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Papillary renal cell carcinoma (PRCC) is well-recognized as a morphologically and molecularly heterogenous group of kidney tumors with variable clinical behavior. Our goal was to analyze a unique histologic pattern of PRCC we have observed in routine practice to evaluate for potential clinical significance or distinct molecular signature. We identified 42 cases of PRCC showing a morphologically distinct architecture characterized by numerous epithelial-lined cysts containing the papillary tumor (herein called “microcysts”), which are typically separated by fibrous stroma. Of the initial 42 case test set with microcystic features, 23 (55%) were stage pT3a or higher. Most tumors had strong and diffuse cytoplasmic immunoreactivity for CK7 (93%, 37/40) and AMACR (100%, 40/40). Fumarate hydratase staining was retained in all cases tested (39/39). We performed next-generation sequencing on 15 of these cases with available tissue and identified chromosomal alterations commonly reported in historically “type 1” PRCC, notably multiple chromosomal gains, particularly of chromosomes 7 and 17, and METalterations. However, alterations in pathways associated with more aggressive behavior (including SETD2, CDKN2A, and members of the NRF pathway) were also identified in 6 of 15 cases tested (40%). Given this molecular and immunophenotypic data, we subsequently reviewed an additional group of 60 consecutive pT2b-pT3 PRCCs to allow for comparisons between cases with and without microcysts, to assess for potential associations with other recently described histologic patterns (ie, “unfavorable architecture”: micropapillary, solid, and hobnail), and to assess interobserver reproducibility for diagnosing architectural patterns and grade. Of the total combined 102 PRCCs, 67 (66%) had microcystic architecture within the intrarenal component but were commonly admixed with other patterns (39% had micropapillary, 31% solid, and 31% hobnail). Twenty-seven cases (26%) had metastatic disease, and 24 of these 27 (89%) had microcystic architecture in the intrarenal tumor. Within the pT3 subset, 21 of 22 cases with metastases (95%) had extrarenal invasion as either individual microcysts in renal sinus fat or aggregates of microcysts bulging beyond the confines of the capsule. Backward elimination and stepwise regression methods to detect features significantly associated with adverse outcome identified solid architecture (hazard ratio [HR]: 6.3; confidence interval [CI]: 2.1-18.8; P=0.001), hobnail architecture (HR: 5.3; CI: 1.7-16.7; P=0.004), and microcystic architecture at the tumor-stromal interface (HR: 4.2; CI: 1.1-16.7; P=0.036) as strongest. Of architectural patterns and grade, the microcystic pattern had a substantial interobserver agreement (κ score=0.795) that was highest among the 6 observers. In summary, PRCCs with microcystic architecture represents a subset of historically “type 1” PRCC with a predilection for morphologically distinctive extrarenal involvement and metastatic disease. Microcysts co-vary with other “unfavorable” architectural patterns also associated with higher risk for aggressive disease (ie, micropapillary, hobnail, and solid), but microcysts were more common and have superior interobserver reproducibility. These findings suggest that microcystic PRCC should be recognized as a potentially aggressive histologic pattern of growth in PRCC.

Bayes's theorem arose from a posthumous publication in 1763 by Thomas Bayes, a non-conformist minister from Tunbridge Wells. Although it gives a simple and uncontroversial result in probability theory, specific [...]

Immunohistology is essential to the practice of modern surgical and cytopathology. There are 3 major types of immunohistologic services provided in clinical practice: traditional immunohistochemistry, morphometric analysis of tumor immunohistochemistry, and immunofluorescence. Proper Current Procedural Terminology coding for these services has been updated to reflect current medical practice. Subsequent to changes in the Current Procedural Terminology coding structure for these services, the valuation of these services have been reviewed by the American Medical Association/Specialty Society Relative Value Update Committee and new valuations instituted by the Centers for Medicare and Medicaid Services. Although valuations for services may be established, the circumstances of payment may be affected by Medicare Contractor’s Local Coverage Determinations or service limits imposed by the National Correct Coding Initiative.

Health care reform has accelerated as the existing health care system undergoes continuing financial stress. Medicare’s new value-based payment system, commonly referred to as MACRA, provides opportunities for physicians to participate in this new system in a variety of ways. However, many of the value-based adjustments are based on existing valuations of services through traditional mechanisms. To achieve appropriate valuation of pathologist’s services in the new payment models, it is imperative that we continue to achieve proper valuation of services through the traditional mechanisms.

Early recognition of BK viral nephropathy is essential for successful management. Our aim in this study was to evaluate a novel fluorescence in situhybridization (FISH) assay for detection of BK virus in renal transplant biopsies in the context of standard detection methods. Renal allograft biopsies (n= 108) were analyzed via H&E, immunohistochemistry (IHC) for simian virus 40, and FISH for BK virus. BK virus was detected in 16 (14.8%) cases by H&E, 13 (12%) cases by IHC, 18 (16.6%) cases by FISH, and 19 (17.6%) cases by real-time PCR; 24 of 108 showed a discrepancy in ≥1 testing modalities. Comparison of H&E, IHC, and FISH showed no statistical difference in detection of BK virus. However, performing comparisons between the different tissue-based assays in the context of plasma or urine real-time PCR results showed significant improvement in detection of BK by FISH over H&E (P= 0.02) but not IHC (P= 0.07). This novel FISH-based approach for BK virus identification in renal allograft biopsy tissue mirrored real-time PCR results and showed superior performance to detection of inclusions by H&E. Therefore, use of FISH for BK virus detection in the setting of renal allograft biopsy is a useful and sensitive detection method and could be adopted in any laboratory that currently performs FISH analysis.

BK virus nephropathy is not an infrequent complication of renal transplantation associated with high rates of graft loss. Although antibodies against SV40 antigen detect different viruses of the polyomavirus family, immunohistochemistry is widely used to confirm the diagnosis of BK virus nephropathy in renal biopsies. Here we aimed to validate the novel silver-enhanced in situ hybridization (SISH) technique for the automated detection of BK virus in renal transplant biopsies. Two different patient cohorts were included. Twenty-nine consecutive patients suspicious for BK virus infection were investigated by SISH and chromogenic in situ hybridization. An additional 26 renal biopsies positive by SV40 immunohistochemistry from 19 patients were analyzed by SISH. Polyomavirus DNA serum levels, as determined by nested PCR analysis, were available for all of these patients. The presence of BK virus DNA in renal tubular cells was identified in 5 of the suspicious cases by both, SISH and chromogenic in situ hybridization . One additional patient was only positive in the SISH. In the second cohort, SISH was positive in all SV40 positive biopsies, but SISH signals were less extensive than SV40 immunohistochemistry. Our results show that the BK virus SISH is an ancillary tool for the detection of polyomavirus DNA in renal biopsies using bright-field microscopy. However, its diagnostic value in comparison with standard immunohistochemistry seems to be limited.

Wegener granulomatosis (WG) is a systemic disease that is often associated with an immune-mediated form of glomerulonephritis (GN). Renal disease most often manifests as microscopic hematuria with or without red blood cell or mixed cellular casts, proteinuria, and an elevated serum creatinine concentration.

The independent prognostic importance of microscopic bladder neck involvement by prostate cancer in radical prostatectomy is questionable. We studied a cohort of 1845 patients to determine the significance of microscopic bladder neck involvement. Bladder neck involvement was defined as prostate cancer present within the coned bladder neck. We further categorized the cases as ‘true bladder neck involvement’ and ‘false bladder neck involvement.‘ True bladder neck involvement required prostate cancer within thick smooth muscle bundles without intermixed benign prostatic glands. False bladder neck involvement was characterized by prostate cancer intermixed with benign prostatic glands. Bladder neck involvement was analyzed in relation to preoperative serum prostate-specific antigen (PSA) level, extraprostatic extension, seminal vesicle involvement, positive surgical margin, lymph node involvement, radical prostatectomy Gleason score, and tumor volume. Of the 90 patients (4.9%) with microscopic bladder neck involvement, 63 were further classified as true bladder neck involvement and 27 as false bladder neck involvement. In univariate model, both types of bladder neck involvement (P<0.001), true (P<0.001), and false (P=0.040), were significantly associated with increased PSA-recurrence risk compared to bladder neck negative cases. In multivariate model the PSA-recurrence relative risk associated with bladder neck involvement (true or false) was not a significant independent prognostic factor. Extraprostatic extension, seminal vesicle involvement, positive surgical margin, lymph node involvement, PSA, and Gleason score were significant independent predictors of PSA recurrence. The time to biochemical recurrence in patients with bladder neck involvement was similar to that of pT2 with positive surgical margin or pT3a with negative surgical margin patients (Kaplan–Meier curves). Bladder neck involvement was associated with other adverse pathologic features, but was not an independent predictor of PSA recurrence. In view of the previous and current data, the staging system for bladder neck involvement should be revised and patients may be best categorized as having pT3a disease.

Randomised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality. This has often been accompanied, however, by an increase in breast cancer incidence, particularly during the early years of a screening programme, which has led to concerns about overdiagnosis, that is to say, the diagnosis of disease that, if left undetected and therefore untreated, would not become symptomatic. We used incidence data from two randomised controlled trials of mammographic screening, the Swedish Two-county Trial and the Gothenburg Trial, to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ(DCIS) in the study groups, to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of 'real' and non-progressive 'overdiagnosed' tumours from the study groups of the trials. We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters. After taking into account the effect of lead time, we estimated that less than 5% of cases diagnosed at prevalence screen and less than 1% of cases diagnosed at incidence screens are being overdiagnosed. Overall, we estimate overdiagnosis to be around 1% of all cases diagnosed in screened populations. These estimates are, however, subject to considerable uncertainty. Our results suggest that overdiagnosis in mammography screening is a minor phenomenon, but further studies with very large numbers are required for more precise estimation.

Antibody-mediated renal allograft rejection has become increasingly recognized and more clearly defined through the use of flow cytometry cross-matching and the deposition of C4d in renal allograft biopsies. All of the cases reported thus far have developed an antibody within 10 years of transplantation, and many lacked HLA and/or donor specificity.The present patient developed an anti-HLA donor-specific antibody between the 22nd and 30th year after a living-related renal transplant. At the 30th year post-transplantation, she experienced a rise in the serum creatinine from 0.7 to 1.9 mg/dL associated with transplant biopsy C4d deposition in peritubular capillaries and glomeruli. After the replacement of azathioprine with mycophenolate mofetil, and six apheresis treatments followed by two infusions of IVIG, the renal function stabilized at 1.9 mg/dL, 33 years after transplantation. Antibody-mediated rejection must be considered as a possible cause or renal allograft dysfunction at all time periods after transplantation.

Antibody‐mediated renal allograft rejection has become increasingly recognized and more clearly defined through the use of flow cytometry cross‐matching and the deposition of C4d in renal allograft biopsies. All of the cases reported thus far have developed an antibody within 10 years of transplantation, and many lacked HLA and/or donor specificity.

Objective: To describe an unusual case of development of diabetes mellitus (DM) several years after manifestation of diabetic nephropathy and to review the related literature. Methods: We present a case report, including detailed laboratory and pathologic findings in a 51-year-old man who was diagnosed as having DM several years after presenting with diabetic nephropathy. The pertinent literature is also reviewed. Results: A 51-year-old African American man presented with proteinuria of 4 g/24 h. Past medical history was significant for impaired glucose tolerance diagnosed 2 years previously. Subsequent follow-up demonstrated fasting blood glucose levels ranging from 108 to 123 mg/dL and glycated hemoglobin levels ranging from 5.3 to 5.8%. The patient also had chronic hepatitis C, hypertension, a history of intravenous drug abuse, and a family history of DM and hypertension. On examination of the patient, his blood pressure was 180/90 mm Hg. Funduscopy revealed mild diabetic retinopathy. Work-up was negative for glomerulonephritis, connective tissue disease, vasculitis, or multiple myeloma. Kidney biopsy revealed thickened glomerular basement membranes and diffuse glomeru-losclerosis, consistent with diabetic nephropathy. During follow-up, 9 years after presenting with proteinuria and 4 years after diagnosis of biopsy-proven diabetic nephropathy, the patient had a blood glucose level of 890 mg/dL and diabetic ketoacidosis. Conclusion: This case provides one explanation for the natural course of patients who present with "diabetic complications" but have no diabetes. Some of those patients may have "prediabetes" and may manifest with DM during follow-up. We also conclude that hyperglycemia is not the only important factor in the pathogenesis of diabetic nephropathy. (Endocr Pract. 2003;9:301-306)

Raman spectroscopy has the potential to provide real-time, in situ diagnosis of breast cancer during needle biopsy or surgery via an optical fiber probe. Understanding the chemical/morphological basis of the Raman spectrum of breast tissue is a necessary step in developing Raman spectroscopy as a tool for in situ breast cancer diagnosis. To understand the relationship between the Raman spectrum of a sample of breast tissue and its disease state, near-infrared Raman spectroscopic images of human breast tissue were acquired using a confocal microscope. These images were then compared with phase contrast and hematoxylin- and eosin-stained images to develop a chemical/morphological model of breast tissue Raman spectra. This model fits macroscopic tissue spectra with a linear combination of basis spectra derived from spectra of the cell cytoplasm, cell nucleus, fat, β-carotene, collagen, calcium hydroxyapatite, calcium oxalate dihydrate, cholesterol-like lipid deposits and water. Each basis spectrum represents data acquired from multiple patients and, when appropriate, from a variety of normal and diseased states. The model explains the spectral features of a range of normal and diseased breast tissue samples, including breast cancer. It can be used to relate the Raman spectrum of a breast tissue sample to diagnostic parameters used by pathologists. Copyright © 2002 John Wiley & Sons, Ltd.

The presence of HER2/neu gene amplification is prognostically and therapeutically significant for patients with breast cancer. We sought to determine whether a relationship exists between HER2/neu gene amplification and the histologic type and grade of tumor. The histologic features and corresponding HER2/neu amplification results of 401 cases of invasive breast carcinoma were reviewed. Lobular carcinomas were less likely than ductal carcinomas to have HER2/neu amplification. Amplification was less frequent in Scarff-Bloom-Richardson grade I ductal carcinomas than in grades 2 and 3. Metastatic carcinomas frequently displayed HER2/neu amplification (6/20 [30%]). Our results support a correlation between HER2/neu amplification and the histologic type and grade of breast cancer. We suggest reexamination of tumors diagnosed as Scarff-Bloom-Richardson grade I invasive ductal carcinomas or lobular carcinomas if the lesion displays HER2/neu amplification to assure the exclusion of a higher grade of lesion or of missed ductal components.

Current TNM staging of renal cell carcinoma is based on the tumor propensity for local extension (T), nodal involvement (N) and metastatic spread (M). Locally advanced renal cell carcinoma may involve the perirenal fat, adrenal glands, renal vein, vena cava and/or urinary collecting system. The existing TNM classification does not reflect the ability of renal cell carcinoma to invade the urothelium. We evaluated the incidence and characteristics as well as overall and cancer specific survival of renal cell carcinoma invading the urinary collecting system.

HypothesisP53 and Ki‐67 status will predict response to treatment, organ preservation, and survival in patients with advanced squamous cell cancers of the head and neck treated with chemoradiotherapy (CRT).

This research investigated the histopathologic and migratory properties of injectable alternatives for vocal fold medialization. Thirteen dogs underwent sectioning of the recurrent laryngeal nerve followed by vocal fold injection with 1 of 4 substances: Teflon, autologous fat, silicone suspension, or hydroxyapatite cement. Six months later, the animals were painlessly sacrificed and histopathologic analysis of the larynx and regional lymph nodes was performed. Although regional lymph node migration was noted, Teflon injection resulted in minimal vocal fold inflammatory reaction. Vocal folds injected with autologous fat exhibited persistence of fat at the injection site without significant inflammation or migration. Silicone suspension caused a localized giant cell reaction without regional lymph node migration, and 1 study subject died secondary to acute inflammation with critical respiratory compromise. Hydroxyapatite cement was well tolerated without inflammation or migration. This pilot study indicates that a wide range of possible substances for vocal fold medialization exist. Many of these may produce results superior to those obtained with Teflon and are thus far untested.

OBJECTIVE The goal was assessment of a revolutionary approach to laryngeal stenting. A radically designed, atraumatic, inflatable, low-pressure, high-volume, endoscopically inserted laryngeal stent for effective intralaryngeal support or long-term prevention of aspiration was prospectively evaluated in a canine model to reveal any significant short-and long-term anatomic and functional changes in the larynx.METHODS A self-sustaining, tube-free, long-term flap tracheostomy was performed in 14 dogs, followed by endoscopic laryngeal stent insertion. The stents were inflated, and their intraluminal pressures were monitored daily. The stenting period ranged between 3 and 46 days (mean 27.4 days). The animals were then euthanized, and total laryngectomy was performed. The larynges underwent gross and microscopic examinations, and a grading scale of reactive changes caused by the stent placement was created on the basis of the findings.RESULTS Dye studies for aspiration were negative in all animals. Gross findings consisted of varying degrees of small ulceration, localized polypoid lesions, and granulomas. Grossly, 9 dogs exhibited small superficial ulceration of the true vocal cords and posterior commissure. Six dogs developed minor polyps or polypoid changes and/or granulomas, respectively. No gross changes were seen in 2 of the dogs. Histopathologically, 10 dogs demonstrated grade I or II histopathologic changes. Only 4 of the dogs exhibited inflammation extending into the underlying cartilages, grade III. One dog did not complete the observation period.CONCLUSION This new stent demonstrated safety and biocompatibility with minimal local tissue reaction to its extended long-term placement. Good tolerance to the stent was documented, with minimal side effects similar to those that would be observed in human subjects after endotracheal intubation. When followed up in human patients, such minimal lesions have not resulted in significant long-lasting functional impairments. These initial results would indicate that this stent is well tolerated for long-term application and qualify as the preferred device for both management of aspiration and postoperative endolaryngeal bolstering support.

Acute rejection (AR) of the transplanted kidney has been identified as the major risk factor for the development of chronic rejection and immunological graft loss. However, the clinical presentation and response to AR therapy can vary considerably between recipients.

PurposeAtheroembolic renal disease is increasingly found in older patients with general atherosclerosis. We evaluated the impact of atheroembolic renal disease on morbidity and survival after surgical revascularization for atherosclerotic renal artery stenosis.Materials and MethodsThe study group comprised 44 patients who underwent surgical revascularization for atherosclerotic renal artery stenosis and concomitant intraoperative renal biopsy. Renal biopsy specimens were reviewed by a pathologist and evaluated for the presence or absence of atheroemboli, and the presence and severity of arteriolar nephrosclerosis. Postoperative patient data were reviewed to evaluate survival, and the incidence of renal and systemic morbid events. Patients were followed for 1 to 14.5 years (median 6.2) after surgical revascularization.ResultsAtheroembolic renal disease was identified in the intraoperative biopsy specimen in 16 patients (36%, group 1) and was absent in 28 (64%, group 2), termed groups 1 and 2. Atheroembolic renal disease correlated significantly with decreased patient survival. The 5-year survival in groups 1 and 2 was 54 and 85%, respectively (p = 0.011). Similarly the incidence of systemic atherosclerotic complications was significantly higher in group 1 than group 2 (86 versus 58%, p <0.05). In addition, renal or renovascular complications developed in more group 1 than group 2 patients (p = 0.07). There was no significant association between the presence or severity of arteriolar nephrosclerosis and postoperative survival or morbid events.ConclusionsOur results indicate that atheroembolic renal disease is associated with decreased survival and an increased incidence of atherosclerotic morbid events after surgical revascularization for atherosclerotic renal artery stenosis. This information may be useful for therapeutic decision making in patients with atherosclerotic renal artery stenosis.

Fifty-six lymph nodes excised from II patients with pancreatic adenocarcinoma were studied for evidence of metastasis by standard light microscopy and immunohistochemistry using an anticytokeratin monoclonal antibody. Eight of 56 nodes contained metastatic carcinoma as demonstrated by conventional techniques. By immunohistochemistry, positive-staining cells were easily identified. In 10 of 56 nodes, the positive staining was accompanied by cytologic atypia, changes consistent with malignancy. In seven additional nodes, positive-staining cells were present, but cytologic atypia was lacking. The use of immunohistochemistry facilitated recognition of malignant cells and raised questions that single-cell metastasis may be present. Positive staining for cytokeratin should prompt a close examination of cells to determine if morphologic features of malignancy are present.

The objective of this study was to determine whether small human pancreatic adenocarcinomas contain activated c-K-rasas an approach to answering the question of whether c-K-rasmutation is an early change in this disease. Eight pancreatic adenocarcinomas in the range 1.2-3 cm were analyzed for c-K-rasmutation at codon 12 by amplifying the c-K-rasgene around codon 12 out of paraffin-embedded tissue sections using the poly-merase chain reaction. c-K-rasmutations were detected by allele-specific oligonucleotide hybridization. Six of the eight small pancreatic adenocarcinomas contained mutated c-K-rasat codon 12, position 2, and two of the six tumors had an additional mutation at position 1 of codon 12. Our results indicate that small pancreatic adenocarcinomas are similar to large, late-stage pancreatic adenocarcinomas in that 75 of the tumors analyzed contain mutated c-K-rasat codon 12, position 2. These data suggest that c-K-rasmutation occurs early and may therefore have a role in initiation of human pancreatic adeno-carcinoma.

We investigated the role of peripheral sympathetic neurons and the adrenal medulla in the cardiovascular responses to cocaine in conscious, unrestrained Sprague-Dawley rats. Surgical adrenal demedullation (ADM) and/or chemical peripheral sympathectomy was used to eliminate one or both components of the sympathoadrenal axis. Phentolamine (5 mg/kg i.v.) was used to evaluate whether cocaine elicited epinephrine (EPI) release from the adrenal medulla. Significant EPI release by cocaine would result in “epinephrine reversal” after phentolamine pretreatment. Cocaine (2.5 mg/kg i.v.) was used in all experiments except the dose–response relationship study. In normal rats, cocaine caused a transient increase in mean blood pressure (MBP). Pretreatment with phentolamine reversed this BP response and this depressor effect was blocked by propranolol (2 mg/kg i.v.) suggesting that the pressor effect of cocaine was mediated by EPI. Chemical sympathectomy alone partially inhibited the pressor effect of cocaine, but pretreatment with phentolamine still reversed the residual action of cocaine on MBP at this time. Two weeks after ADM, the effect of cocaine on MBP was not significantly different from that of the sham-operated rats. However, pretreatment with phentolamine inhibited but did not reverse the effect of cocaine on MBP at that time. In rats with both ADM and chemical sympathectomy, cocaine caused only a decrease in MBP that was not blocked by propranolol or atropine methylnitrate, presumably because of its direct depressive actions. Results of this study suggest that both peripheral sympathetic neurons and the adrenal medulla play important roles in the cardiovascular actions of cocaine.

Three patients with pancreatic adenocarcinoma are studied who had a prior history of malignant lymphoma. No common predisposing factors for the development of pancreatic adenocarcinoma were identified. We conclude that patients with malignant lymphoma who have new or persistent pancreatic masses must be evaluated for the possibility of a second primary neoplasm.

Survival rates for babies born extremely prematurely increased between 1995 and 2006, but few improvements in neonatal morbidity occurred despite appropriate interventions. The current study was undertaken to examine the neurologic and developmental outcomes for babies born at less than 27 weeks’ gestation in 2006 and to compare the survival and outcomes at 3 years of age with those of babies born at 22 to 25 weeks’ gestation in 1995.

ObjectiveTo determine outcomes at age 3 years in babies born before 27 completed weeks’ gestation in 2006, and to evaluate changes in outcome since 1995 for babies born between 22 and 25 weeks’ gestation.DesignProspective national cohort studies, EPICure and EPICure 2.SettingHospital and home based evaluations, England.Participants1031 surviving babies born in 2006 before 27 completed weeks’ gestation. Outcomes for 584 babies born at 22-25 weeks’ gestation were compared with those of 260 surviving babies of the same gestational age born in 1995.Main outcome measuresSurvival to age 3 years, impairment (2008 consensus definitions), and developmental scores. Multiple imputation was used to account for the high proportion of missing data in the 2006 cohort.ResultsOf the 576 babies evaluated after birth in 2006, 13.4% (n=77) were categorised as having severe impairment and 11.8% (n=68) moderate impairment. The prevalence of neurodevelopmental impairment was significantly associated with length of gestation, with greater impairment as gestational age decreased: 45% at 22-23 weeks, 30% at 24 weeks, 25% at 25 weeks, and 20% at 26 weeks (P<0.001). Cerebral palsy was present in 83 (14%) survivors. Mean developmental quotients were lower than those of the general population (normal values 100 (SD 15)) and showed a direct relation with gestational age: 80 (SD 21) at 22-23 weeks, 87 (19) at 24 weeks, 88 (19) at 25 weeks, and 91 (18) at 26 weeks. These results did not differ significantly after imputation. Comparing imputed outcomes between the 2006 and 1995 cohorts, the proportion of survivors born between 22 and 25 weeks’ gestation with severe disability, using 1995 definitions, was 18% (95% confidence interval 14% to 24%) in 1995 and 19% (14% to 23%) in 2006. Fewer survivors had shunted hydrocephalus or seizures. Survival of babies admitted for neonatal care increased from 39% (35% to 43%) in 1995 to 52% (49% to 55%) in 2006, an increase of 13% (8% to 18%), and survival without disability increased from 23% (20% to 26%) in 1995 to 34% (31% to 37%) in 2006, an increase of 11% (6% to 16%). ConclusionSurvival and impairment in early childhood are both closely related to gestational age for babies born at less than 27 weeks’ gestation. Using multiple imputation to account for the high proportion of missing values, a higher proportion of babies admitted for neonatal care now survive without disability, particularly those born at gestational ages 24 and 25 weeks.