What do the teachers want? A targeted needs assessment survey for prospective didactic training of psychiatry medical educators.

Objectives: Physicians and psychologists at psychiatric university hospitals are assigned teaching tasks from the first day of work without necessarily having the prerequisite training in teaching methods. This exploratory survey provides a needs-based analysis for the prospective didactic training of physicians and psychologists at psychiatric hospitals in Germany, Austria and Switzerland. Methods: An online questionnaire was distributed at medical schools via email in German-speaking countries in Europe. All physicians involved in teaching medical students at psychiatry faculties were eligible to participate in the survey. Participants were further requested to recruit eligible participants (snowball sampling). Responses were analyzed descriptively, and differences between groups were calculated using nonparametric Mann-Whitney U tests (p<.05). Results: Overall, 97 respondents (male=55, female=42; mean age= 40.6) from 19 medical schools completed the survey. The respondents consisted of 43 residents, 39 specialists, 6 chief physicians and 9 psychologists. Of the respondents, 97.6% rated didactic competence as either highly relevant or rather relevant for teaching medical students. The highest overall interest was shown for bedside teaching (mode=4; IQR: 2-4) and error culture (mode=3; IQR: 2-4). Respondents expressed the highest training needs for topics regarding presentation and communication (mode=3; IQR: 2-3). Resident physicians were significantly more interested in bedside teaching (U=362.0, p=0.004) and roleplay (U=425.0; p=0.036) than specialist physicians, who were more interested in examination didactics (U=415.0; p=0.022). Chief physicians displayed significantly deeper interest in group dynamics (U=51; p=0.023) than specialist physicians. In-person training was preferred by a majority of respondents, and 27.4% preferred online/web-based training. Conclusions: The majority of physicians and psychologists at psychiatric university hospitals considered professional development for faculty to be helpful for teaching medical students. Bedside teaching and error culture management were the most desired teaching topics for training medical teachers. Tailored educational interventions are recommended, with target-oriented priorities for different hierarchical levels.

[Ethical Considerations of Including Minors in Clinical Trials Using the Example of the Indicated Prevention of Psychotic Disorders]. / Minderjährige in klinischen Prüfungen: Ethische Abwägungen ihres Einbezugs am Beispiel der indizierten Prävention psychotischer Erkrankungen.

Ethical Considerations of Including Minors in Clinical Trials Using the Example of the Indicated Prevention of Psychotic Disorders Abstract: As a vulnerable group, minors require special protection in studies. For this reason, researchers are often reluctant to initiate studies, and ethics committees are reluctant to authorize such studies. This often excludes minors from participating in clinical studies. This exclusion can lead to researchers and clinicians receiving only incomplete data or having to rely on adult-based findings in the treatment of minors. Using the example of the study "Computer-Assisted Risk Evaluation in the Early Detection of Psychotic Disorders" (CARE), which was conducted as an 'other clinical investigation' according to the Medical Device Regulation, we present a line of argumentation for the inclusion of minors which weighs the ethical principles of nonmaleficence (especially regarding possible stigmatization), beneficence, autonomy, and fairness. We show the necessity of including minors based on the development-specific differences in diagnostics and early intervention. Further, we present specific protective measures. This argumentation can also be transferred to other disorders with the onset in childhood and adolescence and thus help to avoid excluding minors from appropriate evidence-based care because of insufficient studies.

SARS-CoV-2 and Adolescent Psychiatric Emergencies at the Tübingen University Hospital: Analyzing Trends, Diagnoses, and Contributing Factors.

Psychiatric emergencies have increased in recent decades, particularly with the onset of the SARS-CoV-2 pandemic, and far too little is known about the backgrounds of these emergencies. In this study, we investigated the extent to which the number of psychiatric emergencies changed during and in the aftermath of the SARS-CoV-2 pandemic at the Child and Adolescent Psychiatry (CAP) Tübingen. We considered age and psychiatric diagnoses. Additionally, we evaluated the backgrounds of the emergencies. We applied a mixed- (quantitative and qualitative) methods approach to data on emergency presentations at the CAP Tübingen from the pre-SARS-CoV-2 pandemic period (October 2019-January 2020) to Restriction Phase 1 (October 2020-January 2021), Restriction Phase 2 (October 2021-January 2022), and endemic phase (October 2022-January 2023). The total number of emergencies and those with eating disorders and affective disorders increased, while obsessive-compulsive disorders, expansive disorders and anxiety disorders decreased. The patients presenting in the pre-SARS-CoV-2 pandemic period were younger than those in the subsequent periods. We content-coded the reasons behind the emergency presentations. We also identified four areas of stressors and personality characteristics associated with the emergency presentations. In light of the increasing number of psychiatric emergencies, the long-term aim should be to meet the growing demands and create options for prevention.

Tübinger Training for Autism Spectrum Disorders (TüTASS): a structured group intervention on self-perception and social skills of children with autism spectrum disorder (ASD).

In autism spectrum disorders (ASD), social communication and stereotypical behaviour patterns affect all areas of life, and can result in a decrease of its quality. Previous research has shown promising results for the social skills of groups of children with ASD. Furthermore, a pilot study of the Tübingen Group Training for Autism Spectrum Disorders (TüTASS) has demonstrated that mindfulness-based elements achieve additional positive effects. To build on these findings, the TüTASS training was adapted and expanded. Indeed, the TüTASS currently includes 20 90-min appointments starting with the basic skills of emotions, body, and communication, which are then transferred to personal, family, peer, and school spheres. The appointments have a fixed, consistent structure and each includes a body awareness exercise. In this study, we evaluated the TÜTASS with 27 children with ASD. The results showed improvements in pre-post comparison in behaviours associated with autism, as well as in externalising and internalising behaviours as assessed by parent reports, participant self-reports, and independent raters in participating children. Furthermore, the perceived parent burden in relation to their children decreased, whereas the participants' self-rated quality of life increased. Overall, both the participants and their parents rated the TüTASS very positively in rating sheets and in free feedback. If replicated in larger controlled trials, TÜTASS training might be a useful treatment tool for groups of children with ASD.

Multimodal Sensor-Based Identification of Stress and Compulsive Actions in Children with Obsessive-Compulsive Disorder for Telemedical Treatment.

In modern psychotherapy, digital health technology offers advanced and personalized therapy options, increasing availability as well as ecological validity. These aspects have proven to be highly relevant for children and adolescents with obsessive-compulsive disorder (OCD). Exposure and Response Prevention therapy, which is the state-of-the-art treatment for OCD, builds on the reconstruction of everyday life exposure to anxious situations. However, while compulsive behavior pre-dominantly occurs in home environments, exposure situations during therapy are limited to clinical settings. Telemedical treatment allows to shift from this limited exposure reconstruction to exposure situations in real life. In the SSTeP KiZ study (smart sensor technology in telepsychotherapy for children and adolescents with OCD), we combine video therapy with wearable sensors delivering physiological and behavioral measures to objectively determine the stress level of patients. The setup allows to gain information from exposure to stress in a realistic environment both during and outside of therapy sessions. In a first pilot study, we explored the sensitivity of individual sensor modalities to different levels of stress and anxiety. For this, we captured the obsessive-compulsive behavior of five adolescents with an ECG chest belt, inertial sensors capturing hand movements, and an eye tracker. Despite their prototypical nature, our results deliver strong evidence that the examined sensor modalities yield biomarkers allowing for personalized detection and quantification of stress and anxiety. This opens up future possibilities to evaluate the severity of individual compulsive behavior based on multi-variate state classification in real-life situations. Clinical Relevance- Our results demonstrate the potential for efficient personalized psychotherapy by monitoring physiological and behavioral changes with multiple sensor modalities in ecologically valid real-life scenarios.

Pembrolizumab in microsatellite instability high or mismatch repair deficient cancers: updated analysis from the phase II KEYNOTE-158 study.

BACKGROUND: Pembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODS: Eligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTS: Three hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% [95% confidence interval (CI) 25.8% to 36.2%]. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONS: Pembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.

[Child and Adolescent Psychiatric Emergencies During the Second Wave of the SARS-CoV2-19 Pandemic: Findings from the Tübingen University Hospital]. / Kinder- und jugendpsychiatrische Notfälle während der zweiten Welle der SARS-CoV2-19-Pandemie.

Child and Adolescent Psychiatric Emergencies During the Second Wave of the SARS-CoV2-19 Pandemic: Findings from the Tübingen University Hospital Abstract. Objective: Child and adolescent psychiatric emergencies during the SARS-CoV2-19 pandemic are part of a controversial discussion. This study investigates the volume of such emergencies, the age of the patients, and the diagnoses of eating disorders and obsessive-compulsive disorders (OCD) that occurred at the Child and Adolescent Psychiatric Center (CAP) Tübingen during the second wave of the pandemic compared to the year before. Methods: We evaluated data on all emergencies at CAP Tübingen (telephone calls, outpatients, patient admissions) from 10/2019-01/2020 (first time period) and 10/2020-01/2021 (second wave). Results: The volume of emergencies during the second wave (319 presentations) was 29.7 % higher than during the first time period, and the number of patients (172 presentations) increased by 10.3 %. Compared to the first time period, the number of inpatients was 27.9 % higher, and the emergency admissions increased by 27.8 %. Patients in the second wave were somewhat older, with an average age of 14.8 years (first period: 14.2 years). Eating disorders were more frequent during the second wave, whereas OCD were more frequent in the first time period. Conclusions: Almost 30 % more emergencies were recorded in the second wave of the pandemic, with especially eating disorders increasing. Systematic emergency records should be documented at all German CAPs to enable demand-oriented planning.

A structured group intervention (TüTASS) with focus on self-perception and mindfulness for children with autism spectrum disorder, ASD. A pilot study.

Autism spectrum disorders (ASD) represent a set of long-lasting severe neurodevelopmental conditions and effective therapeutic interventions are needed. Recent research points to the importance of including mindfulness-based elements to improve emotion and body perception in the psychotherapy of patients with ASD. Therefore, we developed a structured group psychotherapy program The Tübinger Training for Autism Spectrum Disorders (Tübinger Training für Autismus-Spektrum-Störungen; TüTASS) which focuses on mindfulness-based training elements. This pilot study accompanying the TüTASS reports the first results on the feasibility of the program with a pre-post comparison of 25 treated children with ASD. The psychometric assessment comprised five standardized questionnaires/ scales evaluating on the basis of parents and patients self-reports the child's social responsiveness, behavior, strengths and difficulties, quality of life, and depressive symptoms before and after training completion. The results indicated that upon training completion, symptoms with respect to emotional and social problems, externalizing behavior, and attentional and schizoid-compulsive behavior substantially declined. In a questionnaire assessing feasibility and quality of the group training, patients and parents found the therapy highly beneficial, especially as to the focus on emotions and body, and strengths and failures. This training program was developed to bridge the gap of lacking mindfulness-based interventions with the aim to optimize the course of ASD, especially with respect to behavioral disturbances and social-emotional problems.

Molecular correlates of response to capmatinib in advanced non-small-cell lung cancer: clinical and biomarker results from a phase I trial.

BACKGROUND: Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3%-4% of non-small-cell lung cancer (NSCLC) and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer, the best biomarker strategy for the enrichment of a susceptible patient population still remains to be defined. Towards this end we analyze here primary data from a phase I dose expansion study of the MET inhibitor capmatinib in patients with advanced MET-dysregulated NSCLC. PATIENTS AND METHODS: Eligible patients [≥18 years; Eastern Cooperative Oncology Group (ECOG) performance status ≤2] with MET-dysregulated advanced NSCLC, defined as either (i) MET status by immunohistochemistry (MET IHC) 2+ or 3+ or H-score ≥150, or MET/centromere ratio ≥2.0 or gene copy number (GCN) ≥5, or (ii) epidermal growth factor receptor wild-type (EGFRwt) and centrally assessed MET IHC 3+, received capmatinib at the recommended dose of 400 mg (tablets) or 600 mg (capsules) b.i.d. The primary objective was to determine safety and tolerability; the key secondary objective was to explore antitumor activity. The exploratory end point was the correlation of clinical activity with different biomarker formats. RESULTS: Of 55 patients with advanced MET-dysregulated NSCLC, 40/55 (73%) had received two or more prior systemic therapies. All patients discontinued treatment, primarily due to disease progression (69.1%). The median treatment duration was 10.4 weeks. The overall response rate per RECIST was 20% (95% confidence interval, 10.4-33.0). In patients with MET GCN ≥6 (n = 15), the overall response rate by both the investigator and central assessments was 47%. The median progression-free survival per investigator for patients with MET GCN ≥6 was 9.3 months (95% confidence interval, 3.8-11.9). Tumor responses were observed in all four patients with METex14. The most common toxicities were nausea (42%), peripheral edema (33%), and vomiting (31%). CONCLUSIONS: MET GCN ≥6 and/or METex14 are suited to predict clinical activity of capmatinib in patients with NSCLC (NCT01324479).

Nitric oxide is involved in the hypothyroidism with significant morphology changes in female Wistar rats induced by chronic exposure to high water iodine from potassium iodate.

Epidemiological studies indicated that chronic exposure to high water iodine is associated with primary hypothyroidism (PH) and subclinical hypothyroidism (SCH). However, the mechanism is not well understood. In this study, we explored whether chronic exposure to high water iodine from potassium iodate (KIO3) can induce hypothyroidism in addition to determining if nitric oxide (NO) is involved in the pathogenesis. 96 female Wistar rats were divided into six groups: control, I1000µg/L, I3000µg/L, I6000µg/L, N-nitro-L-arginine methylester (L-NAME) and L-NAME+I6000µg/L. After 3 months, urine iodine concentration, thyroid hormone, NO and nitric oxide synthase (NOS) serum levels were determined. Additionally, thyroid expression of inducible nitric oxide synthase (iNOS) was also investigated. Thyroid morphology was observed under light microscopy and transmission electron microscope. SCH as indicated by elevated serum thyrotropin (TSH) was induced among rats exposed to 3000 µg/L I-, while rats treated with 6000 µg/L I- presented PH characterized by elevated TSH and lowered total thyroxine in serum. Moreover, serum NO, NOS and iNOS expression in the thyroid were significantly increased in I3000µg/L and I6000µg/L groups. Changes in thyroid function and morphology in the L-NAME+I6000µg/L group were extenuated compared to I6000µg/L group. These findings suggested that chronic exposure to high water iodine from KIO3 likely induces hypothyroidism with significant morphology changes in female Wistar rats and NO appears to be involved in the pathogenesis.

Identification of miR-200c-3p as a major regulator of SaoS2 cells activation induced by fluoride.

The skeletal lesion of fluoride has become a major concern in many countries due to its damage to bone and joints and even leading to disability. Skeletal fluorosis is characterized by disturbance of bone metabolism, aberrant proliferation and activation of osteoblasts is critical for the pathogenesis. However, the mechanism underlying the osteotoxicity of fluoride has not been clearly illustrated and there is still limited information on the role of miRNAs in skeletal fluorosis. In this study, we found that NaF promoted SaoS2 proliferation and activation by activating BMP4/Smad pathway. NaF increased expression of miR-200c-3p and miR-200c-3p inhibitor reduced activation of SaoS2 induced by NaF via targeting Noggin to repress BMP4/Smad. These findings suggested an important regulatory role of miR-200c-3p on BMP4/Smad pathway during skeletal fluorosis. MiR-200c-3p might be a novel therapeutic target for skeletal fluorosis.

Association between chronic exposure to different water iodine and thyroid cancer: A retrospective study from 1995 to 2014.

The controversy that iodine intake may increase the risk of thyroid cancer has heightened over the past twenty years. In this retrospective study, we mainly analyzed the association between water iodine and thyroid cancer and discussed the possible cause of the increase in thyroid cancer. This study was supported by three hospitals in areas with different water iodine concentration. 5574 patients with thyroid disease were recruited, of which 1429 patients had been diagnosed with thyroid cancer. These samples collectively were used to analyze the relationship of incidence and prevalence associated with water iodine. In addition, the ratio of maximum tumor diameter was analyzed. By analyzing the proportion of patients with thyroid cancer in thyroid diseases, we found a decrease in the proportion of thyroid cancer with increasing water iodine (P<0.0001). In addition, there was no significant correlation between the median water iodine and the prevalence of thyroid cancer, including papillary thyroid cancer (P>0.05). Meanwhile, the 5years' cumulative incidence of thyroid cancer increased with years (P<0.01). Comparing Cao county and Shan county, which are areas with high water iodine, to adequate iodine area such as in Mudan district, an increasing incidence is observed in 2010-2014 in Mudan district. Again, we observed a significant increase in the proportion of thyroid cancer with tumor size <1cm (P<0.01). Therefore, we concluded that cause(s) of increase in thyroid cancer may be ascribed to the sensitive diagnostic techniques and the improvement of living condition, but not water iodine.

Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastases-analysis of an international multicenter database.

BACKGROUND: The imaging response to radium-223 therapy is at present poorly described. We aimed to describe the imaging response to radium-223 treatment. METHODS: We retrospectively evaluated the computed tomography (CT) and bone scintigraphy response of metastatic castration-resistant prostate cancer (CRPC) patients treated with radium-223, in eight centers in three countries. RESULTS: A total of 130 patients were included, the majority (n=84, 65%) received radium-223 post docetaxel. Thirty-four of 99 patients with available data (34%) received concomitant abiraterone or enzalutamide. A total of 54% (n=70) patients completed the planned six injections of radium-223. In patients with available data, a transient increase in bone metastases-related pain was observed in 27% (n=33/124) and an improvement of bone metastases-related pain on treatment with radium-223 was noted in 49% of patients (n=61/124). At 3 and 6 months of treatment with radium-223, bone imaging showed stable disease in 74% (n=84/113) and 94% of patients (n=93/99) with available data, respectively. An increase in the number of bone lesions was documented at 3 months compared with baseline in 26% (n=29/113) and at 6 months compared with 3 months in 6% of patients (n=6/99), respectively. Radiological extraskeletal disease progression occurred in 46% of patients (n=57/124) with available CT data at 3 and/or 6 months. CONCLUSIONS: Progression of bone metastases during radium-223 therapy is uncommon. A bone flare (pain and/or radiological) may be noted during the first 3 months, and should not be confused with progression. Imaging by CT scan should be considered after three and six doses of radium-223 to rule out extraskeletal disease progression.

Matrix Metallopeptidase-2 Gene rs2287074 Polymorphism is Associated with Brick Tea Skeletal Fluorosis in Tibetans and Kazaks, China.

Brick tea skeletal fluorosis is still a public health issue in the north-western area of China. However its pathogenesis remains unknown. Our previous study reveals that the severity of skeletal fluorosis in Tibetans is more serious than that in Kazaks, although they have similar fluoride exposure, suggesting the onset of brick tea type skeletal fluorosis might be genetically influenced. Here we show that MMP-2 rs2287074 SNP (G/A), but not rs243865, was associated with Brick tea type fluorosis in Tibetans and Kazaks, China. The trend test reveals a decline in probability for skeletal fluorosis with increasing number of A alleles in Tibetans. After controlling potential confounders, AA genotype had about 80 percent lower probability of developing skeletal fluorosis than GG genotype in Tibetans (odds ratio = 0.174, 95% CI: 0.053, 0.575), and approximately 53 percent lower probability in Kazaks (odds ratio = 0.462, 95% CI: 0.214, 0.996). A meta-analysis shows that the AA genotype had approximately 63 percent lower odds (odds ratio = 0.373, 95% CI: 0.202, 0.689) compared with GG genotype within the two ethnicities. A significant correlation was also found between the genotype of MMP2 rs2287074 and skeletal fluorosis severity. Therefore, the A allele of MMP2 rs2287074 could be a protective factor for brick tea skeletal fluorosis.

Relationship between fluoride exposure and osteoclast markers during RANKL-induced osteoclast differentiation.

Skeletal fluorosis is a metabolic bone disease caused by excessive accumulation of fluoride. Although the cause of this disease is known, the mechanism by which fluoride accumulates on the bone has not been clearly defined, thus there are no markers that can be used for screening skeletal fluorosis in epidemiology. In this study, osteoclasts were formed from bone marrow cells of C57BL/6 mice-treated with macrophage colony stimulating factor and receptor activator of nuclear factor kappa-B ligand. The mRNA expression of tartrate-resistant acid phosphatase 5b (TRAP5b), osteoclast-associated receptor (OSCAR), calcitonin receptor (CTR), matrix metalloproteinase 9 (MMP9) and cathepsin K (CK) were detected using real-time PCR (RT-PCR). Results showed that fluoride between 0.5 and 8mg/l had no effect on osteoclast formation. However fluoride at 0.5mg/l level significantly decreased the activity of osteoclast bone resorption. Fluoride concentration was negatively correlated with the activity of osteoclast bone resorption. On day 5 of osteoclast differentiation maturity, MMP9 and CK mRNA expression were not only negatively correlated with fluoride concentration, but directly correlated with the activity of osteoclast bone resorption. TRAP5b, CTR and OSCAR mRNA expression were positively correlated with the number of osteoclast and they had no correlation with the activity of osteoclast bone resorption. Thus, it can be seen that MMP9 and CK may reflect the change of activity of bone resorption as well the degree of fluoride exposure. TRAP5b, CTR and OSCAR can represent the change of number of osteoclast formed.

[Molecular diagnostics of lung cancer]. / A tüdorák molekuláris diagnosztikája.

Development of the target therapies of lung cancer was a rapid process which fundamentally changed the pathological diagnosis as well. Furthermore, molecular pathology became essential part of the routine diagnostics of lung cancer. These changes generated several practical problems and in underdeveloped countries or in those with reimbursement problems have been combined with further challenges. The central and eastern region of Europe are characterized by similar problems in this respect which promoted the foundation of NSCLC Working Group to provide up to date protocols or guidelines. This present paper is a summary of the molecular pathology and target therapy guidelines written with the notion that it has to be upgraded continuously according to the development of the field.

Adjuvant treatment of high-risk stage II breast cancer with doxorubicin followed by high-dose chemotherapy and autologous stem-cell transplantation: a single-institution experience with 132 consecutive patients.

Several studies have shown conflicting results with the use of intensive consolidation chemotherapy for breast cancer. The aim of the present study was to investigate the efficacy, feasibility and toxicity of high-dose chemotherapy with stem cell support in patients with high-risk stage II breast cancer. From February 1994 to November 1998, 132 consecutive patients with multinode positive breast cancer were entered to the study. In total, 86 patients had >or=10 positive axillary lymph nodes, and 46 had 4-9 positive axillary lymph nodes with at least two additional predetermined risk factors at diagnosis. All patients were offered adjuvant chemotherapy (doxorubicin, 75 mg/m(2) x 4) followed by high-dose chemotherapy (cyclophosphamide 6000 mg/m(2), carboplatin 800 mg/m(2) and thio-tepa 500 mg/m(2)) and autologous stem cell support with growth factor. In all, 131 patients also received local radiation therapy and tamoxifen based on receptor status. After a median follow-up of 51 months (range 27-87), the disease-free and overall survival rates were 72 and 81%, respectively. There was no difference in the outcome for high-risk patients with > or < than 10 positive axillary lymph nodes. On Cox regression analysis only progesterone receptor status was predictive of disease-free, but not overall survival. There were no treatment-related deaths; grades III-IV toxicity was relatively low. This combined approach of doxorubicin followed by high-dose chemotherapy and stem-cell support, followed by locoregional radiotherapy, was safe and seems to be effective in patients with multinode positive stage II breast cancer. In previous trials of adjuvant high-dose therapy in this patient population, treatment-related morbidity and mortality markedly influenced the outcome. For this high-risk patient population, further testing of intensive chemotherapy regimens with a lower toxicity profile is warranted.

Resection and perfusion thermochemotherapy: a new approach for the treatment of thymic malignancies with pleural spread.

BACKGROUND: Thymoma and thymic carcinoma with pleural spread have a high rate of locoregional recurrence and poor prognosis. Maximal debulking coupled with aggressive local treatment could offer a chance for cure. This study evaluates the early and midterm results of operation and hyperthermic pleural perfusion with cisplatinum for thymic malignancies. METHODS: Fifteen patients (11 men), 20 to 67 years old (10 thymoma, 4 thymic carcinoma, 1 carcinoma in thymic cyst) underwent resection and hyperthermic pleural perfusion between 1995 to 2000. All had pleural spread proven before or intraoperatively. Six of the thymoma cases were recurrent. Current operation included resection without pleurectomy (9 patients), resection with pleurectomy (5), and extrapleural pneumonectomy (1 patient) with intraoperative hyperthermic pleural perfusion in all. Intrapleural temperature reached 40.3 degrees C to 43 degrees C. The total dose of cisplatinum was 150 mg or more in 14 patients. RESULTS: Complete resection (R0) was achieved in 10 patients, subtotal (R1) in 3, and partial (R2) in 2. There was no operative mortality, no hemodynamic or respiratory disturbances during perfusion, and no hematologic, neurologic, or renal complications. Complications consisted of significant bleeding (2 patients), fever (2), and air leak (1 patient). Two patients with thymic carcinoma died after 27 and 34 months, and 1 is alive with no evidence of disease at 54 months. Two patients with thymoma died after 7 and 36 months. Eight are alive after 9 to 70 months. Four patients (all R0) are alive without local recurrence more than 60 months after operation and hyperthermic pleural perfusion. CONCLUSIONS: Operation and thermochemotherpy is feasible and safe in patients with thymic tumors. This method seems to offer excellent local control for patients with stage IV-a thymic malignancies. Midterm results suggest that operation plus hyperthermic pleural perfusion may lengthen survival in stage IV-a thymoma.

Hepatic storage of glycogen in Niemann-Pick disease type B.

We report 2 patients with confirmed Niemann-Pick disease, type B, with previous diagnoses of glycogen storage disease based on excessive glycogen on liver biopsy specimens. These cases emphasize the importance of a complete evaluation, including biochemical confirmation, for patients with suspected metabolic storage diseases.

Staging of pancreatic cancer before and after neoadjuvant chemoradiation.

Neoadjuvant chemoradiation therapy is used at many institutions for treatment of localized adenocarcinoma of the pancreas. Accurate staging before neoadjuvant therapy identifies patients with distant metastatic disease, and restaging after neoadjuvant therapy selects patients for laparotomy and attempted resection. The aims of this study were to (1) determine the utility of staging laparoscopy in candidates for neoadjuvant therapy and (2) evaluate the accuracy of restaging CT following chemoradiation. Staging laparoscopy was performed in 98 patients with radiographically potentially resectable (no evidence of arterial abutment or venous occlusion) or locally advanced (arterial abutment or venous occlusion) adenocarcinoma of the pancreas. Unsuspected distant metastasis was identified in 8 (18%) of 45 patients with potentially resectable tumors and 13 (24%) of 55 patients with locally advanced tumors by CT. Neoadjuvant chemoradiation therapy and restaging CT were completed in a total of 103 patients. Thirty-three patients with potentially resectable tumors by restaging CT underwent surgical exploration and resections were performed in 27 (82%). Eleven (22%) of 49 patients with locally advanced tumors by restaging CT were resected, with negative margins in 55%; the tumors in these 11 patients had been considered locally advanced because of arterial involvement on restaging CT. Staging laparoscopy is useful for the exclusion of patients with unsuspected metastatic disease from aggressive neoadjuvant chemoradiation protocols. Following neoadjuvant chemoradiation, restaging CT guides the selection of patients for laparotomy but may overestimate unresectability to a greater extent than does prechemoradiation CT.