with Acyclovir reduces the duration of the illness. A live attenuated Varicella Zoster Virus vaccine is also available to prevent herpes zoster.

Herpes zoster in the neck. Image from wikipedia.

In a recent study published in JAMA, Hung Fu Tseng et al. examined the effect of a Oka/Merck strain of varicella zoster virus based vaccine in reducing the incidence of herpes zoster. The study was a retrospective cohort study conducted among members of Kaiser Permanente, Southern California. The study included 75761 vaccinated subjects in 60 years or more age group. 227283 unvaccinated subjects in 60 years of more age group were included as controls. The controls were randomly selected and age matched. Immunocompromised individuals were excluded from the study as the vaccine is contraindicated in them. Exclusion of immunocompromised subjects also removes its confounding effect as it is a risk factor for herpes zoster. The main outcome of interest was incidence of herpes zoster. Bias was accessed by measuring the rate ratios of 13 different acute conditions which are not protected by the vaccine. If the rate ratios of these conditions are not grouped around 1, it would indicate that the vaccinated and the unvaccinated groups differ from each other and unmeasured confounders are at play. The rate ratio of herpes zoster was much greater in magnitude than the other conditions indicating that the outcome was not due to any bias.

In univariate analysis, the incidence of herpes zoster in vaccinated individuals was 6.4 (95% CI, 5.9-6.8) per 1000 person-years and among unvaccinated individuals, it was 13.0 (95% CI, 12.6-13.3) per 1000 person-years. The risk of herpes zoster among unvaccinated individuals varied with age, sex, race and lung disease. The difference in incidence of herpes zoster persisted upon adjustment for sex, race, chronic diseases and health care utilization. The fully adjusted analysis gave a hazard ratio of 0.45 (95% CI, 0.42-0.48). When a more strict criteria for immunocompetency was used, the adjusted hazard ratio was 0.46 (95%CI, 0.43-0.49). The vaccine also reduced the risk of herpes zoster ophthalmicus and hospitalization due to herpes zoster. Overall reduction in incidence of herpes zoster was 55%.

The limitations of the study are potentially unmeasured confounders and external validity.

Reference:

Tseng HF, Smith N, Harpaz R, Bialek SR, Sy LS, & Jacobsen SJ (2011). Herpes zoster vaccine in older adults and the risk of subsequent herpes zoster disease. JAMA : the journal of the American Medical Association, 305 (2), 160-6 PMID: 21224457

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Colonoscopy in prevention of colorectal carcinoma

Continuing from my previous post on colorectal carcinoma, I just came across a study by Hermann Brenner et al. showing the effectiveness of colonoscopy in preventing colorectal carcinoma. They had conducted a population based case-control study in Germany to quantify the effectiveness of colonoscopy. 1688 cases and 1932 controls aged over 50 years participated in the study. The selection criteria for the cases were - a first diagnosis of invasive colorectal carcinoma (>30 years), physically and mentally fit to participate and ability to communicate in German. The study used randomly selected population based controls without history of colorectal carcinoma and were age, sex and country matched. The use of population based control prevents selection bias in recruiting controls and Berkson's bias, so this can be counted as a strength of the study.

Colon and rectum. Modified screenshot from Google body browser.

The cases were interviewed by trained interviewers in hospital setting while the controls were examined at their home. It would have been better if the interviewers were blinded to remove interviewer bias. The data on endoscopies during the last 10 years were corroborated with medical records which were available in 84% of the cases; hence there isn't much chance of recall bias. The authors excluded from statistical analysis cases less than 50 years old as screening colonoscopy is not recommended in them, cases with history of inflammatory bowel disease as they undergo surveillance colonoscopy due increased risk of colorectal carcinoma, missing information regarding colonoscopy, had undergone any other endoscopic procedure or if the last colonoscopy was done less than 1 year or more than 10 years ago.

Flow diagram of the study.

The confounding factors accounted for were age, sex, and education level, family history of colorectal carcinoma, smoking, body mass index, non-steroidal anti-inflammatory drug use, hormone replacement therapy use and participation in health screening examinations. The risk of colorectal cancer was estimated by calculating Odds ratio (OR).

The findings of the study clearly show the benefit of colonoscopy in preventing colorectal carcinoma. It should be noted that colonoscopy by itself is not preventive, colonoscopy identifies the early adenomas which are removed. As development of colon cancer follows adenoma-carcinoma sequence, colonoscopy becomes protective by early detection and removal of adenomas. The study found that colonoscopy reduces the overall risk of colorectal carcinoma by 77%. This is substantial. The greatest risk reduction was seen in case of cancers located in the sigmoid colon (adjusted OR=0.14). The least risk reduction was for cancers located in the ascending colon. In general the risk reduction was more for left colon cancers than for right colon cancers.

Adjusted odds ratio according to the site of colorectal cancer (less OR means more protection by colonoscopy).

The beneficial effect of colonoscopy did not vary with sex or with family history of colorectal carcinoma. The risk reducing effect of colonoscopy increased with increasing age in case of right sided colon cancer but such an effect was not observed in case of left sided colon cancers.

The study has few limitations like unaccounted confounders, possible differential rate of participation in the study. Also the authors did not account for the dietary habits of the participants. Increased intake of dietary fiber has a protective effect in development of colorectal cancer while intake of red meat and animal fat has a deleterious effect. It can be argued that BMI is a measure of the diet but I don’t think it can replace dietary history. This is one major point that I think the authors should have addressed.

Brenner H, Chang-Claude J, Seiler CM, Rickert A, & Hoffmeister M (2011). Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Annals of internal medicine, 154 (1), 22-30 PMID: 21200035

How aspirin might prevent colorectal cancer?

I must confess that I am fascinated by the potential of aspirin in colorectal carcinoma prevention. It is worthwhile to look into this in some detail. Before we delve into the mechanism of colorectal carcinoma prevention by aspirin we must examine how colorectal carcinoma develops.

Colorectal carcinogenesis is characterized by a set of genetic alterations. The Fearon and Vogelstein model is a well accepted model explaining the sequence of colorectal cancer development. Their model is based on adenoma-carcinoma sequence. This suggests that colorectal carcinoma is preceded by adenomatous changes. Where adenomatous changes can not be identified, it is considered that the carcinoma directly arose from a dysplastic lesion. The development of colorectal carcinogenesis is taken to occur through through two distinct pathways –

• APC/β-catenin pathway.
• Microsatellite instability pathway.

In both the pathways there is step-wise accumulation of mutations but the genes involved and mutations occurring are different.

The APC/ β-catenin pathway is characterized by the loss of Adenomatous polyposis coli (APC) gene. The APC gene is located in the long arm of the 5^th chromosome (5q21). APC is a dual-function tumor suppressor gene coding for a protein that binds to bundles of microtubules and promotes cell adhesion and migration. The level of β-catenin is also regulated by APC. β-catenin is a mediator in the Wnt/ β-catenin signaling pathway which plays a significant role in normal development of the intestinal epithelium. It is also involved in colorectal carcinoma development. Inactivated APC can be found in more than 80% cases of colorectal cases and 50% of the cases that don’t have APC mutation have β-catenin mutation.

β-catenin, a member of the cadherin based cell adhesive complex, acts as a transcription factor when translocated to the nucleus. In case of APC gene mutation, β-catenin accumulates in the cytoplasm and is subsequently translocated to the nucleus. When inside the nucleus it binds with a family of transcription factors called T-cell factor or lymphoid enhancer factor (TCF or LEF). β-catenin –TCF complex is considered to activate genes associated with regulation of cellular proliferation and apoptosis like c-MYC and CYCLIN D1. Thus mutation in APC gene leads to increased cellular proliferation and decreased cell adhesion.

Mutation of the oncogene K-RAS is thought to occur next. This is the most commonly activated oncogene seen in adenomas and colorectal carcinomas. Allelic loss at chromosome 18q21 occurs and it is suggested to be SMAD2 and SMAD4 which are involved in TGF β signaling. p53 gene mutations occur late in colorectal carcinogenesis and are seen in 70 to 80% cases of colon cancer. Increased telomerase activity has also been found in colorectal cancers.

The microsatellite instability pathway is characterized by genetic lesions in the DNA mismatch repair genes. These lesions are found in the HNPCC (Hereditary Nonpolyposis Colorectal cancer) syndrome and in 10 to 15% of sporadic cases. Inactivation of the DNA mismatch repair genes results in defective DNA repair. Any of the human mismatch repair genes hMSH2, hMLH1, MSH6, hPMS1, hPMS2 may be involved in HNPCC syndrome.

Mutations in mismatch repair genes cause alterations in microsatellites (fragments of repeat sequences in human genome that are prone to misalignment during DNA replication). This leads to microsatellite instability. Some microsatellites are located in the coding or promoter regions of genes like type II TGF – β receptor and BAX. TGF – β signaling is involved in inhibiting the growth of colonic epithelial cells and BAX genes cause apoptosis. Microsatellite instability thus leads to their nonfunctioning and colorectal carcinogenesis.

Now where does aspirin come in all these? Aspirin belongs to a group of drugs called NSAIDs (Non Steroidal Anti Inflammatory Drugs) that inhibit cyclooxygenase (COX) enzymes resulting in decreased prostaglandin synthesis. There are two isoforms of COX, COX-1 which is constitutively expressed and COX-2 which is inducible.

In colorectal carcinogenesis there is overexpression of COX-2 enzyme, there by giving aspirin the chance to bite. However the exact step where aspirin might act is unclear.

Multistep progression of colon cancer and sites of NSAID action. From Postgrad Med J 2005;81:223-227 doi:10.1136/pgmj.2003.008227

Aspirin and other NSAIDs might also act through COX independent pathways to prevent colon cancer. High doses of aspirin have been shown to oppose the survival signaling pathway mediated by the transcription factor NF-kB. This is considered to occur through the inactivation of IkB kinase β. IkB kinase β is responsible for the activation of NF-kB cycle by phosphorylation of the inhibitory subunit of NF-kB. Hence aspirin inhibits the NF-kB pathway and interferes with cell survival.

Molecular mechanisms that mediate the effects of NSAIDs and anticancer drugs on survival and apoptosis in colon cancer cells. Schematic representation of cytokine, EGF-related growth factors and TRAIL ligand-dependent signal transduction pathways for survival and apoptosis. Stimulatory and inhibitory effects are indicated by arrows and bars, respectively. Abbreviations: MAPK=mitogen-activated protein kinase, MAPKK=mitogen-activated protein kinase kinase, JNK=jun kinase, IkB=inhibitor kinase B, NF-kB=nuclear factor kappa B, COX=cyclooxygenase, PI3K=phosphatidylinositol 3 kinase. From:Br J Cancer. 2003 March 24; 88(6): 803–807.

Synergistic effect of NSAIDs with conventional chemotherapeutic drugs has also been observed. The effect of NSAIDs in preventing neoangiogenesis is also important. Neoangiogenesis is a vital event in tumor growth and metastasis and tumor cells need adequate blood supply to derive nutrients. Prostaglandins are thought to be involved in angiogenesis by regulating proangiogenic factor synthesis like vascular endothelial growth factor (VEGF). Both COX-1 and COX-2 are considered to be involved in this.

Relative levels of Bcl-2 proteins regulate eukaryotic cell survival and apoptosis. SC-58125 and NS-398, COX-2 selective inhibitors, downregulates anti-apoptotic protein bcl-1 and sensitizes colorectal and proastate cancer cels to apoptosis. Aspirin upregulates bax and bak (proapoptotic proteins) and activates caspase 3 resulting in apoptosis. AKT, an anti-apoptotic protein kinase and the Fas-associated death domain has also been implicated in NSIAD induced apoptosis.

What remains to be seen is whether the advantages of aspirin will be sufficient considering the risk of GI adverse effects and how much benefit aspirin or any other NSAID provides. I want to remain hopeful.

Reference:

Sangha, S. (2005). Non-steroidal anti-inflammatory drugs and colorectal cancer prevention Postgraduate Medical Journal, 81 (954), 223-227 DOI: 10.1136/pgmj.2003.008227

Ricchi, P., Zarrilli, R., di Palma, A., & Acquaviva, A. (2003). Minireview: Nonsteroidal anti-inflammatory drugs in colorectal cancer: from prevention to therapy British Journal of Cancer, 88 (6), 803-807 DOI: 10.1038/sj.bjc.6600829

KINZLER, K. (1996). Lessons from Hereditary Colorectal Cancer Cell, 87 (2), 159-170 DOI: 10.1016/S0092-8674(00)81333-1