D Kumar

George Eliot Hospital NHS Trust, Nuneaton, England, United Kingdom

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Publications (61)443.08 Total impact

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    ABSTRACT: T regulatory cells are able to suppress anti-tumour immunity in pre-clinical models and in patients. This review highlights the important discoveries in Treg immunology critical to the evolution of targeted immunotherapy. We also describe the therapeutic applications that are currently being assessed and their future potential.
    Biochimica et Biophysica Acta 02/2010; 1806(1):7-17. · 4.66 Impact Factor
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    ABSTRACT: T-regulatory cells suppress anti-tumour immunity in cancer patients and in murine tumour models. Furthermore, their activity is likely to have an effect on the effectiveness of immunotherapeutic treatments for cancer. Here we describe the current status of developing clinical strategies for modulating Treg activity in cancer patients.
    British Journal of Cancer 05/2009; 100(11):1697-703. · 5.08 Impact Factor
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    ABSTRACT: Colorectal cancer is immunogenic. However, it is also associated with suppression of host immunity. Identifying the mechanisms involved in immune suppression is necessary to develop future immunotherapeutic strategies. The aim of this study was to assess immune cell function in colorectal cancer patients. A total of 80 colorectal cancer patients (41 male) prior to treatment and 38 matched controls (21 male) were recruited. Venous blood samples were taken. White blood cell composition was determined using monoclonal antibodies. Levels of cytokines IFN-gamma, TNF-alpha, IL-2, IL-10, IL-4 and IL-6 were measured from the supernatants of activated peripheral blood mononuclear cells (PBMC) following thawing and re-suspension. Peripheral blood mononuclear proliferation was measured using 3H-Thymidine. Stage I-III cancer patients had elevated percentages of CD8 T cell (P = 0.004) whilst stage IV patients had low total lymphocyte percentages (P = 0.016). Monocyte and NKT cell percentage decreased with advanced tumour stages (P = 0.013 and P = 0.038). Patients had lower PBMC proliferation and production of the TH1 cytokines (IFN-gamma and TNF-alpha) (P < 0.001) than that of the controls. IL-6 and IL-4 production were not significantly different. IFN-gamma and TNF-alpha concentrations reduced with tumour vascular invasion (P = 0.011 and P = 0.019). Colorectal cancer induces an immunological response, shifting the cytokine balance. The most profound changes are seen once disease has spread systemically.
    Colorectal Disease 02/2009; 12(6):561-9. · 2.08 Impact Factor
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    ABSTRACT: Advances in immunology and molecular biology have shown that colorectal cancer is potentially immunogenic and that host immune responses influence survival. However, immune surveillance and activation is frequently ineffective in preventing and/or controlling tumour growth. To discuss potential ways in which colorectal cancer induces immune suppression, its effect upon prognosis and avenues for therapeutic development. A literature review was undertaken for evidence of colorectal cancer-induced immune suppression using PubMed and Medline searches. Further studies were identified from the reference lists of identified papers. Immune suppression occurs at a molecular and cellular level and can result in a shift from cellular to humoral immunity. Several mechanisms for immune suppression have been described affecting innate and adaptive immunity with suppression linked to poorer clinical outcome. Colorectal cancer causes direct inhibition of the host's immune response with a detrimental effect upon prognosis. Immunotherapy offers a therapeutic strategy to counteract these effects with promising results seen particularly in precancerous conditions and early tumours. This review strongly suggests that immunotherapy should be incorporated into adjuvant therapeutic trials for stage 2 tumours and be considered as adjuvant treatment in conjunction with standard chemotherapy regimes for advanced disease.
    Alimentary Pharmacology & Therapeutics 11/2006; 24(8):1163-77. · 4.55 Impact Factor
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    ABSTRACT: Aloe vera (AV) is suggested to be beneficial in treating irritable bowel syndrome (IBS) symptoms, but no scientific trials exist to confirm this. We aim to assess the efficacy of AV on IBS in refractory secondary care patients. Patients with IBS were randomised to receive AV or matching placebo for a month. Symptoms were assessed at baseline, 1 and 3 months. Fifty-eight patients randomised, 49 completed the protocol to 1 month and 41 to 3 months. Eleven of thirty-one (35%) AV patients, and 6 of 27 (22%) placebo patients responded at 1 month (p = 0.763). Diarrhoea predominant patients showed a trend towards a response to treatment at 1 month (10/23 V 2/14, p = 0.07). There was no evidence that AV benefits patients with IBS. However, we could not rule out the possibility that improvement occurred in patients with diarrhoea or alternating IBS whilst taking AV. Further investigations are warranted in patients with diarrhoea predominant IBS, in a less complex group of patients.
    International Journal of Clinical Practice 10/2006; 60(9):1080-6. · 2.43 Impact Factor
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    ABSTRACT: This systematic review examined the use of immunomodulators and the risk of postoperative complications after abdominal surgery in patients with inflammatory bowel disease. Electronic databases (PubMed, Embase, Ingenta, Zetoc and Ovid) were searched and the reference lists in all articles identified were hand-searched for further relevant papers. Studies were included if they evaluated postoperative complications and defined exposure to individual immunomodulators. All 11 studies that met the inclusion criteria were observational studies; two were reported only in abstract form. Five studies reported risks associated with azathioprine, five reported risks associated with cyclosporin and three reported risks associated with infliximab. None showed an increased risk of either total or infectious complications associated with immunomodulator use. However, subgroup analysis in one study, published as an abstract, suggested increased rates of anastomotic complications and reoperation associated with azathioprine. Available evidence does not suggest an increased rate of postoperative complications associated with immunomodulator use.
    British Journal of Surgery 08/2006; 93(7):793-9. · 4.84 Impact Factor
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    ABSTRACT: Obesity is increasingly being recognized as a risk factor for a number of benign and malignant gastrointestinal conditions. However, literature on the underlying pathophysiological mechanisms is sparse and ambiguous. Insulin resistance is the most widely accepted link between obesity and disease, particularly colorectal cancer. The recognition that intra-abdominal fat is immunologically active sheds new light not only on the pathogenesis of obesity-related gastrointestinal conditions, but also on inflammatory conditions such as Crohn's disease. To describe the biology of adipose tissue, its impact on the immune system and explores the possible underlying mechanisms linking obesity to gastrointestinal diseases. It also looks at the role of mesenteric fat in determining severity and course of Crohn's disease. Relevant English-language literature and abstracts cited on MEDLINE database were reviewed. Our recent finding of an association between obesity and subclinical bowel inflammation suggests that, apart from promoting generalized immune activation, fat also evokes local immune responses. We propose that the proinflammatory milieu promoted by obesity could underlie many of these associations and that the mechanism implicating insulin resistance may merely represent an epiphenomenon. In Crohn's disease, on the other hand, intra-abdominal fat may provide a protective mechanism. The potential of adipose tissue as a therapeutic target is vast and needs exploration.
    Alimentary Pharmacology & Therapeutics 07/2006; 23(11):1511-23. · 4.55 Impact Factor
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    ABSTRACT: Colorectal cancer development is associated with a shift in host immunity with suppression of the cell-mediated immune system (CMI) and a predominance of humoral immunity (HI). Tumour progression is also associated with increased rates of cell proliferation and apoptosis. The aim of this study was to investigate whether these factors correlate and have an influence upon prognosis. Long-term follow-up was performed on 40 patients with colorectal cancer who had levels of tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-10 measured from stimulated blood cultures before surgery. Their archived tumour specimens were analysed to determine a Ki-67-derived proliferation index (PI) and a M30-derived apoptosis index (AI). Tumour necrosis factor-alpha levels negatively correlated to tumour proliferation (rho=-0.697, P=0.01). Interleukin-10 levels had a positive correlation with tumour proliferation (rho=0.452, P=0.05) and apoptosis (rho=0.587, P=0.01). Patient survival correlates to tumour pathological stage (P=0.0038) and vascular invasion (P=0.0014). An AI< or =0.6% and TNF-alpha levels > or =8148 pg ml(-1) correlate to improved survival (P=0.032, P=0.021). Tumour proliferation and apoptosis correlate to progressive suppression of the CMI-associated cytokine TNF-alpha and to and higher levels of IL-10. Survival is dependent upon the histological stage of the tumour, vascular invasion, rates of apoptosis and proliferation and systemic immunity which are all interconnected.
    British Journal of Cancer 06/2006; 94(10):1412-9. · 5.08 Impact Factor
  • Alimentary Pharmacology & Therapeutics (Suppl) 01/2006; 24(7):1129-1131.
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    ABSTRACT: Short-course pre-operative radiotherapy (SCPRT) and total mesorectal excision (TME) have been shown to reduce the rate of relapse and improve survival in patients with rectal cancer. Concerns about morbidity have limited its application in some centres. The aim of this study was to assess long-term toxicity of pre-operative RT in patients with rectal cancer. Permanent toxicity was assessed in 20 patients who were alive >12 months after pre-operative RT (25Gy/ 5#), using a validated LENT SOMA scoring system. Ten patients with rectal cancer who had been operated on >12 months ago, but had not received pre-operative RT were assessed similarly. Patients who had received SCPRT appeared to have a significantly higher rectal toxicity, urinary and male sexual dysfunction, compared with the controls. No significant difference was noted in female sexual dysfunction. The combination of pre-operative RT and TME appears to be associated with significant long-term toxicity. Better methods of staging the tumours may improve selection of patients for SCPRT.
    The surgeon: journal of the Royal Colleges of Surgeons of Edinburgh and Ireland 11/2005; 3(5):347-51. · 1.97 Impact Factor
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    ABSTRACT: The Royal College of Pathologists' guidelines for reporting colorectal cancer state that all lymph nodes in a colorectal cancer specimen should be sampled, regardless of site or size. The only means by which one can be certain that all nodes have been sampled is to clear the fat and visualise the lymph nodes. Methods of fat clearance have been available for many years, but few are acceptable in routine practice. Here, a simple, effective and economical solution to the problem is described, which should be amenable to any laboratory with a spare or back-up tissue-processing machine.
    British journal of biomedical science 02/2005; 62(3):120-3. · 0.83 Impact Factor
  • P Roy, D Kumar
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    ABSTRACT: Advances in the use of bowel-sparing surgery for Crohn's disease have led to the development of strictureplasty as an important technique to conserve small bowel length and reduce morbidity associated with malabsorption. A literature review of long-term studies on strictureplasty was undertaken, and evidence of its safety and efficacy was evaluated. The safety and efficacy of strictureplasty is confirmed in retrospective studies carried out over a period of 5-10 years, particularly when employed in patients at risk of short bowel syndrome, but certain questions regarding bowel function and disease activity after surgery remain unanswered. There is also concern that diseased tissue is left in situ after strictureplasty; this tissue has the potential for malignant transformation in the long term. Strictureplasty has been used in surgery for Crohn's disease for the past 25 years. Studies have proven its efficacy in the treatment of carefully selected patients at risk of malabsorption owing to short bowel syndrome.
    British Journal of Surgery 12/2004; 91(11):1428-37. · 4.84 Impact Factor
  • A G Heriot, A Skull, D Kumar
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    ABSTRACT: Rectoceles are traditionally repaired transvaginally and sexual dysfunction can be a significant complication. The aim of this study was to evaluate the functional and physiological outcome following transanal repair of rectoceles. Forty-five patients of mean age 57.1 (range 34-78) years with a symptomatic anterior rectocele, selected by contrast retention greater than 15 per cent on isotope defaecography, underwent transanal repair of rectocele. Preoperative and postoperative symptoms were assessed by means of a questionnaire. A proportion of patients underwent anorectal physiology and isotope defaecography before and after surgery. Median(range) follow-up was 24 (2-50) months. One patient developed a wound infection after surgery. Thirty-five patients reported an excellent, good or fair result, with seven reporting a moderate and three a poor result. There was a reduction in incomplete evacuation (P < 0.001) confirmed by isotope defaecography (mean(s.d.) rectal emptying before surgery 57(14) per cent versus 76(9) per cent after surgery; P = 0.020), and a reduction in vaginal (P < 0.001) and perineal (P = 0.004) digitation. Symptomatic feeling of prolapse (vaginal bulging) was significantly improved (P < 0.001). There was no increase in incontinence (P = 0.688). Resting and squeeze anal canal pressures were unchanged after operation. Surgery did not result in sexual dysfunction. Transanal repair of rectocele is a safe alternative to posterior colporrhaphy. It provides improvement in symptoms, reflected by anatomical improvement with minimal complications and no increase in dyspareunia.
    British Journal of Surgery 11/2004; 91(10):1340-4. · 4.84 Impact Factor
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    ABSTRACT: To evaluate the impact of adjuvant biofeedback following sphincter surgery. Thirty-eight patients were randomized into sphincter repair or sphincter repair plus biofeedback groups. Outcome measures included a symptom questionnaire, patient's rating of satisfaction with continence function and improvement, change in continence score, quality of life and anorectal physiology. Endoanal ultrasonography was also performed pre- and post-operatively. Immediately following surgery, there was no statistically significant difference in any of the functional or physiological variables between the groups. Continence and patient satisfaction scores improved with a mean difference of -0.48 (95% CI: -3.30-2.33, P = 0.73) and 1.03 (95% CI: -1.40-3.46, P = 0.39), respectively. Only the difference in embarrassment scores reached statistical significance (mean) 0.56 (95% CI: 0.12-0.99, P = 0.014). Resting and squeeze pressures also improved. Thirteen of 14 in the biofeedback and 11 of 17 (control) reported symptomatic improvement. In the biofeedback group, although not statistically significant continence and satisfaction scores improved and were sustained over time. In the control group, continence and satisfaction scores changed little between 3 and 12 months (P = NS). Quality of life measures improved within the biofeedback group but there was no statistical difference between the groups. Following surgery continence function improves in all patients but adjuvant biofeedback therapy improves quality of life and maintains symptomatic improvement over time.
    Alimentary Pharmacology & Therapeutics 10/2004; 20(5):539-49. · 4.55 Impact Factor
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    ABSTRACT: Colonic diverticular disease is more common in Western populations than in developing countries. To determine whether the frequency of colonic diverticular disease is different in British patients of Indian-subcontinent Asian origin compared with other ethnic groups. All colonoscopies performed over a 3-year period in a London hospital were studied. Patients of Indian-subcontinent Asian origin were identified by name. Five of 134 Indian-subcontinent Asian males (4%) had colonic diverticular disease, compared with 278 of 1268 patients of other ethnic groups (22%; P < 0.001). Five of 91 Indian-subcontinent Asian females (6%) had colonic diverticular disease, compared with 333 of 1486 patients of other ethnic groups (23%; P < 0.001). Although patients of Indian-subcontinent Asian origin (54.8 +/- 15.8 years) were younger than those of other ethnic groups (60.3 +/- 17.8 years; P < 0.0001), the ethnic difference in the frequency of diverticular disease persisted even when age was taken into account. There is a lower frequency of colonic diverticular disease in Indian-subcontinent Asians presenting for colonoscopy, compared with other ethnic groups. This cannot be explained by sex or age differences. Our findings require confirmation, but may provide opportunities for research into the aetiology of colonic diverticular disease.
    Alimentary Pharmacology & Therapeutics 05/2004; 19(7):765-9. · 4.55 Impact Factor
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    ABSTRACT: Approximately 0.6-9 per cent of vaginal deliveries are complicated by third-degree tears. The precise impact of such injuries on future pelvic floor function remains unknown. The aim of this study was to define the extent of structural and physiological damage to the anal sphincter and to investigate anorectal function in women who sustained third-degree tears during vaginal delivery. Fifty-six women who sustained a third-degree tear were investigated prospectively. All patients had a primary repair of the anal sphincter complex, and were assessed by anorectal physiology and endoanal ultrasonography at a mean of 3.6 months. Symptoms were assessed by direct personal interview and also by a self-completed questionnaire. Forty-four patients had a persistent anal sphincter defect on ultrasonography. The mean resting and squeeze anal canal pressures were significantly lower in patients with a combined defect than in those in whom the repair was intact (P = 0.036 and P = 0.005 respectively). At direct interview three patients volunteered current symptoms of faecal and/or urinary incontinence whereas 32 reported bothersome symptoms on the questionnaire (P < 0.001). The anatomical and physiological damage sustained during third-degree tears appears to be much greater than is generally appreciated. Primary repair does not provide lasting integrity. A self-administered questionnaire appears to be more accurate in defining the symptomatology.
    British Journal of Surgery 12/2003; 90(12):1573-9. · 4.84 Impact Factor
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    ABSTRACT: Colorectal motor activity in slow-transit idiopathic constipation has not been fully evaluated under physiological conditions. The aim of this study was to evaluate colorectal motor activity in chronic idiopathic constipation using 24-h ambulant pancolonic manometry. Ten healthy volunteers (six females) 19-31 years of age, and eight females 25-46 years of age with slow-transit idiopathic constipation were studied. Motor activity was measured using two custom-made silicone-coated catheters, each with five solid-state pressure transducers. Bowel preparation or sedation was not used. Frequency of high-amplitude propagated contractions was reduced in chronic idiopathic constipation, median 1.9/24 h vs 6/24 h (P = 0.01). Contractile frequency of low-amplitude complexes was reduced throughout the colon in slow-transit idiopathic constipation (P < 0.0001). The interval between contractile complexes was reduced in the transverse colon and splenic flexure (P < 0.0001). This study demonstrates that colonic motor activity is abnormal in slow-transit idiopathic constipation; decreased motor activity leads to a reduction in propulsion of intraluminal contents.
    Neurogastroenterology and Motility 10/2003; 15(5):515-22. · 2.94 Impact Factor
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    K Davis, D Kumar, J Poloniecki
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    ABSTRACT: It has been previously shown that 'bulking' of internal anal sphincter defects may provide an effective method to treat patients with faecal incontinence, but the benefit wears off with time. To assess the efficacy of a larger molecule, bulking agent (Durasphere) over the short- and long-term in patients with an internal anal sphincter defect refractory to conservative management. Eighteen patients (nine male, nine female) with a mean age of 60 years were recruited. All patients had persistent faecal leakage/soiling. Durasphere was injected in the submucosal plane to restore anal canal symmetry. All patients had anorectal physiology, endoanal ultrasound, continence grading, patient satisfaction and quality of life scores assessed at 1, 3, 6 and 12 months. The mean follow-up is 28.5 months. Changes from baseline were not statistically significant up to 6 months. At 12 months there was significant improvement in the continence grading (P=0.003), patient satisfaction (P=0.053) and all quality of life subscales: lifestyle (P=0.004), coping (P=0.011), depression (P=0.024) and embarrassment (P=0.059). Anorectal physiological parameters apart from the maximum tolerable rectal volume at 12 months (P=0.036) showed no significant improvement. Anal sphincter bulking with Durasphere is safe and effective in the short term as well as the longer term. More importantly, there is no evidence of attenuation of effect over time.
    Alimentary Pharmacology & Therapeutics 08/2003; 18(2):237-43. · 4.55 Impact Factor
  • British Journal of Surgery 01/2003; 89(12):1622; author reply 1622. · 4.84 Impact Factor
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    S Zar, M J Benson, D Kumar
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    ABSTRACT: Bloating is a frequently reported symptom in functional bowel disorders. It usually occurs in combination with other symptoms, but may also occur in isolation. The severity of bloating tends to worsen during the course of the day and improves overnight. Although frequently considered to be a subjective phenomenon, recent studies have shown that bloating is associated with a measurable increase in abdominal girth. The pathophysiology of bloating remains elusive, but the evidence supports a sensorimotor dysfunction of the bowel. The possible mechanisms include abnormal gas trapping, fluid retention, food intolerance and altered gut microbial flora. Further studies are needed to define the sensorimotor abnormalities associated with bloating, which might be segmental and transient rather than generalized and persistent. The lack of understanding of this symptom is paralleled by a limited availability of therapeutic options. Conventional medications used in functional bowel disorders are not helpful and may indeed worsen the symptoms. In future, new drugs with activity against serotonin and kappa receptors, or novel approaches such as the use of exclusion diets, probiotics and hypnotherapy, may prove to be useful.
    Alimentary Pharmacology & Therapeutics 12/2002; 16(11):1867-76. · 4.55 Impact Factor

Publication Stats

1k Citations
443.08 Total Impact Points

Institutions

  • 2006
    • George Eliot Hospital NHS Trust
      Nuneaton, England, United Kingdom
  • 1998–2006
    • St. George's School
      • • Department of Surgery
      • • Department of Obstetrics and Gynaecology
      • • Division of Gastroenterology, Endocrinology and Metabolism
      Middletown, Rhode Island, United States
  • 1997–2006
    • St George's, University of London
      • Division of Clinical Sciences
      Londinium, England, United Kingdom
  • 2002
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom