Single-centre experience with peptide receptor radionuclide therapy for neuroendocrine tumours (NETs): results using a theranostic molecular imaging-guided approach.

AIM: To summarise our centre's experience managing patients with neuroendocrine tumours (NETs) in the first 5 years after the introduction of peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-octreotate (LUTATE). The report emphasises aspects of the patient management related to functional imaging and use of radionuclide therapy. METHODS: We describe the criteria for treatment with LUTATE at our centre, the methodology for patient selection, and the results of an audit of clinical measures, imaging results and patient-reported outcomes. Subjects are treated initially with four cycles of ~ 8 GBq of LUTATE administered as an outpatient every 8 weeks. RESULTS: In the first 5 years offering LUTATE, we treated 143 individuals with a variety of NETs of which approx. 70% were gastroentero-pancreatic in origin (small bowel: 42%, pancreas: 28%). Males and females were equally represented. Mean age at first treatment with LUTATE was 61 ± 13 years with range 28-87 years. The radiation dose to the organs considered most at risk, the kidneys, averaged 10.6 ± 4.0 Gy in total. Median overall survival (OS) from first receiving LUTATE was 72.5 months with a median progression-free survival (PFS) of 32.3 months. No evidence of renal toxicity was seen. The major long-term complication seen was myelodysplastic syndrome (MDS) with a 5% incidence. CONCLUSIONS: LUTATE treatment for NETs is a safe and effective treatment. Our approach relies heavily on functional and morphological imaging informing the multidisciplinary team of NET specialists to guide appropriate therapy, which we suggest has contributed to the favourable outcomes seen.

Avelumab in unresectable/metastatic, progressive, grade 2-3 neuroendocrine neoplasms (NENs): Combined results from NET-001 and NET-002 trials.

BACKGROUND: Higher grade neuroendocrine neoplasm (NENs) continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionised the treatment of many cancers, its role in NENs remains unclear. We aimed to investigate the efficacy and safety of avelumab, a PD-L1-directed antibody, in patients with advanced unresectable/metastatic higher grade NENs. METHODS: NET001 and NET002 are phase II studies investigating avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastroenteropancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0-2 prior lines of systemic therapy (excluding SSAs). Patients were treated with avelumab 10 mg/kg intravenously every two weeks for 26 cycles. NET001 investigated G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 investigated G2-3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was overall response rate (ORR) by RECIST v1.1; secondary endpoints included progression-free survival, overall survival, disease control rate at six months and toxicity. RESULTS: Twenty-seven patients were enrolled (21 GEP, 6 lung; 10 in NET-001, 17 in NET-002); median age 64 (range 37-80), 30% ECOG PS 1-2 and 78% received 1+ lines of prior therapy. The median Ki-67 index was 35% (range 10-100). Twelve of the twenty-seven patients had died at the time of data lock. The median time on treatment was 85 days (seven cycles). No objective responses were observed. Stable disease was achieved in 33% of patients, and the disease control rate at 6 mo was 21%. The median PFS was 3.3 months (range 1.2-24.6), and the median OS was 14.2 months. Treatment-related adverse events (all grades) occurred in 58% of patients. Three patients had treatment-related grade 3-4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). CONCLUSION: Single-agent PD-L1 blockade with avelumab showed limited antitumour activity in patients with G2-3 NENs. Correlative studies are underway. Further studies are needed to explore the role of dual immunotherapy and other combinations in this population with few treatment alternatives.

Prospective evaluation of the utility of cross-matching prior to first transfusion in cats: 101 cases.

OBJECTIVES: To: (1) assess the frequency of crossmatch incompatibility in naïve feline blood transfusion recipients using two crossmatching methods, (2) measure the effect of crossmatch incompatibility on change in packed cell volume following transfusion, (3) assess the frequency of acute transfusion reactions and errors in blood transfusions in cats and (4) assess the impact of crossmatch incompatibility on the likelihood of transfusion reactions. MATERIALS AND METHODS: Cats being administered a first AB-matched transfusion in a veterinary teaching hospital were prospectively recruited for this observational study. A slide agglutination method and a commercial test were both used for major and minor crossmatching. We measured increase in packed cell volume at 12 hours after transfusion relative to the mass of red blood cells given per recipient bodyweight and recorded transfusion reactions. RESULTS: A total of 101 cats was included. Crossmatch incompatibility was common using the slide agglutination method (27% and 10% major and minor incompatibility, respectively), but less common with the commercial test (major and minor incompatibility both 4%). Crossmatch incompatibility with any method was not associated with less effective transfusion in terms of change in packed cell volume. Transfusion reactions occurred in 20 cats, most commonly febrile non-haemolytic transfusion reactions (n = 9) and haemolytic transfusion reactions (n = 7). The commercial test appeared to be most specific for predicting haemolytic transfusion reactions. CLINICAL SIGNIFICANCE: Transfusion reactions were fairly common but not associated with increased mortality. Use of crossmatch-compatible blood did not lead to a greater increase in PCV at 12 hours. The commercial test may predict a haemolytic transfusion reaction.

External Beam Radiotherapy in the Treatment of Gastroenteropancreatic Neuroendocrine Tumours: A Systematic Review.

AIMS: External beam radiotherapy (EBRT) is infrequently used to treat gastroenteropancreatic neuroendocrine tumours (GEPNETS), with little published data to date. We carried out a systematic review to assess the activity of EBRT for GEPNETS. MATERIALS AND METHODS: Major databases were searched for papers including at least five patients treated with contemporary EBRT techniques. Eligible studies underwent dual independent review. The primary end points were response rate for lesions treated with definitive intent and recurrence-free survival for primary lesions treated with neoadjuvant or adjuvant intent. RESULTS: Of 11 included studies (all retrospective), seven investigated pancreatic neuroendocrine tumours (PNETs, 100 patients, 14% grade 3) and four studies investigated extra-pancreatic neuroendocrine tumours (84 patients, 14% grade 3). Trials investigating PNETs administered a median of 50.4 Gy via three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. EBRT was given with neoadjuvant or adjuvant intent in 56 patients, with a recurrence rate of 15%. For the 44 patients not undergoing surgery, the radiological response rate was 46%. Grade 3 + toxicity rates were 11% (acute) and 4% (late). Twelve patients with anorectal neuroendocrine carcinoma received 58 Gy to the primary tumour. Seventy-two patients were treated to sites of metastatic disease (34 bone, 27 brain, 11 soft tissue). Local and distant control were poorly reported. Overall survival ranged from 9 to 19 months. No studies in this group reported toxicity outcomes. CONCLUSIONS: There are limited, retrospective data on the overall activity and safety of EBRT in GEPNETS. EBRT generally seems to be well tolerated in selected PNET patients with encouraging activity. Well-designed prospective studies in clearly defined populations are required to clarify the role of EBRT in neuroendocrine tumours.

High-dose versus low-dose botulinum toxin in anal fissure disease.

BACKGROUND: There is no consensus on the optimal dosage of botulinum toxin (BT) as a sphincter sparing alternative to lateral internal sphincterotomy for chronic anal fissure. The aim of this study was to assess the long-term efficacy of high-dose BT as well as the presence of incontinence following the treatment of chronic anal fissure at a single institution. METHODS: A retrospective case-control study was performed at a single institution over a 6-year period (2009-2014). Patients given high-dose (80-100 IU) BT were compared to low-dose (20-40 IU) case controls. Clinical notes were reviewed, and follow-up was carried out via a telephone questionnaire. RESULTS: One hundred and fifty-eight patients were treated with BT injections within the study period (103 high dose; 55 low dose). The mean length of follow-up was 25 months (range 4-52 months). Classic posterior fissures with high anal tone were more prevalent in the low-dose group (40 vs 47%, p = 0.3). Patient satisfaction was higher in the high-dose group (90 vs 78%, p = 0.05). Long-term recurrence (6 months after the last treatment) was also lower (23 vs 53%, p = 0.0001) on multivariate analysis. No long-term incontinence was observed. CONCLUSIONS: In this series, the recurrence rate post-BT injection was significantly lower in the high-dose group. There was no long-term incontinence. Further studies are needed to confirm our results.

Predicting Outcome in dogs with Primary Immune-Mediated Hemolytic Anemia: Results of a Multicenter Case Registry.

BACKGROUND: Outcome prediction in dogs with immune-mediated hemolytic anemia (IMHA) is challenging and few prognostic indicators have been consistently identified. OBJECTIVES: An online case registry was initiated to: prospectively survey canine IMHA presentation and management in the British Isles; evaluate 2 previously reported illness severity scores, Canine Hemolytic Anemia Score (CHAOS) and Tokyo and to identify independent prognostic markers. ANIMALS: Data from 276 dogs with primary IMHA across 10 referral centers were collected between 2008 and 2012. METHODS: Outcome prediction by previously reported illness-severity scores was tested using univariate logistic regression. Independent predictors of death in hospital or by 30-days after admission were identified using multivariable logistic regression. RESULTS: Purebreds represented 89.1% dogs (n = 246). Immunosuppressive medications were administered to 88.4% dogs (n = 244), 76.1% (n = 210) received antithrombotics and 74.3% (n = 205) received packed red blood cells. Seventy-four per cent of dogs (n = 205) were discharged from hospital and 67.7% (n = 187) were alive 30-days after admission. Two dogs were lost to follow-up at 30-days. In univariate analyses CHAOS was associated with death in hospital and death within 30-days. Tokyo score was not associated with either outcome measure. A model containing SIRS-classification, ASA classification, ALT, bilirubin, urea and creatinine predicting outcome at discharge was accurate in 82% of cases. ASA classification, bilirubin, urea and creatinine were independently associated with death in hospital or by 30-days. CONCLUSIONS AND CLINICAL IMPORTANCE: Markers of kidney function, bilirubin concentration and ASA classification are independently associated with outcome in dogs with IMHA. Validation of this score in an unrelated population is now warranted.

Comparison of computed tomography pulmonary angiography and point-of-care tests for pulmonary thromboembolism diagnosis in dogs.

OBJECTIVES: To evaluate the feasibility of CT pulmonary angiography for identification of naturally occurring pulmonary thromboembolism in dogs using predefined diagnostic criteria and to assess the ability of echocardiography, cardiac troponins, D-dimers and kaolin-activated thromboelastography to predict the presence of pulmonary thromboembolism in dogs. METHODS: Twelve dogs with immune-mediated haemolytic anaemia and evidence of respiratory distress were prospectively evaluated. Dogs were sedated immediately before CT pulmonary angiography using intravenous butorphanol. Spiral CT pulmonary angiography was performed with a 16 detector-row CT scanner using a pressure injector to infuse contrast media through peripheral intravenous catheters. Pulmonary thromboembolism was diagnosed using predefined criteria. Contemporaneous tests included echocardiography, arterial blood gas analysis, kaolin-activated thromboelastography, D-dimers and cardiac troponins. RESULTS: Based on predefined criteria, four dogs were classified as pulmonary thromboembolism positive, three dogs were suspected to have pulmonary thromboembolism and the remaining five dogs had negative scans. The four dogs identified with pulmonary thromboembolism all had discrete filling defects in main or lobar pulmonary arteries. None of the contemporaneous tests was discriminant for pulmonary thromboembolism diagnosis, although the small sample size was limiting. CLINICAL SIGNIFICANCE: CT pulmonary angiography can be successfully performed in dogs under sedation, even in at-risk patients with respiratory distress and can both confirm and rule out pulmonary thromboembolism in dogs.

Repeat cytoreductive surgery (CRS) for recurrent colorectal peritoneal metastases: yes or no?

PURPOSE: To clarify the role of repeat CRS for recurrent colorectal carcinoma (CRC) through: (i) Systematic review of the literature (ii) Analysis of survival outcomes in a prospective cohort. METHODS: (i) Pubmed and MEDLINE from 1980 to July 2013 searched using terms: colorectal carcinoma, peritonectomy, cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), redo, repeat, and iterative. (ii) Kaplan-Meier Survival analysis of consecutive patients undergoing repeat CRS at St George Hospital between Jan 2000 and July 2013. RESULTS: (i) The search strategy yielded 309 articles, 5 meeting inclusion criteria, reporting on 91 patients. Median overall survival from first CRS ranged from 39 to 57.6 months with 3-yr survival of 50%, and 5-year survival of 30%. Median survival from second CRS was 20-months with 1-yr survivals of 72% and 66% and 2-year survivals of 50% and 44%. (ii) Repeat CRS performed on 18 patients found median survival from first CRS was 59 months, with 1, 3, and 5-year survival of 100%, 52% and 26% respectively. Median survival from repeat CRS was 22.6 months with 1, 2, and 3-year survival of 94%, 48% and 12% respectively. CONCLUSION: The current data on repeat CRS in CRC is relatively immature and more data is required before drawing clear conclusions. Patient selection should be on a case by case basis conducted through a MDT process with emphasis on surrogate markers for favourable outcomes.

The immunopathology of sepsis: pathogen recognition, systemic inflammation, the compensatory anti-inflammatory response, and regulatory T cells.

Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen-associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro-inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient-based clinical research in this area of human and veterinary medicine.

Serial assessment of the coagulation status of dogs with immune-mediated haemolytic anaemia using thromboelastography.

This study investigated the coagulation status of dogs with immune-mediated haemolytic anaemia (IMHA) over time. Thirty animals with primary IMHA were blood sampled on three occasions over a 5 day period and assays performed included prothrombin time, activated partial thromboplastin time, D-dimer and fibrinogen concentration, antithrombin activity and recalcified unactivated thromboelastography (TEG). Based on TEG, dogs with IMHA were significantly hypercoagulable vs. controls (P<0.001) and over the 5 day period, 3/4 of the TEG parameters reflected increased clotting kinetics (P ≤ 0.02). The 30 day survival of these patients was 80% and, at hospital admission, the TEG maximum amplitude (MA) was significantly higher in survivors than non-survivors (P=0.015). Each unit increase in MA was associated with an increased odds of 30 day survival of 1.13 (95%; CI 1.02-1.25). Based on TEG, most dogs with IMHA were hypercoagulable on admission and their clotting kinetics increased with time. Relative hypocoagulability identified by TEG at initial assessment was found to be a negative prognostic indicator.

Hypercoagulability in dogs with protein-losing enteropathy.

BACKGROUND: Dogs with protein-losing enteropathy (PLE) have previously been reported to present with thromboembolism; however, the prevalence and pathogenesis of hypercoagulability in dogs with PLE have not been investigated so far. HYPOTHESIS: Dogs with PLE are hypercoagulable compared with healthy control dogs. ANIMALS: Fifteen dogs with PLE. Thirty healthy dogs served as controls (HC). METHODS: A prospective study was performed including 15 dogs with PLE. All dogs were scored using the canine chronic enteropathy activity index (CCECAI). Thromboelastography (TEG) and other measures of coagulation were evaluated. Recalcified, unactivated TEG was performed and reaction time (R), kinetic time (K), alpha angle (α), and maximum amplitude (M(A)) values were recorded. Nine dogs were reassessed after initiation of immunosuppressive treatment. RESULTS: All dogs with PLE in the study were hypercoagulable with decreased R (PLE: median 7.8, range [2.4-11.2]; HC: 14.1 [9.1-20.3]), decreased K (PLE: 2.5 [0.8-5.2]; HC: 8.25 [4.3-13.1]), increased α (PLE: 56.7 [38.5-78.3]; HC: 25.6 [17-42.4]), and increased M(A) (PLE: 68.2 [54.1-76.7]; HC: 44.1, [33.5-49]) (all P < .001). Median antithrombin (AT) concentration was borderline low in PLE dogs; however, mean serum albumin concentration was severely decreased (mean 1.67 g/dL ± 5.1, reference range 2.8-3.5 g/dL). Despite a significant improvement in serum albumin and CCECAI, all 9 dogs with PLE were hypercoagulable at re-examination. CONCLUSIONS AND CLINICAL IMPORTANCE: The hypercoagulable state in dogs with PLE cannot be solely attributed to loss of AT. Despite good clinical response to treatment, dogs remained hypercoagulable and could therefore be predisposed to thromboembolic complications.

Use of serum concentrations of interleukin-18 and monocyte chemoattractant protein-1 as prognostic indicators in primary immune-mediated hemolytic anemia in dogs.

BACKGROUND: The cytokine response in immune-mediated hemolytic anemia (IMHA) is poorly characterized and correlation with outcome is unknown. HYPOTHESIS/OBJECTIVES: To determine if cytokine activity is correlated with outcome in dogs with IMHA. ANIMALS: Twenty dogs with primary IMHA and 6 control dogs. METHODS: Prospective study on dogs with IMHA with blood sampling at admission. Serum activity of interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL-8, IL-10, IL-15, IL-18, monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony stimulating factor (GM-CSF), interferon-inducible protein-10, interferon-gamma, and keratinocyte chemoattractant (KC) was assessed. RESULTS: Thirty-day case fatality rate was 25% (5/20 dogs). Increased concentrations (median [range]) of IL-2 (45.5 ng/L [0;830] versus 0 ng/L [0;46.8]), IL-10 (8.2 ng/L [0;60.6] versus 0 ng/L [0;88.2]), KC (1.7 µg/L [0.3;4.7] versus 0.5 µg/L [0.2;1.1]), and MCP-1 (162 ng/L [97.6;438] versus 124 ng/L [90.2;168]) were observed in dogs with IMHA compared with controls. The cytokine profile was indicative of a mixture of pro- and anti-inflammatory cytokines of various cellular origins. Cytokines/chemokines strongly associated with macrophage/monocyte activation and recruitment were significantly increased in nonsurvivors compared with survivors; IL-15 (179 ng/L [48.0;570] versus 21.3 ng/L [0;193]), IL-18 (199 ng/L [58.7;915] versus 37.4 ng/L [0;128]), GM-CSF (134 ng/L [70.0;863] versus 57.6 ng/L [0;164]), and MCP-1 (219 ng/L [135;438] versus 159 ng/L [97.6;274]), respectively. Logistic regression suggested increased IL-18 and MCP-1 concentrations were independently associated with mortality in this population (P<.05, Wald's type 3). CONCLUSIONS AND CLINICAL IMPORTANCE: A mixed cytokine response is present in dogs with IMHA and mediators of macrophage activation and recruitment might serve as prognostic indicators.

Association between hypercoagulability and decreased survival in horses with ischemic or inflammatory gastrointestinal disease.

BACKGROUND: Coagulopathies are common in horses with ischemic or inflammatory gastrointestinal (GI) disturbances. There is indirect evidence suggesting that early stages of these diseases are characterized by hypercoagulability (HC). HYPOTHESIS/OBJECTIVES: HC, assessed via thromboelastography (TEG), is common in horses with ischemic or inflammatory GI diseases. The degree of HC is correlated with nonsurvival and thrombotic complications. ANIMALS: Thirty client-owned horses with ischemic or inflammatory GI disease, 30 client-owned horses with nonischemic or inflammatory GI disease, and 30 healthy horses (control group). METHODS: Prospective, observational clinical study. TEG profiles of 30 horses with ischemic or inflammatory GI disease were obtained on admission and 48 hours after admission, and these were compared with profiles from 30 horses with nonischemic or inflammatory GI disease and 30 healthy controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin activity (AT), and D-Dimer concentrations were also determined in horses with GI disease. RESULTS: Horses with ischemic or inflammatory GI disease had shorter R times compared with healthy horses (14.8±8.3 versus 22.8±12 minute; P=.011). However, changes were subtle and TEG profiles did not resembled those obtained from animals or humans presumed to be hypercoagulable. Although conventional coagulation testing supported the presence of HC (decreased AT and increased D-Dimer concentrations), TEG and coagulation abnormalities were rarely found in the same horses and the methods were not statistically related. CONCLUSIONS AND CLINICAL IMPORTANCE: There is evidence of HC in horses with GI disease but techniques for diagnoses require refinement.

Relationship among plasma amino acids, C-reactive protein, illness severity, and outcome in critically ill dogs.

BACKGROUND: Alterations in circulating amino acids have been documented in animal models and in critically ill people but have not been evaluated in dogs with spontaneously occurring disease. HYPOTHESIS/OBJECTIVES: To compare amino acid concentrations in critically ill dogs and healthy controls and to investigate potential relationships among amino acids, markers of inflammation, illness severity, and clinical outcome. ANIMALS: Forty-eight critically ill dogs and 24 healthy control dogs. METHODS: Plasma was analyzed for amino acids and C-reactive protein (CRP) was measured in serum. The Fischer ratio (the molar ratio of branched chain amino acids [BCAA] to aromatic amino acids [AAA]) and survival prediction index (SPI2) were calculated. RESULTS: Median CRP concentrations were significantly higher in the critically ill dogs compared with controls (P < .001). Critically ill dogs had significantly lower concentrations of alanine (P= .001), arginine (P < .001), citrulline (P < .001), glycine (P < .001), methionine (P < .001), proline (P < .001), and serine (P= .001) but significantly higher concentrations of lysine (P= .02) and phenylalanine (P < .001; Table 1). This pattern resulted in a significantly lower Fischer ratio (P= .001) in the critically ill group. Median SPI2 score was significantly higher in dogs that survived (P= .03). Concentrations of arginine (P= .02), isoleucine (P= .01), leucine (P= .04), serine (P= .04), valine (P= .04), total BCAA (P= .03), and the Fischer ratio (P= .03) were significantly higher in survivors compared with nonsurvivors. CONCLUSIONS AND CLINICAL IMPORTANCE: Critically ill dogs have altered amino acid profiles and additional research to investigate potential benefits of amino acid supplementation is warranted.

Concurrent immune-mediated haemolytic anaemia and severe thrombocytopenia in 21 dogs.

The medical records of 21 dogs with concurrent immune-mediated haemolytic anaemia (imha) and severe thrombocytopenia (defined as an automated platelet count of less than 50x10(9)/l, confirmed by the examination of a blood smear) were reviewed. Their mean (sd) age was 5.8 (2.5) years. When compared with the 24,759 dogs in the hospital population for the same period Airedale terriers and dobermanns appeared to be over-represented with odds ratios of 22.5 (95 per cent confidence interval [ci] 5.2 to 97.9) and 7.6 (95 per cent ci 1.8 to 32.7) respectively. The median duration of the dogs' clinical signs was seven days, with a range from one to 17 days. Eleven of the dogs had a history of a tendency to bleed, and 15 had evidence of bleeding when examined. Twenty of the 21 dogs had been treated with glucocorticoids, nine with vincristine, and seven with azathioprine. Their median stay in hospital was four days, with a range from one to 17 days. The median period for which they survived after admission to hospital was five days, with a range from one to 558 days, and 16 of the 21 dogs had died or been euthanased within 30 days of their admission.

The role of nutrients in modulating disease.

The role of nutrition in the management of diseases has often centred on correcting apparent nutrient deficiencies or meeting estimated nutritional requirements of patients. Nutrition has traditionally been considered a supportive measure akin to fluid therapy and rarely it has been considered a primary means of ameliorating diseases. Recently, however, further understanding of the underlying mechanisms of various disease processes and how certain nutrients possess pharmacological properties have fuelled an interest in exploring how nutritional therapies themselves could modify the behaviour of various conditions. Nutrients such as omega-3 fatty acids, antioxidants and certain amino acids such as arginine and glutamine have all been demonstrated to have at least the potential to modulate diseases. Developments in the area of critical care nutrition have been particularly exciting as nutritional therapies utilising a combination of approaches have been shown to positively impact outcome beyond simply proving substrate for synthesis and energy. Application of certain nutrients for the modulation of diseases in veterinary patients is still in early stages, but apparent successes have already been demonstrated, and future studies are warranted to establish optimal approaches. This review describes the rationale of many of these approaches and discusses findings both in human beings and in animals, which may guide future therapy.