APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas.

BACKGROUND: Studies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies. PATIENTS AND METHODS: APOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance. RESULTS: APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis. CONCLUSIONS: APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

Core-binding factor leukemia hijacks the T-cell-prone PU.1 antisense promoter.

The blood system serves as a key model for cell differentiation and cancer. It is orchestrated by precise spatiotemporal expression of crucial transcription factors. One of the key master regulators in the hematopoietic systems is PU.1. Reduced levels of PU.1 are characteristic for human acute myeloid leukemia (AML) and are known to induce AML in mouse models. Here, we show that transcriptional downregulation of PU.1 is an active process involving an alternative promoter in intron 3 that is induced by RUNX transcription factors driving noncoding antisense transcription. Core-binding factor (CBF) fusions RUNX1-ETO and CBFß-MYH11 in t(8;21) and inv(16) AML, respectively, activate the PU.1 antisense promoter that results in a shift from sense toward antisense transcription and myeloid differentiation blockade. In patients with CBF-AML, we found that an elevated antisense/sense transcript and promoter accessibility ratio represents a hallmark compared with normal karyotype AML or healthy CD34+ cells. Competitive interaction of an enhancer with the proximal or the antisense promoter forms a binary on/off switch for either myeloid or T-cell development. Leukemic CBF fusions thus use a physiological mechanism used by T cells to decrease sense transcription. Our study is the first example of a sense/antisense promoter competition as a crucial functional switch for gene expression perturbation by oncogenes. Hence, this disease mechanism reveals a previously unknown Achilles heel for future precise therapeutic targeting of oncogene-induced chromatin remodeling.

Tumor mutational burden and immune infiltrates in renal cell carcinoma and matched brain metastases.

BACKGROUND: Tumor mutational burden (TMB) and density of tumor-infiltrating lymphocytes (TIL) have been postulated as predictive biomarkers for immunotherapy. Therefore, we investigated the concordance of TMB and TIL of primary/extracranial renal cell carcinoma (RCC) specimens and matched brain metastases (BM). PATIENTS AND METHODS: Twenty specimens from 10 patients were retrieved from the Vienna Brain Metastasis Registry (6/10 primary tumor, 4/10 lung metastasis, 10/10 matched BM). TMB was assessed using the TruSight Oncology 500 gene panel with libraries sequenced on a NextSeq instrument. TIL subsets (CD3+, CD8+, CD45RO+, FOXP3+, PD-L1+) were investigated using immunohistochemistry (Ventana Benchmark Ultra system) and automated tissue analysis (Definiens software). RESULTS: No significant difference in TMB, CD3+, CD8+, CD45RO+, FOXP3+ or PD-L1+ expression was observed between extracranial and matched intracranial specimens (P > 0.05). Higher CD8+ TIL (P = 0.053) and CD45RO+ TIL (P = 0.030) densities in the primary tumor compared with the intracranial samples were observed in specimens collected after exposure to systemic treatment. Neither extracranial sample origin (lung metastasis versus primary RCC) nor extracranial disease status at BM diagnosis (progressive versus stable disease) were significantly associated with TMB or TIL densities in extracranial and intracranial samples (P > 0.05). No significant correlation was found between the median differences of TMB or TIL densities from extracranial to intracranial samples and BM-free survival. CONCLUSION: The comparable immunological microenvironment of extra- and intracranial tumor samples in our study underscores the immunological activation also in BM from RCC, and therefore, supports the development of immune modulatory treatments also in patients with brain metastatic RCC.

Hospital volume and outcome in inguinal hernia repair: analysis of routine data of 133,449 patients.

INTRODUCTION: Inguinal hernias are repaired using either open or minimally invasive surgical techniques. For both types of surgery it has been demonstrated that a higher annual surgeon volume is associated with a lower risk of recurrence. This present study investigated the volume-outcome implications for recurrence operations, surgical complications, rate of chronic pain requiring treatment, and 30-day mortality based on the hospital volume. MATERIALS AND METHODS: The data basis used was the routine data collected throughout the Federal Republic of Germany for persons insured by the Local General Sickness Fund "AOK" who had undergone inpatient inguinal hernia repair between 2013 and 2015. Complications were recorded by means of indicators. Hospitals were divided into five groups on the basis of the annual caseload volume: 1-50, 51-75, 76-100, 101-125, and ≥ 126 inguinal hernia repairs per year. The effect of the hospital volume on the indicators was assessed using multiple logistic regression. RESULTS: 133,449 inguinal hernia repairs were included. The incidence for recurrence operations was 0.95%, for surgical complications 4.22%, for chronic pain requiring treatment 2.87%, and for the 30-day mortality 0.28%. Low volume hospitals (1-50 and 51-75 inguinal hernia repairs per year) showed a significantly increased recurrence risk compared to high volume hospitals with ≥ 126 inguinal hernia repairs per year (odds ratio: 1.53 and 1.24). No significant correlations were found for the other results. CONCLUSIONS: The study gives a detailed picture of hospital care for inguinal hernia repair in Germany. Furthermore, it was noted that the risk of hernia recurrence decreases in line with a rising caseload of the treating hospital.

Editor's Choice - Carotid Stenosis Treatment: Variation in International Practice Patterns.

OBJECTIVES: The aim was to determine current practice for the treatment of carotid stenosis among 12 countries participating in the International Consortium of Vascular Registries (ICVR). METHODS: Data from the United States Vascular Quality Initiative (VQI) and the Vascunet registry collaboration (including 10 registries in Europe and Australasia) were used. Variation in treatment modality of asymptomatic versus symptomatic patients was analysed between countries and among centres within each country. RESULTS: Among 58,607 procedures, octogenarians represented 18% of all patients, ranging from 8% (Hungary) to 22% (New Zealand and Australia). Women represented 36%, ranging from 29% (Switzerland) to 40% (USA). The proportion of carotid artery stenting (CAS) among asymptomatic patients ranged from 0% (Finland) to 26% (Sweden) and among symptomatic patients from 0% (Denmark) to 19% (USA). Variation among centres within countries for CAS was highest in the United States and Australia (from 0% to 80%). The overall proportion of asymptomatic patients was 48%, but varied from 0% (Denmark) to 73% (Italy). There was also substantial centre level variation within each country in the proportion of asymptomatic patients, most pronounced in Australia (0-72%), Hungary (5-55%), and the United States (0-100%). Countries with fee for service reimbursement had higher rates of treatment in asymptomatic patients than countries with population based reimbursement (OR 5.8, 95% CI 4.4-7.7). CONCLUSIONS: Despite evidence about treatment options for carotid artery disease, the proportion of asymptomatic patients, treatment modality, and the proportion of women and octogenarians vary considerably among and within countries. There was a significant association of treating more asymptomatic patients in countries with fee for service reimbursement. The findings reflect the inconsistency of the existing guidelines and a need for cooperation among guideline committees all over the world.

Next-generation sequencing identifies major DNA methylation changes during progression of Ph+ chronic myeloid leukemia.

Little is known about the impact of DNA methylation on the evolution/progression of Ph+ chronic myeloid leukemia (CML). We investigated the methylome of CML patients in chronic phase (CP-CML), accelerated phase (AP-CML) and blast crisis (BC-CML) as well as in controls by reduced representation bisulfite sequencing. Although only ~600 differentially methylated CpG sites were identified in samples obtained from CP-CML patients compared with controls, ~6500 differentially methylated CpG sites were found in samples from BC-CML patients. In the majority of affected CpG sites, methylation was increased. In CP-CML patients who progressed to AP-CML/BC-CML, we identified up to 897 genes that were methylated at the time of progression but not at the time of diagnosis. Using RNA-sequencing, we observed downregulated expression of many of these genes in BC-CML compared with CP-CML samples. Several of them are well-known tumor-suppressor genes or regulators of cell proliferation, and gene re-expression was observed by the use of epigenetic active drugs. Together, our results demonstrate that CpG site methylation clearly increases during CML progression and that it may provide a useful basis for revealing new targets of therapy in advanced CML.

Soluble and membrane-bound interleukin (IL)-15 Rα/IL-15 complexes mediate proliferation of high-avidity central memory CD8+ T cells for adoptive immunotherapy of cancer and infections.

The lack of persistence of infused T cells is a principal limitation of adoptive immunotherapy in man. Interleukin (IL)-15 can sustain memory T cell expansion when presented in complex with IL-15Rα (15Rα/15). We developed a novel in-vitro system for generation of stable 15Rα/15 complexes. Immunologically quantifiable amounts of IL-15 were obtained when both IL-15Rα and IL-15 genes were co-transduced in NIH 3T3 fibroblast-based artificial antigen-presenting cells expressing human leucocyte antigen (HLA) A:0201, ß2 microglobulin, CD80, CD58 and CD54 [A2-artificial antigen presenting cell (AAPC)] and a murine pro-B cell line (Baf-3) (A2-AAPC15Rα/15 and Baf-315Rα/15 ). Transduction of cells with IL-15 alone resulted in only transient expression of IL-15, with minimal amounts of immunologically detectable IL-15. In comparison, cells transduced with IL-15Rα alone (A2-AAPCRα ) demonstrated stable expression of IL-15Rα; however, when loaded with soluble IL-15 (sIL-15), these cells sequestered 15Rα/15 intracellularly and also demonstrated minimal amounts of IL-15. Human T cells stimulated in vitro against a viral antigen (CMVpp65) in the presence of 15Rα/15 generated superior yields of high-avidity CMVpp65 epitope-specific T cells [cytomegalovirus-cytotoxic T lymphocytes (CMV-CTLs)] responding to ≤ 10- 13 M peptide concentrations, and lysing targets cells at lower effector : target ratios (1 : 10 and 1 : 100), where sIL-15, sIL-2 or sIL-7 CMV-CTLs demonstrated minimal or no activity. Both soluble and surface presented 15Rα/15, but not sIL-15, sustained in-vitro expansion of CD62L+ and CCR7+ central memory phenotype CMV-CTLs (TCM ). 15Rα/15 complexes represent a potent adjuvant for augmenting the efficacy of adoptive immunotherapy. Such cell-bound or soluble 15Rα/15 complexes could be developed for use in combination immunotherapy approaches.

Statistical controversies in clinical research: an initial evaluation of a surrogate end point using a single randomized clinical trial and the Prentice criteria.

Surrogate end point research has grown in recent years with the increasing development and usage of biomarkers in clinical research. Surrogacy analysis is derived through randomized clinical trial data and it is carried out at the individual level and at the trial level. A common surrogate analysis at the individual level is the application of the Prentice criteria. An approach for the evaluation of the Prentice criteria is discussed, with a focus on its most difficult component, the determination of whether the treatment effect is captured by the surrogate. An interpretation of this criterion is illustrated using data from a randomized clinical trial in prostate cancer.

Adeno-associated virus type 6 is retrogradely transported in the non-human primate brain.

We recently demonstrated that axonal transport of adeno-associated virus (AAV) is serotype-dependent. Thus, AAV serotype 2 (AAV2) is anterogradely transported (e.g., from cell bodies to nerve terminals) in both rat and non-human primate (NHP) brain. In contrast, AAV serotype 6 (AAV6) is retrogradely transported from terminals to neuronal cell bodies in the rat brain. However, the directionality of axonal transport of AAV6 in the NHP brain has not been determined. In this study, two Cynomolgus macaques received an infusion of AAV6 harboring green fluorescent protein (GFP) into the striatum (caudate and putamen) by magnetic resonance (MR)-guided convection-enhanced delivery. One month after infusion, immunohistochemical staining of brain sections revealed a striatal GFP expression that corresponded well with MR signal observed during gene delivery. As shown previously in rats, GFP expression was detected throughout the prefrontal, frontal and parietal cortex, as well as the substantia nigra pars compacta and thalamus, indicating retrograde transport of the vector in NHP. AAV6-GFP preferentially transduced neurons, although a few astrocytes were also transduced. Transduction of non-neuronal cells in the brain was associated with the upregulation of the major histocompatibility complex-II and lymphocytic infiltration as previously observed with AAV1 and AAV9. This contrasts with highly specific neuronal transduction in the rat brain. Retrograde axonal transport of AAV6 from a single striatal infusion permits efficient transduction of cortical neurons in significant tissue volumes that otherwise would be difficult to achieve.

Palifermin is efficacious in recipients of TBI-based but not chemotherapy-based allogeneic hematopoietic stem cell transplants.

Palifermin, a recombinant human keratinocyte growth factor, is commonly given to prevent mucositis following autologous transplantation. In the allogeneic hematopoietic stem cell transplant (allo-HSCT) setting, safety and efficacy data are limited. We conducted a retrospective study in 251 patients undergoing allo-HSCT, 154 of whom received peritransplant palifermin. In all patients, palifermin significantly decreased the mean number of days of total parenteral nutrition (TPN, 13 vs 16 days, P=0.006) and patient-controlled analgesia (PCA, 6 vs 10 days, P=0.023), as well as the length of initial hospital stay (LOS, 32 vs 37 days, P=0.014). However, the effect of palifermin was only significant in patients who received a TBI- but not BU-based chemotherapy conditioning regimen. In TBI recipients, palifermin decreased the mean number of days of TPN (13 vs 17 days, P<0.001) and PCA (7 vs 12 days, P=0.033), and the length of stay (32 vs 38 days, P=0.001). Palifermin did not affect GVHD, graft failure or relapse. Therefore, in the largest analysis with this patient population to date, we demonstrate that palifermin is safe in allo-HSCT patients, decreases TPN and PCA use and decreases LOS following TBI-based but not chemotherapy-based allo-HSCT.

International variations in infrainguinal bypass surgery - a VASCUNET report.

OBJECTIVES: To compare practice in lower limb bypass surgery in nine countries. DESIGN: A prospective study amalgamating and analysing data from national and regional vascular registries. METHODS: A table of data fields and definitions was agreed by all member countries of the Vascunet Collaboration. Data from January 2005 to December 2009 was submitted to a central database. RESULTS: 32,084 cases of infrainguinal bypass (IIB) in nine countries were analysed. Procedures per 100,000 population varied between 2.3 in the UK and 24.6 in Finland. The proportion of women varied from 25% to 43.5%. The median age for all countries was 70 for men and 76 for women. Hungary treated the youngest patients. IIB was performed for claudication for between 15.7% and 40.8% of all procedures. Vein grafts were used in patients operated on for claudication (52.9%), for rest pain (66.7%) and tissue loss (74.1%). Italy had the highest use of synthetic grafts. Among claudicants 45% of bypasses were performed to the below knee popliteal artery or more distally. Graft patency at 30 days varied between 86% and 99%. CONCLUSIONS: Significant variations in practice between countries were demonstrated. These results should be interpreted alongside the known limitations of such registry data with respect to quality and completeness of the data. Variation in data completeness and data validation between countries needs to be improved for useful international comparison of outcomes.

Challenging narrow distal aorta in abdominal aortic aneurysm--endovascular repair using a reversed flared endoprosthesis.

INTRODUCTION: Narrow aortic bifurcations are a challenging issue while treating abdominal aortic aneurysm by endovascular means. Off-the-shelf products are often not suitable and special considerations and custom-made endoprostheses are necessary. REPORT: Alternatively, some morphologies qualify for a flared tube graft. We report two successful aneurysm exclusions using custom-made (Anaconda, Vascutek/Terumo) step-down diameter grafts in patients with tight distal aortas without the need for pre-interventional endograft adjustments. DISCUSSION: In these two cases, implantation of a custom-made proximally flared tube endograft in treating a localised abdominal aortic aneurysm with a narrow and calcified bifurcation seems feasible. They represent uncommon, yet challenging, issues worthy of attention.

Second-line age-adjusted International Prognostic Index in patients with advanced non-Hodgkin lymphoma after T-cell depleted allogeneic hematopoietic SCT.

T-cell depleted allogeneic hematopoietic SCT (TCD-HSCT) have shown durable disease-free survival with a low risk of GVHD in patients with AML. We investigated this approach in 61 patients with primary refractory or relapsed non-Hodgkin lymphoma (NHL), who underwent TCD-HSCT from January 1992 through September 2004. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, followed by either thiotepa and cyclophosphamide (45 patients) or thiotepa and fludarabine (16 patients). We determined the second-line age-adjusted International Prognostic Index score (sAAIPI) before transplant transplant. Median follow-up of surviving patients is 6 years. The 10-year OS and EFS were 50% and 43%, respectively. The relapse rate at 10 years was 21% in patients with chemosensitive disease and 52% in those with resistant disease at time of HSCT. Nine of the 18 patients who relapsed entered a subsequent CR. OS (P=0.01) correlated with the sAAIPI. The incidence of grades II-IV acute GVHD was 18%. We conclude that allogeneic TCD-HSCT can induce high rates of OS and EFS in advanced NHL with a low incidence of GVHD. Furthermore, the sAAIPI can predict outcomes and may be used to select the most appropriate patients for this type of transplant.

[Measurement of medical outcome quality using administative data in Germany]. / Zur Messung und Darstellung von medizinischer Ergebnisqualität mit administrativen Routinedaten in Deutschland.

While internationally low-effort reporting and quality assurance systems based on routine data for hospitals were implemented a long time ago, the evaluation of the treatment quality in hospitals according to section sign 137 SGB V in Germany still relies on special data collection, which demands considerable extra time and effort for the healthcare providers. The current article starts by addressing the question whether quality analyses using primary data sources should be preferred to analyses using secondary data analyses. Subsequently, current possibilities of measuring outcome quality, using administrative routine data, will be illustrated, referring to the large collaborative project Quality Assurance of Hospital Care with Routine Data (QSR). This project was carried out in order to examine possibilities of measuring quality based on routine administrative data in Germany from 2002-2007. The objectives of this article are to present a summary of the project's current status as well as to provide perspectives of future quality assurance with routine data in Germany. In addition, some general problems in measurement of outcome quality, the volume-prevalence problem and the problem of risk adjustment are presented, and possible solutions are proposed.

Intraoperative duplex ultrasonography in carotid endarterectomy: the impact on indication for immediate revision and intermediate-term outcome.

BACKGROUND: Thromboembolic complications in relation to carotid endarterectomies (CEA) are frequently associated with technical errors. We analyzed prospectively the impact of intraoperative duplex ultrasonography (IODS) in CEA on immediate revision and postoperative results. PATIENTS AND METHODS: We have observed 70 patients with 74 CEA. Indications for surgery were asymptomatic high grade stenosis (70-99%) or symptomatic stenosis of > 50%. IODS findings were rated as "relevant", "minor" or "normal". Relevant findings were immediately repaired. Peri- and postoperative neurological events were analyzed in Duplex Scans controls in a median length of follow-up of 17.3 months. Outcome of patients with "minor" findings (group A) were compared with patients having "normal" or corrected "relevant" findings (group B). RESULTS: In 8/74 cases (11%) we found relevant findings leading to immediate revision. In 25/74 (34%) cases minor findings were detected which were not revised. In group A (n = 25, 34%) two asymptomatic occlusions and one recurrent high grade stenosis were found during follow-up. In group B (n = 49, 66%) we detected two high and two low grade stenosis. The 30 day death and stroke rate was 1.4% (n = 1). CONCLUSIONS: IODS is a sensitive method to detect immediately pathological findings. Its correction seems to reduce the incidence of early occlusions and therefore early neurological events.

Long-term follow-up of patients treated with daclizumab for steroid-refractory acute graft-vs-host disease.

Daclizumab has been shown to have activity in acute GVHD, but appears to be associated with an increased risk of infection. To investigate further the long-term effects of daclizumab, we performed a retrospective review of 57 patients who underwent an allogeneic hematopoietic stem cell transplant from January 1993 through June 2000 and were treated with daclizumab for steroid-refractory acute GVHD. The median number of daclizumab doses given was 5 (range 1-22). GVHD was assessed at baseline, days 15, 29 and 43. By day 43, 54% patients had an improvement in their overall GVHD score, including 76% patients aged < or =18. Opportunistic infections developed in 95% patients. Forty-three patients (75%) died following treatment with daclizumab. The causes of death included active GVHD and infection (79%), active GVHD (5%), chronic GVHD (2%) and relapse (14%). Patients with grade 3-4 GVHD had a significantly shorter median survival than patients with grade 1-2 GVHD (2.0 vs 5.1 months, P=0.001). Daclizumab has no infusion-related toxicity, is active in steroid-refractory GVHD, especially among pediatric patients, but is associated with significant morbidity and mortality due to infectious complications. Careful patient selection and aggressive prophylaxis against viral and fungal infections are recommended.

Small is beautiful: why profundaplasty should not be forgotten.

BACKGROUND: Surgical profundaplasty (SP)is used mainly as an adjunct to endovascular management of peripheral vascular disease (PAD) today. Results from earlier series of profundaplasty alone have been controversial, especially regarding its hemodynamic effect. The question is: Can profundaplasty alone still be useful? Our aim was to evaluate its role in the modern management of vascular patients. METHODS: This was a retrospective outcome study. A consecutive series of 97 patients (106 legs) from January 2000 through December 2003 were included. In 55 (52%) legs, the superficial femoral artery was occluded. These patients were included in the current analysis. Of these patients 14 (25%) were female. Mean age was 71 ((11) years. Nineteen (35%) were diabetic. The indication for operation was claudication in 29 (53%), critical leg ischemia (CLI) in 26 (47%), either with rest pain in 17 (31%), or ulcer/gangrene in 9 (16%). Endarterectomy with patch angioplasty with bovine pericardium was performed in all cases. Mean follow-up was 33 ( 14 months. Mean preoperative ankle brachial index (ABI) was 0.6. Sustained clinical efficacy was defined as upward shift of 1 or greater on the Rutherford scale without repeat target limb revascularization (TLR) or amputation. Mortality, morbidity, need for TLR, or amputation were separate endpoints. RESULTS: Postoperatively, ABI was significantly improved (mean = 0.7), in 24 (44%) by more than 0.15. At three years, cumulative clinical success rate was 80%. Overall, patients with claudication had a better outcome than those with CLI (p = 0.04). Two (4%) major amputations and 2 (4%) minor ones were performed, all in patients with CLI. None of the 9 (16%) ulcers healed. CONCLUSION: Profundaplasty is still a valuable option for patients with femoral PAD and claudication without tissue loss. It is a straightforward procedure that combines good efficacy with low complication rates. Further endovascular treatment may be facilitated. It is not useful for patients with the combination of critical ischemia and tissue loss.

Final height in pediatric patients after hyperfractionated total body irradiation and stem cell transplantation.

Impaired linear growth has been shown to occur in individuals treated during childhood with single-dose and fractionated total body irradiation (TBI) before stem cell transplantation. Our objective was to describe the final heights attained and patient/treatment factors correlating with final height in a cohort of childhood cancer survivors treated with hyperfractionated TBI (total dose 1375 or 1500 cGy). Thirty individuals (18 men) were included in the study. The mean final height standard deviation score (s.d.s.) was -1.9 +/- 0.2, significantly lower than height s.d.s. at TBI (-0.2 +/- 0.2, P < 0.001). Final height s.d.s. was significantly correlated with age at diagnosis, age at TBI and target height (P = 0.04, P < 0.001, P < 0.001, respectively). Treatment with growth hormone (GH) (n = 7) maintained mean height s.d.s. at -2.0 from the onset of GH therapy until attainment of final height. The mean final sitting height s.d.s. was -2.2 +/- 0.2 (n = 16), significantly shorter than mean final standing height s.d.s. (P < 0.01). In conclusion, treatment with hyperfractionated TBI is associated with a reduction in standing height and an even greater reduction in sitting height. Final height after hyperfractionated TBI was similar to that reported after fractionated TBI.