Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial.

BACKGROUND & AIMS: The impact of thiopurine de-escalation while on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. METHODS: This multicenter randomized controlled trial recruited UC patients on vedolizumab 300 mg intravenously every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore ≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score ≥3 and fecal calprotectin >150 µg/g or increase in Mayo endoscopic subscore ≥1 from baseline), fecal calprotectin remission (<150 µg/g), C-reactive protein remission (<5 mg/L), centrally read endoscopic remission (Mayo endoscopic subscore = 0), histologic remission (Nancy index = 0), histo-endoscopic remission, and adverse events. RESULTS: In total, 62 patients were randomized to continue (n = 20) or withdraw (n = 42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7 µg/mL, interquartile rate [IQR], 12.3-18.5 µg/mL versus 15.9 µg/mL, IQR, 10.1-22.7 µg/mL, respectively, P = 0.36). The continue group had significantly higher fecal calprotectin remission (95.0%, 19/20 versus 71.4%, 30/42; P = .03), histologic remission (80.0%, 16/20 versus 48.6%, 18/37; P = .02), and histo-endoscopic remission (75.0%, 15/20 versus 32.4%, 12/37; P = .002) than the withdrawal group. Histologic activity (hazard ratio [HR], 15.5; 95% confidence interval [CI], 1.6-146.5; P = .02) and prior anti-tumor necrosis factor exposure (HR, 6.5; 95% CI, 1.3-33.8; P = .03) predicted clinical relapse after thiopurine withdrawal. CONCLUSIONS: Thiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic, and histo-endoscopic activity. Histologic activity and prior anti-tumor necrosis factor exposure may predict disease relapse on thiopurine withdrawal for patients using vedolizumab for UC. Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Knowledge and attitudes towards the use of histological assessments in ulcerative colitis by gastroenterologists vs pathologists.

BACKGROUND: Histological remission is increasingly accepted as a treatment endpoint in the management of ulcerative colitis (UC). However, the knowledge of histology guidelines and the attitudes towards their use in clinical practice by gastroenterologists and pathologists is unknown. AIM: To evaluate the knowledge of histology guidelines and attitudes towards the use of histology in UC by gastroenterologists and pathologists. METHODS: A prospective, cross-sectional nationwide survey of gastroenterologists and pathologists who analyse UC specimens was conducted. The survey consisted of 34 questions to assess gastroenterologists' and pathologists' knowledge (score out of 19) and attitudes towards histological assessment in UC. Survey questions were formulated using the European Crohn's and Colitis position paper on histopathology and the British Society of Gastroenterology biopsy reporting guidelines. It included knowledge of histological assessment of disease activity and dysplasia, knowledge of histological scoring systems for ulcerative colitis, uptake of histology scoring systems in routine practice, attitudes towards the role of histological activity, and the use of histological activity in clinical scenarios. RESULTS: Of 89 responders (77 gastroenterologists, 12 pathologists), there was almost universal acceptance that histological assessment should form part of UC evaluation [95% gastroenterologists, 92% pathologists]. However, gastroenterologists reported that 92% of their pathologists do not use a histological scoring system. Utilisation of a formal histological scoring system was preferred by 77% of gastroenterologists and 58% of pathologists. Both groups lacked awareness of the Geboes Score, Nancy Index and Robarts Histopathological Index scoring systems with 91%, 87%, and 92% of gastroenterologists respectively; and 83%, 83%, and 92% pathologists respectively, being uncertain of scoring systems' remission definitions. Histology knowledge score was not significantly different between gastroenterologists and pathologists [9/19 (IQR: 8-11) vs 8/19 (IQR: 7-10), P = 0.54]. Higher knowledge scores were predicted by hospital attending gastroenterologists (P = 0.004), participation in inflammatory bowel disease (IBD) multidisciplinary teams (P = 0.009), and self-declared IBD sub-specialist (P = 0.03). CONCLUSION: Histological remission is a recognised target for both gastroenterologists and pathologists. Despite this, knowledge of histological scoring systems and their utilisation is poor.

Cardiac manifestations of IgG4-related disease: a case series.

Background: IgG4-related disease (IgG4-RD) is an autoimmune condition affecting almost every organ system, with an early inflammatory phase and later fibrotic consequences. Vascular manifestations, particularly, large-vessel involvement in IgG4-RD, are well described. However, important IgG4-related effects on medium-sized arteries and the pericardium are less well recognized. These less frequently reported cardiovascular effects of IgG4-RD include coronary artery stenosis, pericardial disease, cardiac masses, and valvular heart disease. Case summary: This case series focuses on three patients that demonstrate the cardiovascular effects of IgG4-RD and the pitfalls and importance of early diagnosis. Cases 1 and 2 presented with cardiac manifestations prior to more typical organ systems being affected which led to a delay in diagnosis. Case 1 presented with an acute myocardial infarction secondary to IgG4-RD of the coronary arteries and Case 2 presented with pericarditis which progressed to pericardial constriction due to IgG4-RD. Case 3 already had a diagnosis of IgG4-RD from a prior renal biopsy which raised the index of suspicion that his pericardial disease and thoracic mass were also related to IgG4-RD. Discussion: Cardiac manifestations of IgG4-RD remain under-recognized and include coronary artery and pericardial disease. These manifestations often precede more typical manifestations in other organ systems. Recognizing cardiac manifestations of IgG4-RD on cardiac imaging can raise clinical suspicion and act as a catalyst to ascertain a confirmatory diagnosis. Early diagnosis and treatment are crucial to prevent potentially fatal outcomes and irreversible fibrosis.

Prostate adenocarcinoma with mucinous features - is it PSMA avid?

Mucinous prostate adenocarcinoma represents <0.1% of prostate cancers. To our knowledge, no previous report has described the 68 Ga-PSMA-PET characteristics of this entity at the primary site. We present a case of a fit 85-year-old with PSA 0.55 ng/mL and ISUP grade 4 acinar adenocarcinoma with mucinous features on biopsy. 68 Ga-PSMA-PET revealed an intensely avid primary lesion in the right prostate (SUVmax 10.9), concordant with biopsy findings and encompassing both the PI-RADS 5 lesion identified on MRI and a PI-RADS 1 lesion that presumably represented the mucinous component. The patient was treated with definitive radiotherapy to the prostate and lymph nodes with 6 months of androgen deprivation therapy.

Glomerular, Mesangial, and Tubular Cytoplasmic Fibrillary Inclusions in a Patient with Light-Chain Proximal Tubulopathy.

Monoclonal immunoglobulin or free light chains, produced in the setting of plasma cell dyscrasias, are a common cause of kidney injury with a wide variety of disease patterns. Light-chain proximal tubulopathy is a rare form of this disease that is often difficult to diagnose due to its relatively indolent presentation, subtle light microscopic findings, and often negative immunofluorescence using routine laboratory techniques. We report a case of light-chain proximal tubulopathy with cytoplasmic fibrillary inclusions in tubular cells, glomerular endothelial cells, and mesangial cells, which were positive for κ light chains on immunostaining after pronase digestion. Cytoplasmic fibrillary inclusions, composed of monoclonal protein, are strongly suggestive of underlying plasma cell dyscrasias, and such cases warrant further hematological investigations.

The causes, significance and consequences of inflammatory fibrosis in kidney transplantation: The Banff i-IFTA lesion.

Inflammation within areas of interstitial fibrosis and tubular atrophy (i-IFTA) is associated with adverse outcomes in kidney transplantation. We evaluated i-IFTA in 429 indication- and 2052 protocol-driven biopsy samples from a longitudinal cohort of 362 kidney-pancreas recipients to determine its prevalence, time course, and relationships with T cell-mediated rejection (TCMR), immunosuppression, and outcome. Sequential histology demonstrated that i-IFTA was preceded by cellular interstitial inflammation and followed by IF/TA. The prevalence and intensity of i-IFTA increased with developing chronic fibrosis and correlated with inflammation, tubulitis, and immunosuppression era (P < .001). Tacrolimus era-based immunosuppression was associated with reduced histologic inflammation in unscarred and scarred i-IFTA compartments, ameliorated progression of IF, and increased conversion to inactive IF/TA (compared with cyclosporine era, P < .001). Prior acute (including borderline) TCMR and subclinical TCMR were followed by greater 1-year i-IFTA, remaining predictive by multivariate analysis and independent of humoral markers. One-year i-IFTA was associated with accelerated IF/TA, arterial fibrointimal hyperplasia, and chronic glomerulopathy and with reduced renal function (P < .001 versus no i-IFTA). In summary, i-IFTA is the histologic consequence of active T cell-mediated alloimmunity, representing the interface between inflammation and tubular injury with fibrotic healing. Uncontrolled i-IFTA is associated with adverse structural and functional outcomes.

Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: a matched historical control study.

BACKGROUND: This study examined the association between overall survival and Glutathione S-transferase Pi (GST Pi) expression and genetic polymorphism in stage C colon cancer patients after resection alone versus resection plus 5-fluourouracil-based adjuvant chemotherapy. METHODS: Patients were drawn from a hospital registry of colorectal cancer resections. Those receiving chemotherapy after it was introduced in 1992 were compared with an age and sex matched control group from the preceding period. GST Pi expression was assessed by immunohistochemistry. Overall survival was analysed by the Kaplan-Meier method and Cox regression. RESULTS: From an initial 104 patients treated with chemotherapy and 104 matched controls, 26 were excluded because of non-informative immunohistochemistry, leaving 95 in the treated group and 87 controls. Survival did not differ significantly among patients with low GST Pi who did or did not receive chemotherapy and those with high GST Pi who received chemotherapy (lowest pair-wise p = 0.11) whereas patients with high GST Pi who did not receive chemotherapy experienced markedly poorer survival than any of the other three groups (all pair-wise p <0.01). This result was unaffected by GST Pi genotype. CONCLUSION: Stage C colon cancer patients with low GST Pi did not benefit from 5-fluourouracil-based adjuvant chemotherapy whereas those with high GST Pi did.

Src tyrosine kinase phosphorylation of nuclear receptor HNF4α correlates with isoform-specific loss of HNF4α in human colon cancer.

Src tyrosine kinase has long been implicated in colon cancer but much remains to be learned about its substrates. The nuclear receptor hepatocyte nuclear factor 4α (HNF4α) has just recently been implicated in colon cancer but its role is poorly defined. Here we show that c-Src phosphorylates human HNF4α on three tyrosines in an interdependent and isoform-specific fashion. The initial phosphorylation site is a Tyr residue (Y14) present in the N-terminal A/B domain of P1- but not P2-driven HNF4α. Phospho-Y14 interacts with the Src SH2 domain, leading to the phosphorylation of two additional tyrosines in the ligand binding domain (LBD) in P1-HNF4α. Phosphomimetic mutants in the LBD decrease P1-HNF4α protein stability, nuclear localization and transactivation function. Immunohistochemical analysis of approximately 450 human colon cancer specimens (Stage III) reveals that P1-HNF4α is either lost or localized in the cytoplasm in approximately 80% of tumors, and that staining for active Src correlates with those events in a subset of samples. Finally, three SNPs in the human HNF4α protein, two of which are in the HNF4α F domain that interacts with the Src SH3 domain, increase phosphorylation by Src and decrease HNF4α protein stability and function, suggesting that individuals with those variants may be more susceptible to Src-mediated effects. This newly identified interaction between Src kinase and HNF4α has important implications for colon and other cancers.

Clinicopathological correlates and prognostic significance of glutathione S-transferase Pi expression in 468 patients after potentially curative resection of node-positive colonic cancer.

AIMS: This study investigated the association between glutathione S-transferase Pi (GST Pi) expression, histopathology and overall survival in 468 patients after resection of stage C colonic adenocarcinoma. METHODS AND RESULTS: Data were drawn from a prospective hospital registry of consecutive bowel cancer resections with a minimum follow-up of 5 years. Nuclear and cytoplasmic GST Pi expression, assessed by both intensity of staining and percentage of stained cells at both the central part of the tumour and the invasive tumour front, were evaluated retrospectively by tissue microarray immunohistochemistry on archival specimens. The most effective measure of GST Pi expression was the percentage of immunostained nuclei in central tumour tissue, where >40% stained was associated significantly with high grade, invasion beyond the muscularis propria, involvement of a free serosal surface or apical node, and invasion into an adjacent organ or structure. After adjustment of other predictors, GST Pi expression remained independently prognostic for reduced overall survival (hazard ratio 1.4, P = 0.002). CONCLUSIONS: In patients with clinicopathological stage C colonic cancer, GST Pi expression is associated with features of tumour aggressiveness and with reduced overall survival. Further appropriately designed studies should aim to discover whether GST Pi can predict response to adjuvant chemotherapy.

Proteomic comparison of colorectal tumours and non-neoplastic mucosa from paired patient samples using iTRAQ mass spectrometry.

Quantitative mass spectrometry using iTRAQ was used to identify differentially expressed proteins from 16 colorectal cancer (CRC) tumours compared to patient-paired adjacent normal mucosa. Over 1400 proteins were identified and quantitated, with 118 determined as differentially expressed by >1.3-fold, with false discovery rate < 0.05. Gene Ontology analysis indicated that proteins with increased expression levels in CRC tumours include those associated with glycolysis, calcium binding, and protease inhibition. Proteins with reduced levels in CRC tumours were associated with loss of ATP production through: (i) reduced ß-oxidation of fatty acids, (ii) reduced NADH production by the tricarboxylic acid cycle and (iii) decreased oxidative phosphorylation activity. Additionally, biosyntheses of glycosaminoglycans and proteoglycans were significantly reduced in tumour samples. Validation experiments using immunoblotting and immunohistochemistry (IHC) showed strong concordance with iTRAQ data suggesting that this workflow is suitable for identifying biomarker candidates. We discuss the uses and challenges of this approach to generate biomarker leads for patient prognostication.

Non-invasive estimation of liver fibrosis in non-alcoholic fatty liver disease using the 13 C-caffeine breath test.

BACKGROUND AND AIM: Fibrotic progression in non-alcoholic fatty liver disease (NAFLD) is associated with impaired hepatic function. The (13) C-caffeine breath test (CBT) is a non-invasive, quantitative test of liver function. We sought to determine the utility of the CBT in detecting hepatic fibrosis in NAFLD. METHODS: The CBT was applied to 48 patients with NAFLD. CBT results were compared to clinical, biochemical and histological data. Twenty-four healthy subjects served as controls. RESULTS: Patients with simple steatosis had similar CBT values (2.28 ± 0.71 Δ‰ per 100 mg caffeine) to controls (2.31 ± 0.85, P = 1.0). However, CBT was significantly reduced in patients with non-alcoholic steatohepatitis (1.59 ± 0.65, P = 0.005) and cirrhosis (1.00 ± 0.73, P < 0.001). CBT significantly correlated with Brunt's fibrosis score (r = -0.49, P < 0.001) but not with steatosis (P = 0.23) or inflammation (P = 0.08). CBT also correlated with international normalized ratio (r = -0.61, P < 0.001), albumin (r = 0.37, P = 0.009), aspartate aminotransferase/alanine aminotransferase (r = -0.34, P = 0.018) and platelets (r = 0.31, P = 0.03). On multivariate analysis, age (odds ratio 1.12, 95% confidence interval 1.042-1.203, P = 0.002) and CBT (OR 0.264, 95% CI 0.084-0.822, P = 0.02) were independent predictors of significant fibrosis (F ≥ 2). CBT yielded an area under the receiver operating characteristic curve of 0.86 for the diagnosis of cirrhosis. CONCLUSIONS: The CBT reflects the extent of hepatic fibrosis in NAFLD and represents a non-invasive predictor of fibrosis severity in this condition.

Clinicopathological correlates and prognostic significance of maspin expression in 450 patients after potentially curative resection of node-positive colonic cancer.

AIMS: The tumour suppressor maspin has been investigated for its association with conventional histopathological features in colorectal cancer and for its potential as an independent predictor of survival and response to adjuvant chemotherapy. The aim of this study was to examine associations between maspin expression, other histopathology and survival in a large consecutive series of patients after potentially curative resection of node-positive colonic adenocarcinoma. METHODS AND RESULTS: Nuclear and cytoplasmic maspin expression in both superficial and deep parts of the tumour were assessed retrospectively by tissue microarray and immunohistochemistry in specimens from 450 patients whose other histopathology had been recorded in a prospective hospital registry of large bowel cancer resections from 1971 to 2001 with a minimum follow-up of 5 years. Among 13 clinicopathological features examined, the only associations that persisted across all four maspin assessments were stronger expression in right- than in left-sided tumours (P=0.001-0.011) and stronger expression in high-grade tumours (P<0.001-0.007). There was no significant association between intensity of maspin expression and overall survival. CONCLUSIONS: In this large and thoroughly documented series of patients with clinicopathological stage C colonic tumour, maspin expression was correlated with few other conventional histopathology variables and was not a significant prognostic factor.

Fascin expression predicts survival after potentially curative resection of node-positive colon cancer.

Fascin, an actin-bundling protein, is expressed in many neoplasms including colorectal cancer. It is considered to be a mediator of tumor cell invasion and an indicator of aggressive phenotype; however, there are few reports on the association between fascin and prognosis in colorectal cancer. The aims of this study were to: (a) investigate the expression of fascin in the central part of the tumor and at the invasive front in patients who had a potentially curative resection for node-positive colonic carcinoma; (b) examine the method of scoring fascin expression; and (c) investigate the association between fascin expression and overall survival and other clinicopathologic features. Fascin expression was assessed by immunostaining of microarrays from archived tissue of 470 patients who were followed for a minimum of 5 years after resection. Other clinicopathologic data had been recorded prospectively according to a standardized protocol. Analysis of overall survival was by the Kaplan-Meier method and Cox regression. For both central tumor tissue and the invasive front, it was found that the percentage of stained cells was a sufficient measure of fascin expression in relation to survival, with staining intensity providing no significant additional information. At both levels, there was a significant independent association between high fascin expression and diminished survival, although this association was much stronger in the central region (adjusted hazard ratio 1.6, P<0.001) than at the invasive front (adjusted hazard ratio 1.1, P=0.044). Fascin expression predicted overall survival but did not displace other routinely collected clinicopathologic predictors.

Transcriptome changes of chronic tubulointerstitial damage in early kidney transplantation.

BACKGROUND: Tubulointerstitial damage (TID) is a key feature of chronic kidney transplant failure; however, the associated gene expression changes are poorly defined. METHODS: This pilot study used RNA from 59 protocol kidney transplant biopsies at implantation, 1, 3, and 12 months (n=18 patients), processed into cDNA and hybridized to 8K human cDNA microarrays. Gene expression was correlated with graft histology categorized by the Banff schema. RESULTS: Gene and pathway expression were differentially activated according to the time after transplantation. Immune pathway activity peaked at 1 month, fibrotic expression at 3 months, wound healing-remodelling and cell proliferation-repair processes were activated between 3 and 12 months, whereas macrophage-related gene expression occurred late by 12 months. Forty percent of genes and 50% pathways initially activated persisted to 3 months. Biopsies with TID displayed 262 differentially expressed genes (P<0.001, B>2 compared with implantation), dominated by upregulated fibrogenic and immune-related genes reflecting unique immune (10% to 15% of genes) and fibrotic (15% vs. 4% in normal) pathway activation. Profibrotic genes were expressed before interstitial fibrosis was observed by sequential microscopic analysis. Kidneys progressing to TID by 3 months demonstrated 30 unique genes (B>1, P<0.05) versus nonprogressors with 95 genes (B>1, P<0.009). Fourteen of these progressor genes also occurred in the top decile from an independent validation set. CONCLUSIONS: Allografts display predictable immune and fibrotic gene expression profiles, with patterns of expression gradually varying by time after transplantation. The pathology reflects differential activation of intrinsic pathways. Gene expression predated histologic damage, suggesting its possible use in early diagnostic testing.

Tumor budding and survival after potentially curative resection of node-positive colon cancer.

PURPOSE: The aim of this study was to investigate the relationship between tumor budding and other pathology features and overall survival after resection of clinicopathological stage III colon cancer. METHODS: The number of buds and other histopathological features were assessed in 477 patients who were operated on between 1971 and 2001, with follow-up to December 2006. Overall survival was analyzed using the Kaplan-Meier method and Cox regression. RESULTS: The number of buds was dichotomized as low (0 to 8) vs high (>or=9). High budding was more common in men, in high-grade tumors, in the presence of venous invasion, and where the tumor had involved a free serosal surface, but budding was not associated with 8 other clinical and pathological features. The 5-year survival rate for patients with 0 to 8 buds was 51.0% (95% confidence interval, 44.9-55.1), whereas that for patients with 9 or more buds was 33.9% (95% confidence interval, 25.2-42.8). This association, however, disappeared after adjustment for other variables independently associated with survival (hazard ratio, 1.2; 95% confidence interval, 0.94-1.54; P = .139). CONCLUSION: In stage III colon cancer, tumor budding did not provide additional independent prognostic information beyond that given by routine pathology reporting.

Epithelial-to-mesenchymal transition in early transplant tubulointerstitial damage.

It is unknown whether epithelial-to-mesenchymal transition (EMT) leads to tubulointerstitial fibrosis in renal transplants. In this study, interstitial fibrosis and markers of EMT were followed in protocol transplant biopsies in 24 patients. Tubulointerstitial damage (TID) increased from 34 to 54% between 1 and 3 mo after transplantation. Detection of EMT depended on the marker used; low levels of alpha-smooth muscle actin were found in 61% of biopsies, but the less specific marker S100 calcium binding protein-A4 (also known as Fsp1) suggested a higher incidence of EMT. The presence or development of TID did not correlate with EMT but instead significantly correlated with subclinical immune activity (P < 0.05). Among biopsies showing TID, microarray analysis revealed differential regulation of 127 genes at 1 mo and 67 genes at 3 mo compared with baseline; these genes were predominantly associated with fibrosis, tissue remodeling, and immune response. Of the 173 EMT-associated genes interrogated, however, only 8.1% showed an expression pattern consistent with EMT at 1 mo and 6.3% at 3 mo. The remainder were not differentially altered, or their changes in expression were opposite those expected to promote EMT. Quantitative reverse transcriptase-PCR revealed that the expression pattern of 12 EMT-associated genes was inconsistent over time, opposite that expected, or consistent with subclinical rejection or inflammation. In conclusion, EMT does not seem to play a significant role in the development of early allograft fibrosis.

Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants.

BACKGROUND: Subclinical rejection (SCR) causes chronic allograft damage, which may be prevented by antirejection therapy. METHODS: A pilot study of the effect of routine treatment of SCR was performed in 88 recipients of either a kidney (n=59) or combined kidney-pancreas transplant (n=29) undergoing protocol biopsy (PBX) surveillance at 1 and 3 months, using calcineurin inhibitors, mycophenolate mofetil, and corticosteroid therapy. RESULTS: SCR was seen in 46.6% (41/88 patients), as 30 borderline and 11 acute SCR. From 279 transplant biopsies, the prevalence of SCR was 25% (22/88) at 1 month, 10.2% (9/88) at 3 months, and 8.3% (2/24) at 12 months PBX. Treatment included bolus intravenous or oral corticosteroids (n=20) and augmented immunosuppression, either by conversion to tacrolimus (n=6) or increased doses of maintenance therapy (n=14), whereas OKT3 was used in one case of subclinical vascular rejection. Borderline episodes were not treated in 12 patients. In biopsies taken to assess therapeutic response, persistent SCR was present in 46.1% (6/13). Treatment of SCR at 1 month was followed by lower acute Banff sum scores at 3 months PBX (P<0.01-0.0001). Early chronic damage was already present in the 1 month PBX, associated with SCR (P<0.0005 versus without SCR), although by 3 months these differences were lost. Rates of opportunistic infections and BK nephropathy were not increased by SCR treatment. CONCLUSION: Early chronic allograft damage was associated with SCR and therapy appeared to ameliorate further immune-mediated injury, although the efficacy of corticosteroids alone may be inadequate. A controlled trial of therapy for SCR is warranted.

Height and social adjustment: are extremes a cause for concern and action?

OBJECTIVE: Growth hormone treatment of hormone-sufficient short youths is predicated on the belief that short stature is associated with social problems with peers. This study assessed peer relations and social adjustment as a function of height in a community sample. METHODS: A cross-sectional study was conducted at 1 public school district in Western New York of students of both genders who attended grades 6 to 12 (N = 956). Target groups included participants of short stature (height or=1.6 standard deviation; >or=95th percentile; n = 58) and classmates of average height (between the 25th and 75th percentiles; n = 123) used for within-class comparisons. All remaining unclassified classmates (n = 704) also provided data. Self- and peer-rated assessment of social reputation and social acceptance was measured. RESULTS: Minimal effects of height on measures of social functioning were detected despite substantial statistical power. We detected no significant relationships between height and measures of friendship, popularity, or reputation with peers. Findings did not vary by gender of participant, by peer- or self-report, or by whether data from the entire sample were used or target groups were contrasted with comparison participants. Shorter students were perceived by peers to be younger than their age. This influence was restricted to lower grades and did not have an impact on measures of social acceptance or reputation with peers. CONCLUSIONS: Extremes of stature in the general population-either short or tall-have minimal detectable impact on peer perceptions of social behavior, friendship, or acceptance. Findings are not supportive of the need to intervene a priori because of the potential risk of negative stature-related social sequelae. Furthermore, if problems with peer relationships are identified among short or tall youths, then factors other than stature should be considered as etiologically important.