A DNA methylation atlas of normal human cell types.

DNA methylation is a fundamental epigenetic mark that governs gene expression and chromatin organization, thus providing a window into cellular identity and developmental processes1. Current datasets typically include only a fraction of methylation sites and are often based either on cell lines that underwent massive changes in culture or on tissues containing unspecified mixtures of cells2-5. Here we describe a human methylome atlas, based on deep whole-genome bisulfite sequencing, allowing fragment-level analysis across thousands of unique markers for 39 cell types sorted from 205 healthy tissue samples. Replicates of the same cell type are more than 99.5% identical, demonstrating the robustness of cell identity programmes to environmental perturbation. Unsupervised clustering of the atlas recapitulates key elements of tissue ontogeny and identifies methylation patterns retained since embryonic development. Loci uniquely unmethylated in an individual cell type often reside in transcriptional enhancers and contain DNA binding sites for tissue-specific transcriptional regulators. Uniquely hypermethylated loci are rare and are enriched for CpG islands, Polycomb targets and CTCF binding sites, suggesting a new role in shaping cell-type-specific chromatin looping. The atlas provides an essential resource for study of gene regulation and disease-associated genetic variants, and a wealth of potential tissue-specific biomarkers for use in liquid biopsies.

Patient-specific signaling signatures predict optimal therapeutic combinations for triple negative breast cancer.

Triple negative breast cancer (TNBC) is a heterogeneous group of tumors which lack estrogen receptor, progesterone receptor, and HER2 expression. Targeted therapies have limited success in treating TNBC, thus a strategy enabling effective targeted combinations is an unmet need. To tackle these challenges and discover individualized targeted combination therapies for TNBC, we integrated phosphoproteomic analysis of altered signaling networks with patient-specific signaling signature (PaSSS) analysis using an information-theoretic, thermodynamic-based approach. Using this method on a large number of TNBC patient-derived tumors (PDX), we were able to thoroughly characterize each PDX by computing a patient-specific set of unbalanced signaling processes and assigning a personalized therapy based on them. We discovered that each tumor has an average of two separate processes, and that, consistent with prior research, EGFR is a major core target in at least one of them in half of the tumors analyzed. However, anti-EGFR monotherapies were predicted to be ineffective, thus we developed personalized combination treatments based on PaSSS. These were predicted to induce anti-EGFR responses or to be used to develop an alternative therapy if EGFR was not present.In-vivo experimental validation of the predicted therapy showed that PaSSS predictions were more accurate than other therapies. Thus, we suggest that a detailed identification of molecular imbalances is necessary to tailor therapy for each TNBC. In summary, we propose a new strategy to design personalized therapy for TNBC using pY proteomics and PaSSS analysis. This method can be applied to different cancer types to improve response to the biomarker-based treatment.

MRI prediction of neoadjuvant chemotherapy response is equivalent in patients with or without mammographic calcifications: a step towards adapting surgical approach?

OBJECTIVES: Current surgical policy recommends comprehensive excision of tumorous calcifications in breast cancer patients following neoadjuvant chemotherapy (NAC) regardless of MRI outcomes, despite MRI defining tumor response superior to mammography. The current study examines MRI prediction of response in tumors with vs without calcifications, using post-NAC surgical pathology as the standard of reference. METHODS: Retrospective analysis of 114 NAC patients between 2011 and 2018 including demographics, mammography, 3 T-MRI, and pathology compared two sub-groups: without (n = 62) or with (n = 52) mammographic calcifications. In the calcification cohort, the mammographic extent of calcifications and MRI enhancement overlapped. MRI prediction of response to NAC was correlated with pathology. Two-tailed paired T and Fisher's exact tests and Cohen's kappa coefficient were applied for analysis. RESULTS: There was no significant difference between the two sub-groups regarding demographics. Tumors demonstrated equivalent features regarding size, lymph node involvement, and DCIS component. ER-negative/HER2-positive tumors more commonly exhibited calcifications (33% n = 17 calcified vs 13% n = 8 non-calcified; p < 0.05); triple negative pathology rarely calcified (6% n = 3 calcified vs 33% n = 20 non-calcified; p < 0.05). NME was more common with calcifications (62% n = 32 calcified vs 29% n = 18 non-calcified; p < 0.05) and mass enhancement without (90% n = 56 non-calcified vs 81% n = 42 calcified; p < 0.05). Both groups responded similarly to NAC (pCR = 37% non-calcified vs 38% calcified); response on MRI equally correlated with pathology (69% both subgroups; p = 0.988). CONCLUSION: We propose utilizing post-NAC MRI findings rather than mammography in planning surgery, as MRI prediction is independent of the presence or absence of calcifications. Prospective studies to evaluate this approach are warranted. KEY POINTS: • No difference was found in demographic, clinical, pathology, or imaging characteristics between patients with or without tumoral calcifications on mammography prior to neoadjuvant chemotherapy. • Residual mammographic calcifications are inadequate predictors of residual invasive disease. MRI accurately recognized complete response and correctly correlated with post-treatment surgical pathology in 69% of patients, regardless of the presence or absence of mammographic calcifications. • We propose utilizing post-NAC MRI findings rather than mammography in planning post-NAC surgery, as MRI prediction of response is independent of the presence or absence of calcifications.

Probing lipids relaxation times in breast cancer using magnetic resonance spectroscopic fingerprinting.

OBJECTIVES: To investigate the clinical relevance of the relaxation times of lipids within breast cancer and normal fibroglandular tissue in vivo, using magnetic resonance spectroscopic fingerprinting (MRSF). METHODS: Twelve patients with biopsy-confirmed breast cancer and 14 healthy controls were prospectively scanned at 3 T using a protocol consisting of diffusion tensor imaging (DTI), MRSF, and dynamic contrast-enhanced (DCE) MRI. Single-voxel MRSF data was recorded from the tumor (patients) - identified using DTI - or normal fibroglandular tissue (controls), in under 20 s. MRSF data was analyzed using in-house software. Linear mixed model analysis was used to compare the relaxation times of lipids in breast cancer VOIs vs. normal fibroglandular tissue. RESULTS: Seven distinguished lipid metabolite peaks were identified and their relaxation times were recorded. Of them, several exhibited statistically significant changes between controls and patients, with strong significance (p < 10-3) recorded for several of the lipid resonances at 1.3 ppm (T1 = 355 ± 17 ms vs. 389 ± 27 ms), 4.1 ppm (T1 = 255 ± 86 ms vs. 127 ± 33 ms), 5.22 ppm (T1 = 724 ± 81 ms vs. 516 ± 62 ms), and 5.31 ppm (T2 = 56 ± 5 ms vs. 44 ± 3.5 ms, respectively). CONCLUSIONS: The application of MRSF to breast cancer imaging is feasible and achievable in clinically relevant scan time. Further studies are required to verify and comprehend the underling biological mechanism behind the differences in lipid relaxation times in cancer and normal fibroglandular tissue. KEY POINTS: •The relaxation times of lipids in breast tissue are potential markers for quantitative characterization of the normal fibroglandular tissue and cancer. •Lipid relaxation times can be acquired rapidly in a clinically relevant manner using a single-voxel technique, termed MRSF. •Relaxation times of T1 at 1.3 ppm, 4.1 ppm, and 5.22 ppm, as well as of T2 at 5.31 ppm, were significantly different between measurements within breast cancer and the normal fibroglandular tissue.

Anterior intercostal artery perforator flap for immediate reconstruction following breast conservation surgery.

INTRODUCTION: Oncoplastic breast surgery following breast conservation surgery (BCS) utilizes aesthetic breast reduction techniques, and these reconstructions entail either volume displacement or volume replacement depending on the size and location of the excised tumor. The anterior Intercostal flap (AICAP) for immediate reconstruction after BCS is scarcely described in the literature. In this study, we present our experience with the Anterior Intercoastal Artery Perforator flap in 16 patients with small breast sizes. PATIENTS AND METHODS: Sixteen patients underwent lumpectomy followed by immediate reconstruction with Anterior ICAP flap between 2019 and 2021 at Hadassah University Hospital. Median age was 49 (range 28-67). Breast cup size, lumpectomy to breast size ration, defect measurements and location are provided. Flap design and flap in-setting was planned and executed according to the size and location of the defect determined at the time of surgery. Surgical technique is described. Diagram of proposed reconstruction according to defect location is proposed. RESULTS: Flap dimensions clinically matched the defect size or were slightly larger due to anticipated shrinkage of tissue post radiation with mean of 5.4 × 3.9 × 3.75 cm (range of 2.5-13 × 2-13.2 × 0.8-4.5 cm). Complications, namely one seroma and one mild infection, were seen in two patients. Median follow up was 3 months after completion of radiation. All reconstructions were satisfactory by both surgeon and patient at last post-operative follow-up visit. CONCLUSION: The anterior ICAP flap is an important addition to the armamentarium of immediate reconstruction options after BCS, particularly in patients smaller size breast sizes.

Revision Rate of Direct-to-Implant Breast Reconstruction: Is it Truly a Single-Stage Reconstruction? A Single-Surgeon Experience.

INTRODUCTION: There has been increased interest in direct-to-implant (DTI) reconstruction in recent years. The goal of this study was to focus on the re-operation rate of DTI in comparison with two-stage tissue expander (TE) reconstruction. PATIENTS AND METHODS: In total, 165 consecutive patients (222 breasts) underwent skin sparing mastectomy and immediate implant-based reconstruction between January 2010 and December 2019. Patients were divided to TE procedure and DTI (42,180 breasts, respectively). Data collected included demographics, operative details and oncological medical treatment, complications classified according to Clavien-Dindo, capsular contracture Baker 3-4 and re-operation due to complication or due to patient's wish to improve aesthetic appearance. RESULTS: There were significantly more prophylactic mastectomies and BRCA gene mutation in the DTI breast reconstruction group, and more smokers and diabetic patients in the TE group. No significant difference was found in the complication rates between the groups (DTI-26.1%, TE-40.5%). However, major complication and re-operation rate due to complications were significantly different ( DTI-16.7% and 10.6%, TE-26.2% and 31%, respectively, p= 0.035, p = 0.008). No significant differences were found in Clavien-Dindo stages between the groups except for Grade 3b. Re-operation due to desire for aesthetic improvement was significantly higher in the TE group (DTI-38%. TE-69%, p=0.0003). CONCLUSION: DTI immediate breast reconstruction can provide a good alternative to the traditional two-stage TE/implant operation. Both patients and surgeons can be reassured that the majority of the cases are one-stage reconstruction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Breast MRI during lactation: effects on tumor conspicuity using dynamic contrast-enhanced (DCE) in comparison with diffusion tensor imaging (DTI) parametric maps.

PURPOSE: To investigate the effect of lactation on breast cancer conspicuity on dynamic contrast-enhanced (DCE) MRI in comparison with diffusion tensor imaging (DTI) parametric maps. MATERIALS AND METHODS: Eleven lactating patients with 16 biopsy-confirmed pregnancy-associated breast cancer (PABC) lesions were prospectively evaluated by DCE and DTI on a 1.5-T MRI for pre-treatment evaluation. Additionally, DCE datasets of 16 non-lactating age-matched breast cancer patients were retrospectively reviewed, as control. Contrast-to-noise ratio (CNR) comprising two regions of interests of the normal parenchyma was used to assess the differences in the tumor conspicuity on DCE subtraction images between lactating and non-lactating patients, as well as in comparison against DTI parametric maps of λ1, λ2, λ3, mean diffusivity (MD), fractional anisotropy (FA), and maximal anisotropy index, λ1-λ3. RESULTS: CNR values of breast cancer on DCE MRI among lactating patients were reduced by 62% and 58% (p < 0.001) in comparison with those in non-lactating patients, when taking into account the normal contralateral parenchyma and an area of marked background parenchymal enhancement (BPE), respectively. Among the lactating patients, DTI parameters of λ1, λ2, λ3, MD, and λ1-λ3 were significantly decreased, and FA was significantly increased in PABC, relative to the normal lactating parenchyma ROIs. When compared against DCE in the lactating cohort, the CNR on λ1, λ2, λ3, and MD was significantly superior, providing up to 138% more tumor conspicuity, on average. CONCLUSION: Breast cancer conspicuity on DCE MRI is markedly reduced during lactation owing to the marked BPE. However, the additional application of DTI can improve the visualization and quantitative characterization of PABC, therefore possibly suggesting an additive value in the diagnostic workup of PABC. KEY POINTS: • Breast cancer conspicuity on DCE MRI has decreased by approximately 60% among lactating patients compared with non-lactating controls. • DTI-derived diffusion coefficients and the anisotropy indices of PABC lesions were significantly different than those of the normal lactating fibroglandular tissue. • Among lactating patients, breast cancer conspicuity on DTI-derived parametric maps provided up to 138% increase in contrast-to-noise ratio compared with DCE imaging.

Preoperative MRI for Evaluation of Extent of Disease in IDC Compared to ILC.

OBJECTIVES: The purpose of this study was to assess the incremental value of preoperative breast MRI over mammography and US in depicting the accurate extent of disease in invasive duct carcinoma (IDC) compared to invasive lobular carcinoma (ILC). PATIENTS AND METHODS: Retrospective analysis of pre-operative mammography, US and MRI was performed in 239 patients with either IDC (n = 193) or ILC (n = 46). Images were evaluated for solitary, multifocal or multi centric disease and compared for concordance with postsurgical pathology. Discordance was documented as either overestimation or underestimation. Two tailed paired T and Fischer's exact tests were used for analysis. RESULTS: Multifocality was present on pathology in 35% and 61% of patients with IDC and ILC (P < .05) and multicentricity in 23% and 41% respectively (P = .84). In ILC, MRI demonstrated better concordance with pathology compared to mammography and US (89%, 44%, 49% for multifocality [P < .05] and 80.5%, 63%, 71% for multicentricity [P = .3]). For IDC, concordance with pathology for all modalities was similar (65%-76%). Among discordant cases, underestimation was significantly more common for mammography and US, while MRI more frequently overestimated disease extent. MRI very rarely overestimated multifocal disease in ILC (2%). CONCLUSION: MRI demonstrates an 80% to 90% concordance rate with pathology for ILC, superior to mammography and US. The addition of MRI in IDC patients may decrease underestimation of disease extent and potentially contribute to a reduction in post-operative residual disease.

Thyroid Hormones and Morphological Features of Primary Breast Cancer.

BACKGROUND/AIM: Many experimental studies have suggested the importance of thyroid hormones in breast cancer (BC) morphogenesis. The aim of this study was to evaluate the association of thyroid hormone levels in serum of patients with primary BC with morphological presentations of the disease in pathological specimens and prognosis. PATIENTS AND METHODS: We measured the serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), along with serum thymidine kinase 1 activity and examined their relation to pathological features and prognosis of 158 patients with primary BC. RESULTS: We found a significant positive association of serum FT3 level with the presence of carcinoma in situ component (CIS) (p=0.032) and its size (p=0.047), with the presence (p=0.022) and the number of multifocal/multicentric tumors (MMTs) (p=0.002), as well as with increased proliferative activity in terms of serum thymidine kinase 1 (p=0.002). Moreover, we report that each 1.0 unit rise of FT3/FT4 ratio×10 was associated with an odds ratio of 1.77 (95% confidence interval=1.17-3.30, p=0.007), 1.97 (95% confidence interval=1.17-2.67, p=0.010) and 1.56 (95% confidence interval=1.02-2.37, p=0.039) for the detection of patients with CIS, MMTs and lymphovascular invasion, respectively, after adjusting for age. We did not find statistically significant associations of serum TSH level with breast cancer`s parameters. A Cox regression survival analysis identified serum FT3 level >5.95 pmol/l as a risk factor for BC recurrence (relative risk=2.65, p=0.017), a finding that retained significance in a multivariate model (relative risk=2.52, p=0.027). CONCLUSION: The FT3/FT4 ratio is a valuable parameter predicting the presence of CIS, MMTs and lymphovascular invasion in pathological specimens. An elevated serum FT3 level is associated with the presence of CIS, MMTs, increased proliferative activity and poor prognosis.

Elevated Free Triiodothyronine Is Associated With Increased Proliferative Activity in Triple-negative Breast Cancer.

BACKGROUND/AIM: Thyroid hormones (THs) stimulate breast cancer (BC) cell proliferation. We hypothesized that these hormones and the proliferative marker thymidine kinase 1 (TK1) represent the initial and final steps of the proliferative pathway, respectively. PATIENTS AND METHODS: We measured the serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), and free thyroxine (FT4), along with serum TK1 activity, in 144 newly diagnosed BC patients, and examined the associations between THs and proliferation in different BC receptor profiles. RESULTS: TK1 activity did not correlate with TSH (r=0.06, p=0.473) or FT4 levels (r=0.04, p=0.665), but did correlate with FT3 levels (r=0.28, p=0.001). Elevated FT3 (>6.0 pmol/l) predicted increased TK1 activity (>140 Du/l) after adjusting for age (odds ratio 4.1, p=0.014). We also found a significant association of the combined elevation of FT3 and TK1, assumed as a surrogate marker of accomplished proliferative signal, with triple-negative (TN) profile (p=0.003). The rates of combined FT3 and TK1 elevation in TN and ER-positive profiles were 20.0% and 1.8%, respectively (p=0.005). CONCLUSION: FT3 may be involved in proliferative signaling, as measured by TK1 activity, predominately in TN breast cancer.

"High-Risk Breast Cancer Screening in BRCA1/2 Carriers Leads to Early Detection and Improved Survival After a Breast Cancer Diagnosis".

BACKGROUND: Germline BRCA1/2 pathogenic variant (PV) carriers have high lifetime risk of developing breast cancer and therefore subjected to intense lifetime screening. However, solid data on the effectiveness of high-risk screening of the BRCA1/2 carrier population is limited. PATIENTS AND METHODS: Retrospectively, we analyzed 346 women diagnosed with breast tumors. Patients were divided according to the timing of BRCA1/2 PVrecognition, before (BRCA-preDx awareness, N = 62) or after (BRCA-postDx awareness group, N = 284) cancer diagnosis. RESULTS: Median follow-up times were 131.42 and 93.77 months in the BRCA-preDx awareness and BRCA-postDx awareness groups, respectively. In the BRCA-preDx awareness group, 78.7% of the patients had invasive tumors and 21.3% were diagnosed with pure ductal carcinoma in situ. In contrast, in the BRCA-postDx awareness group over 93% of women were diagnosed with invasive cancer and only 6.4% had in situ disease. The mode of tumor detection differed significantly between the groups: 71.9% in the BRCA-postDx awareness group and 26.2% in the BRCA-preDx awareness group were diagnosed after personally palpating a lump. Tumor size and nodal involvement were significantly more favorable in the BRCA-preDx awareness group. T stage was significantly lower in the BRCA-preDx awareness group: 54.84% at T1 and 20.96% at Tis. In the BRCA-postDx awareness group, only 37.54% were at T1 and 6.49% at Tis. The N stage was also significantly lower in the BRCA-preDx awareness group: 71% had no lymph node metastases, compared with 56.1% in the BRCA-postDx awareness group. Additionally, therapeutic procedures varied between the groups: BRCA-preDx awareness group patients underwent more breast conserving surgeries. Axillary lymph node dissection was done in 38% of women in the BRCA-postDx awareness group and in only 8.7% of the BRCA-preDx awareness group patients. Interestingly, improved survival was found among patients who underwent high-risk screening (hazard ratio=0.34). CONCLUSIONS: High-risk screening might facilitate downstaging of detected breast tumor among BRCA1/2 carrier population.

Thyroid Hormones, Silencing Mediator for Retinoid and Thyroid Receptors and Prognosis in Primary Breast Cancer.

BACKGROUND/AIM: Silencing mediator of retinoid and thyroid receptors (SMRT) is a nuclear corepressor in thyroid and estrogen hormones pathways. The aim was to evaluate SMRT expression in relation to thyroid hormone levels and prognostic markers in breast cancer (BC). PATIENTS AND METHODS: Serum and tumor tissues were obtained from 36 patients with benign breast disease (BBD) and 79 BC patients. SMRT expression was determined by immunohistochemistry. Free-triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH) were measured in serum. RESULTS: Higher FT4, lower FT3/FT4 ratio and higher expression of SMRT were found in BC compared to BBD (for all p<0.001). In BC, increased SMRT expression was associated with lower FT3 (p=0.028), higher tumor grade (p=0.031), increased KI67 proliferation index (p=0.015), higher risk of recurrence (p=0.014) and shorter disease-free survival (p=0.006). In multivariate analysis, SMRT overexpression and below-median levels of TSH were independent prognostic factors in BC. CONCLUSION: Elevated FT4 and decreased FT3/FT4 in BC patients suggest a role for thyroid hormones in malignant transformation. SMRT tumor overexpression is associated with lower FT3 levels, tumor proliferative activity and an aggressive clinical course.

Regulation of Cellular Heterogeneity and Rates of Symmetric and Asymmetric Divisions in Triple-Negative Breast Cancer.

Differentiation events contribute to phenotypic cellular heterogeneity within tumors and influence disease progression and response to therapy. Here, we dissect mechanisms controlling intratumoral heterogeneity within triple-negative basal-like breast cancers. Tumor cells expressing the cytokeratin K14 possess a differentiation state that is associated with that of normal luminal progenitors, and K14-negative cells are in a state closer to that of mature luminal cells. We show that cells can transition between these states through asymmetric divisions, which produce one K14+ and one K14- daughter cell, and that these asymmetric divisions contribute to the generation of cellular heterogeneity. We identified several regulators that control the proportion of K14+ cells in the population. EZH2 and Notch increase the numbers of K14+ cells and their rates of symmetric divisions, and FOXA1 has an opposing effect. Our findings demonstrate that asymmetric divisions generate differentiation transitions and heterogeneity, and identify pathways that control breast cancer cellular composition.

Adjuvant Autologous Melanoma Vaccine for Macroscopic Stage III Disease: Survival, Biomarkers, and Improved Response to CTLA-4 Blockade.

Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine to prevent disease recurrence. Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival. Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better (p = 0.0001) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone (p = 0.007). Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.

Port complications following laparoscopic adjustable gastric banding for morbid obesity.

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) has gained widespread acceptance. However, the technique has problems intrinsic to the material wear and tear around the port and connecting tubing that can lead to failure. Port complications are considered to be minor; however, few studies have analyzed them, and the optimal technique of port implantation and management has not been elucidated. METHODS: All patients who suffered from complications involving the tubing or access-port were included in this study. Their complaints, imaging studies, operative reports and hospitalization files were retrospectively reviewed. RESULTS: 1,272 of the patients were available for a mean follow-up period of 37 months. During this time, 91 patients (7.1%) experienced port complications that required 103 revisional operations. Of these patients, 62 had system leaks, 19 infectious problems, and 10 miscellaneous problems requiring operative correction. Overall port problems led to band removal in 6 patients, and replacement in 1 patient. CONCLUSION: Access-port complications after the Lap-Band procedure are among the most common and annoying ones, and can render the device susceptible to failure. Careful surgical technique and routine use of radiologic guidance for band adjustments are the keys to avoiding complications.

Effectiveness, safety, and tolerability of risperidone in adolescents with schizophrenia: an open-label study.

Data on risperidone's efficacy and tolerability in adolescents with schizophrenia are scarce. We found only one prospective, open-label study in this population. The aim of this open-label, prospective study was to estimate the effectiveness, safety, and tolerability of risperidone treatment in adolescents with first-episode schizophrenia. Subjects were adolescent inpatients diagnosed with Diagnostic and Statistical Manual of Mental Disorders (fourth edition) first-episode schizophrenia by the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present Episode version. Most of the patients (10/11) were drug naïve. Improvement was assessed during the first 6 weeks of treatment using the Positive and Negative Syndrome Scale (PANSS), the Brief Psychiatric Rating Scale (BPRS), and the Clinical Global Impression (CGI) scale. Side effects were monitored using the Abnormal Involuntary Movement Scale, the Simpson-Angus Scale, the Barnes Akathisia Rating Scale, and the Udvalg for Kliniske Undersogelser Side Effect Rating Scale. Eleven adolescents between 15.5 and 20 years of age (mean = 17.27, SD = 1.27 years) were included in this study. Risperidone in an average dose of 3.14 mg/day (SD = 1.60 mg/day) produced a significant improvement on the total PANSS score (28%, p < 0.01), BPRS score (30.11%, p < 0.01), and CGI-Severity score (31.36%, p < 0.01). Risperidone was ineffective in the treatment of negative signs as assessed by the PANSS. The major side effects were extrapyramidal side effects, somnolence, depression, and weight gain. In conclusion risperidone appears to be a safe, acceptably tolerated, and effective antipsychotic medication for the treatment of adolescent-onset schizophrenia.