Working along sudden gains: Responsiveness on small and subtle early changes and exceptions

When mental health is monitored over the course of treatment, many clients report strong and stable changes, particularly early in psychotherapy. Such changes can occur both in singular events, such as sudden gains in particular symptoms, and more comprehensive ways across the World Health Organization definition of health (WHO, 1948), which includes well-being and psychosocial functioning. The present practical guideline illustrates a systematized sequence of tasks that explore rapid changes and sudden gains at a very early stage of therapy, as well as how such changes can be used in future therapeutic work. These tasks include (1) exploration of the change situation, (2) reinforcement of generalized self-efficacy and hope bonding, and (3) benefit for therapy.

Variation in precursor lesions of pancreatic cancer among high-risk groups

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups. EXPERIMENTAL DESIGN Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0-127 months) or 36 months (0-110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery. RESULTS Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable. CONCLUSION In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group.

Late toxicity and five year outcomes after high-dose-rate brachytherapy as a monotherapy for localized prostate cancer

BACKGROUND To determine the 5-year outcome after high-dose-rate brachytherapy (HDR-BT) as a monotherapy. METHODS Between 10/2003 and 06/2006, 36 patients with low (28) and intermediate (8) risk prostate cancer were treated by HDR-BT monotherapy. All patients received one implant and 4 fractions of 9.5 Gy within 48 hours for a total prescribed dose (PD) of 38 Gy. Five patients received concomitant androgen deprivation therapy (ADT). Toxicity was scored according to the common terminology criteria for adverse events from the National Cancer Institute (CTCAE) version 3.0. Biochemical recurrence was defined according to the Phoenix criteria and analyzed using the Kaplan Meier method. Predictors for late grade 3 GU toxicity were analyzed using univariate and multivariate Cox regression analyses. RESULTS The median follow-up was 6.9 years (range, 1.5-8.0 years). Late grade 2 and 3 genitourinary (GU) toxicity was observed in 10 (28%) and 7 (19%) patients, respectively. The actuarial proportion of patients with late grade 3 GU toxicity at 5 years was 17.7%. Late grade 2 and 3 gastrointestinal (GI) toxicities were not observed. The crude erectile function preservation rate in patients without ADT was 75%. The 5 year biochemical recurrence-free survival (bRFS) rate was 97%. Late grade 3 GU toxicity was associated with the urethral volume (p = 0.001) and the urethral V120 (urethral volume receiving ≥120% of the PD; p = 0.0005) after multivariate Cox regression. CONCLUSIONS After HDR-BT monotherapy late grade 3 GU was observed relatively frequently and was associated with the urethral V120. GI toxicity was negligible, the erectile function preservation rate and the bRFS rate was excellent.

Biological, diagnostic and therapeutic relevance of the MET receptor signaling in head and neck cancer.

Head and neck cancer constitutes the 6th most common malignancy worldwide and affects the crucial anatomical structures and physiological functions of the upper aerodigestive tract. Classical therapeutic strategies such as surgery and radiotherapy carry substantial toxicity and functional impairment. Moreover, the loco-regional control rates as well as overall survival still need to be improved in subgroups of patients. The scatter-factor/hepatocyte growth factor receptor tyrosine kinase MET is an established effector in the promotion, maintenance and progression of malignant transformation in a wide range of human malignancies, and has been gaining considerable interest in head and neck cancer over the last 15 years. Aberrant MET activation due to overexpression, mutations, tumor-stroma paracrine loops, and cooperative/redundant signaling has been shown to play prominent roles in epithelial-to-mesenchymal transition, angiogenesis, and responses to anti-cancer therapeutic modalities. Accumulating preclinical and translational evidence highly supports the increasing interest of MET as a biomarker for lymph node and distant metastases, as well as a potential marker of stratification for responses to ionizing radiation. The relevance of MET as a therapeutic molecular target in head and neck cancer described in preclinical studies remains largely under-evaluated in clinical trials, and therefore inconclusive. Also in the context of anti-cancer targeted therapy, a large body of preclinical data suggests a central role for MET in treatment resistance towards multiple therapeutic modalities in malignancies of the head and neck region. These findings, as well as the potential use of combination therapies including MET inhibitors in these tumors, need to be further explored.

The tumor border configuration of colorectal cancer as a histomorphological prognostic indicator.

Histomorphological features of colorectal cancers (CRC) represent valuable prognostic indicators for clinical decision making. The invasive margin is a central feature for prognostication shaped by the complex processes governing tumor-host interaction. Assessment of the tumor border can be performed on standard paraffin sections and shows promise for integration into the diagnostic routine of gastrointestinal pathology. In aggressive CRC, an extensive dissection of host tissue is seen with loss of a clear tumor-host interface. This pattern, termed "infiltrative tumor border configuration" has been consistently associated with poor survival outcome and early disease recurrence of CRC-patients. In addition, infiltrative tumor growth is frequently associated with presence of adverse clinicopathological features and molecular alterations related to aggressive tumor behavior including BRAFV600 mutation. In contrast, a well-demarcated "pushing" tumor border is seen frequently in CRC-cases with low risk for nodal and distant metastasis. A pushing border is a feature frequently associated with mismatch-repair deficiency and can be used to identify patients for molecular testing. Consequently, assessment of the tumor border configuration as an additional prognostic factor is recommended by the AJCC/UICC to aid the TNM-classification. To promote the assessment of the tumor border configuration in standard practice, consensus criteria on the defining features and method of assessment need to be developed further and tested for inter-observer reproducibility. The development of a standardized quantitative scoring system may lay the basis for verification of the prognostic associations of the tumor growth pattern in multivariate analyses and clinical trials. This article provides a comprehensive review of the diagnostic features, clinicopathological associations, and molecular alterations associated with the tumor border configuration in early stage and advanced CRC.

Clinical Significance of NOTCH1 and NOTCH2 Expression in Gastric Carcinomas: An Immunohistochemical Study.

BACKGROUND NOTCH signaling can exert oncogenic or tumor suppressive functions and can contribute to chemotherapy resistance in cancer. In this study, we aimed to clarify the clinicopathological significance and the prognostic and predictive value of NOTCH1 and NOTCH2 expression in gastric cancer (GC). METHODS NOTCH1 and NOTCH2 expression was determined immunohistochemically in 142 primarily resected GCs using tissue microarrays and in 84 pretherapeutic biopsies from patients treated by neoadjuvant chemotherapy. The results were correlated with survival, response to therapy, and clinico-pathological features. RESULTS Primarily resected patients with NOTCH1-negative tumors demonstrated worse survival. High NOTCH1 expression was associated with early-stage tumors and with significantly increased survival in this subgroup. Higher NOTCH2 expression was associated with early-stage and intestinal-type tumors and with better survival in the subgroup of intestinal-type tumors. In pretherapeutic biopsies, higher NOTCH1 and NOTCH2 expression was more frequent in non-responding patients, but these differences were statistically not significant. CONCLUSION Our findings suggested that, in particular, NOTCH1 expression indicated good prognosis in GC. The close relationship of high NOTCH1 and NOTCH2 expression with early tumor stages may indicate a tumor-suppressive role of NOTCH signaling in GC. The role of NOTCH1 and NOTCH2 in neoadjuvantly treated GC is limited.

Consensus and differences in primary radiotherapy for localized and locally advanced prostate cancer in Switzerland: A survey on patterns of practice

INTRODUCTION External beam radiotherapy (EBRT), with or without androgen deprivation therapy (ADT), is an established treatment option for nonmetastatic prostate cancer. Despite high-level evidence from several randomized trials, risk group stratification and treatment recommendations vary due to contradictory or inconclusive data, particularly with regard to EBRT dose prescription and ADT duration. Our aim was to investigate current patterns of practice in primary EBRT for prostate cancer in Switzerland. MATERIALS AND METHODS Treatment recommendations on EBRT and ADT for localized and locally advanced prostate cancer were collected from 23 Swiss radiation oncology centers. Written recommendations were converted into center-specific decision trees, and analyzed for consensus and differences using a dedicated software tool. Additionally, specific radiotherapy planning and delivery techniques from the participating centers were assessed. RESULTS The most commonly prescribed radiation dose was 78 Gy (range 70-80 Gy) across all risk groups. ADT was recommended for intermediate-risk patients for 6 months in over 80 % of the centers, and for high-risk patients for 2 or 3 years in over 90 % of centers. For recommendations on combined EBRT and ADT treatment, consensus levels did not exceed 39 % in any clinical scenario. Arc-based intensity-modulated radiotherapy (IMRT) is implemented for routine prostate cancer radiotherapy by 96 % of the centers. CONCLUSION Among Swiss radiation oncology centers, considerable ranges of radiotherapy dose and ADT duration are routinely offered for localized and locally advanced prostate cancer. In the vast majority of cases, doses and durations are within the range of those described in current evidence-based guidelines.

Vascularised fibula grafts for early tibia reconstruction in infants with congenital pseudarthrosis

Congenital pseudarthrosis of the tibia (CPT) is caused by an ill-defined, segmental disturbance of periosteal bone formation leading to spontaneous bowing, followed by fracture and subsequent pseudarthrosis in the first 2 years of life. The results of conventional treatment modalities (e.g., bracing, internal and external fixation and bone grafting) are associated with high failure rates in terms of persisting pseudarthrosis, malunion and impaired growth. As a more promising alternative, a more aggressive approach, including wide resection of the affected bone, reconstruction with free vascularised fibula grafts from the healthy contralateral leg and stable external fixation at a very early stage has been suggested. Between 1995 and 2007, 10 children (age 12-31 months, median 20 months) suffering from CPT were treated at our institutions according to this principle. Two patients were treated before a fracture had occurred. The length of the fibula graft was 7-9cm. End-to-end anastomoses were performed at the level of the distal tibia stump. The follow-up was 80 months (median, range 12 months to 12 years). Radiologic examination at 6 weeks postoperatively showed normal bone density and structure of the transplanted fibula in all cases and osseous consolidation at 19 of the 20 graft/tibia junctions. One nonunion was sucessfully treated with bone grafting and plate osteosynthesis. Pin-tract infection occurred in three patients. Five children sustained graft fractures that were successfully treated with internal or external fixation. Two patients developed diminished growth of the affected limb or foot; all others had equal limb length and shoe size. At long-term follow-up, tibialisation of the transplant had occurred, and normal gait and physical activities were possible in all children. We conclude that in spite of a relatively high complication rate and the reluctance to perform free flap surgery in infants at this young age, the present concept may successfully prevent the imminent severe sequelae associated with CPT.

Breathing adapted radiotherapy: a 4D gating software for lung cancer

Purpose Physiological respiratory motion of tumors growing in the lung can be corrected with respiratory gating when treated with radiotherapy (RT). The optimal respiratory phase for beam-on may be assessed with a respiratory phase optimizer (RPO), a 4D image processing software developed with this purpose. Methods and Materials Fourteen patients with lung cancer were included in the study. Every patient underwent a 4D-CT providing ten datasets of ten phases of the respiratory cycle (0-100% of the cycle). We defined two morphological parameters for comparison of 4D-CT images in different respiratory phases: tumor-volume to lung-volume ratio and tumor-to-spinal cord distance. The RPO automatized the calculations (200 per patient) of these parameters for each phase of the respiratory cycle allowing to determine the optimal interval for RT. Results Lower lobe lung tumors not attached to the diaphragm presented with the largest motion with breathing. Maximum inspiration was considered the optimal phase for treatment in 4 patients (28.6%). In 7 patients (50%), however, the RPO showed a most favorable volumetric and spatial configuration in phases other than maximum inspiration. In 2 cases (14.4%) the RPO showed no benefit from gating. This tool was not conclusive in only one case. Conclusions The RPO software presented in this study can help to determine the optimal respiratory phase for gated RT based on a few simple morphological parameters. Easy to apply in daily routine, it may be a useful tool for selecting patients who might benefit from breathing adapted RT.

Intraoperative localization of tantalum markers for proton beam radiation of choroidal melanoma by an opto-electronic navigation system: a novel technique

External beam proton radiation therapy has been used since 1975 to treat choroidal melanoma. For tumor location determination during proton radiation treatment, surgical tantalum clips are registered with image data. This report introduces the intraoperative application of an opto-electronic navigation system to determine with high precision the position of the tantalum markers and their spatial relationship to the tumor and anatomical landmarks. The application of the technique in the first 4 patients is described.

Is dental erosion really a problem?

Dental erosion is the non-carious dental substance loss induced by direct impact of exogenous or endogenous acids. It results in a loss of dental hard tissue, which can be serious in some groups, such as those with eating disorders, in patients with gastroesophageal reflux disease, and also in persons consuming high amounts of acidic drinks and foodstuffs. For these persons, erosion can impair their well-being, due to changes in appearance and/or loss of function of the teeth, e.g., the occurrence of hypersensitivity of teeth if the dentin is exposed. If erosion reaches an advanced stage, time- and money-consuming therapies may be necessary. The therapy, in turn, poses a challenge for the dentist, particularly if the defects are diagnosed at an advanced stage. While initial and moderate defects can mostly be treated non- or minimally invasively, severe defects often require complex therapeutic strategies, which often entail extensive loss of dental hard tissue due to preparatory measures. A major goal should therefore be to diagnose dental erosion at an early stage, to avoid functional and esthetic impairments as well as pain sensations and to ensure longevity of the dentition.

Early and nonreversible decrease of CD161++ /MAIT cells in HIV infection

HIV infection is associated with immune dysfunction, perturbation of immune-cell subsets and opportunistic infections. CD161++ CD8+ T cells are a tissue-infiltrating population that produce IL17A, IL22, IFN, and TNFα, cytokines important in mucosal immunity. In adults they dominantly express the semi-invariant TCR Vα7.2, the canonical feature of mucosal associated invariant T (MAIT) cells and have been recently implicated in host defense against pathogens. We analyzed the frequency and function of CD161++ /MAIT cells in peripheral blood and tissue from patients with early stage or chronic-stage HIV infection. We show that the CD161++ /MAIT cell population is significantly decreased in early HIV infection and fails to recover despite otherwise successful treatment. We provide evidence that CD161++ /MAIT cells are not preferentially infected but may be depleted through diverse mechanisms including accumulation in tissues and activation-induced cell death. This loss may impact mucosal defense and could be important in susceptibility to specific opportunistic infections in HIV.

[Arterial Hypertension - when are which combination therapies useful?]

Arterial hypertension is a widely prevalent risk factor for cardiovascular diseases with well documented harmful effects on the heart and the vascular system. Despite a broad antihypertensive drug armamentarium control of hypertension is worldwide suboptimal. Daily practice as well as large intervention trials show that single-drug therapy often fails to adequately control blood pressure (BP). Therefore, the early introduction of a combination therapy may lead to a better and more rapid BP lowering effect, particularly in patients with more than stage I hypertension or in patients with mild hypertension and high cardiovascular risk. In addition, side effects of an antihypertensive drug can be prevented by a meaningful (low dose) combination with a second antihypertensive agent. Moreover, combination of antihypertensive drugs, especially if provided fixed, may substantially improve compliance. However, the choice of the drug combination primarily relates on the demographic features and co-morbidities of the patient. Although BP lowering is the main determinant of cardiovascular risk reduction in the treatment of hypertension, some antihypertensive drugs may exhibit protective effects beyond BP reduction that have to be considered when antihypertensive drugs are combined. In recent large intervention studies, the combination of an ACE inhibitor with a calcium channel blocker was especially advantageous in high risk hypertensive patients. The addition of a thiazide type diuretic to a blocker of the renin-angiotensin system is also sensible and popular with numerous available fixed combinations.

Risk assessment and preventive measures

A prerequisite for preventive measures is to diagnose erosive tooth wear and to evaluate the different etiological factors in order to identify persons at risk. No diagnostic device is available for the assessment of erosive defects. Thus, they can only be detected clinically. Consequently, erosion not diagnosed in the early stage may render timely preventive measures difficult. In order to assess the risk factors, patient should record their dietary intake for a distinct period of time. Then a dentist can determine the erosive potential of the diet. Particularly, patients with more than four dietary acid intakes have a higher risk for erosion when other risk factors (such as holding the drink in the mouth) are present. Regurgitation of gastric acids (reflux, vomiting, alcohol abuse, etc.) is a further important risk factor for the development of erosion which has to be taken into account. Based on these analyses, an individually tailored preventive program may be suggested to the patients. It may comprise dietary advice, optimization of fluoride regimes, stimulation of salivary flow rate, use of buffering medicaments and particular motivation for nondestructive toothbrushing habits with a low abrasive toothpaste. The frequent use of fluoride gel and fluoride solution in addition to fluoride toothpaste offers the opportunity to reduce somewhat abrasion of tooth substance. It is also advisable to avoid abrasive tooth cleaning and whitening products, since they may remove the pellicle and may render teeth more susceptible to erosion. Since erosion, attrition and abrasion often occur simultaneously all causative components must be taken into consideration when planning preventive strategies.