Protein kinase C isoform expression as a predictor of disease outcome on endocrine therapy in breast cancer

Background

Although in vitro breast cancer models have demonstrated a role for protein kinase C (PKC) α and δ isoforms in endocrine insensitivity and resistance respectively, there is currently little clinical evidence to support these observations.

Aims

To define the pattern of PKC α and δ expression using breast cancer cell lines, with and without endocrine resistance, and also breast cancer samples, where expression can be correlated with clinicopathological and endocrine therapy outcome data.

Methods

PKC isoform expression was examined in tamoxifen responsive, oestrogen receptor positive (ER⁺), ER⁺ acquired tamoxifen resistant (TAM‐R) and oestrogen receptor negative (ER⁻) cell lines by western blotting and immunocytochemical analysis. PKC isoform expression was then examined by immunohistochemistry in archival breast cancer specimens from primary breast cancer patients with known clinical outcome in relation to endocrine response and survival on therapy.

Results

ER⁺ breast cancer cell lines expressed considerable PKC‐δ but barely detectable levels of PKC‐α, whereas ER⁻ cell lines expressed PKC‐α but little PKC‐δ. ER⁺ acquired TAM‐R cell lines expressed substantial levels of both PKC‐α and δ. In clinical samples, high PKC‐δ expression correlated to endocrine responsiveness whereas PKC‐α expression correlated to ER negativity. PKC‐δ was an independent predictor of duration of response to therapy. Patients showing a PKC‐δ⁺/PKC‐α⁻ phenotype had a six times longer endocrine response than patients with the PKC‐δ⁺/ PKC‐α⁺ phenotype (equating to tamoxifen resistance in vitro).

Conclusions

Levels of PKC‐α and δ expression appear to be indicative of response to anti‐oestrogen therapy and could be useful in predicting a patient''s suitability for endocrine therapy.Anti‐hormone therapies such as tamoxifen are widely used to treat breast cancer patients.¹ A small but significant number of patients receiving tamoxifen however will not respond or will develop resistance.^2,3 Many mechanisms have been suggested which may play a role in tamoxifen resistance but the mechanisms have not yet been fully elucidated.^4,5,6,7 Although rapid progress is being made in understanding the biology of oestrogen receptor (ER) function, the only predictive markers for endocrine therapy that currently yield sufficient levels of evidence to be recommended for routine practice, are ER and progesterone receptors, and to a lesser extent HER‐2 status.¹ Better ways of predicting which patients are suitable for endocrine therapy would prove useful in the fight against breast cancer. Expression of the signal transduction molecule, protein kinase C (PKC) is increased in breast cancer models of poor prognosis; for example, ER⁻ cell lines express significantly more PKC than ER⁺ cell lines.^8,9 However, multiple isoforms of PKC exist, with variation in their expression profile and mechanism of activation.^10,11,12 We have previously shown that ER⁺ MCF‐7 cell lines have high PKC‐δ and low PKC‐α expression, whereas ER⁻ MDA‐MB‐231 cells have high PKC‐α and low PKC‐δ expression. A wealth of literature now support these observations^13,14,15,16 linking PKC‐α expression to loss of ER expression and adverse cellular features,^13,15 and there is also emerging data that PKC‐δ expression can relate to loss of endocrine sensitivity in vitro.¹⁷ These studies did not however investigate the effect of PKC‐δ expression on clinical outcome. Moreover, a recent clinical study showed PKC‐α to be decreased in advanced breast cancer samples,¹⁸ suggesting that laboratory observations may not translate to the clinic.We have therefore established cell line models of tamoxifen resistance,^19,20 and used these models and well‐characterised clinical specimens^21,22 with known response to endocrine therapy, to study PKC expression. We have shown that PKC‐α and δ may prove useful in predicting whether patients will respond or not to endocrine therapy.     

Expressed emotion as a predictor of outcome among bipolar patients undergoing family therapy

BACKGROUND: Levels of expressed emotion (EE) in relatives are consistent predictors of relapse among bipolar and other mood disordered patients followed naturalistically. However, few studies have examined whether levels of EE predict the course of illness for patients engaged in psychosocial interventions. METHODS: This study examined whether EE levels among caregivers moderated the success of family-based psychosocial interventions for patients with bipolar disorder. EE was examined as a predictor of symptomatic outcome in two groups: (1) bipolar patients receiving family-focused psychoeducational treatment (FFT) or integrated family and individual treatment (IFIT), and (2) bipolar patients receiving crisis management (CM), a less intensive intervention designed to emulate community care. Bipolar patients (N = 125) began the study in an acute illness episode, were stabilized on standard pharmacotherapy regimens, and followed for up to 2 years. RESULTS: Family EE status was not associated with time to relapse in either group. However, patients with high EE relatives reported higher levels of depression over the 2-year term of follow-up, regardless of treatment condition. An examination of the dimensions of EE (critical comments and emotional overinvolvement) indicated that a higher frequency of critical comments predicted higher levels of mania and depression at follow-up. Additionally, the association between EE criticism and levels of mania symptoms was stronger among patients in CM than among patients in family treatment. LIMITATIONS: The participants were recruited from two separate treatment protocols. Patients in the IFIT protocol were not randomly assigned to treatments. CONCLUSIONS: EE is a predictor of symptom severity among bipolar patients undergoing pharmacological and psychosocial treatments, but family intervention may mitigate this association.     

Clinical history as a predictor of penicillin skin test outcome.

BACKGROUND: Up to 10% of the population reports an "allergy" to penicillin, whereas approximately 1.1% has positive penicillin skin test results. Where penicillin skin tests are unavailable, some have advocated using history to decide whether to use a penicillin-related antibiotic. OBJECTIVE: To determine if clinical history predicts penicillin skin test results. METHOD: Retrospective medical record review of 94 consecutive patients who had previously taken penicillin referred for penicillin allergy. Case histories were taken, penicillin skin tests performed, and an oral challenge recommended if skin test results were negative. RESULTS: Of 91 cases studied, the average patient age was 27 years (range, 6 months to 82 years; 36% female). Fifty-two (57%) experienced hives as their main adverse reaction. Sixteen (18%) had at least 1 positive test result. Of this group, 9 had hives as their main symptom, whereas 1 had respiratory problems and 1 had angioedema. Most patients with positive skin test results had experienced their reaction at least 3 years ago. Regression analysis showed that age, sex, and clinical history, including type of reaction, time of reaction after penicillin ingestion, or time since the last reaction, were not associated with skin test positivity. Seventy-two (96%) of the 75 patients who had negative skin test results underwent oral challenge. Seventy had negative challenge results. The negative predictive value of a negative penicillin skin test result was 97%. CONCLUSION: Clinical history was not predictive of subsequent penicillin skin test results.     

Dissociation as a predictor of cognitive behavior therapy outcome in patients with obsessive-compulsive disorder

BACKGROUND: Previous studies have found a strong association between dissociation and obsessive-compulsive disorder (OCD). The purpose of the present study was to evaluate whether dissociation is a predictor of cognitive behavior therapy (CBT) outcome in patients with OCD. METHODS: Fifty-two patients with OCD were assessed using the Dissociative Experience Scale (DES), the Yale-Brown Obsessive-Compulsive Scale and the Beck Depression Inventory. CBT lasted on average 9.5 weeks and included exposure therapy. RESULTS: Patients who dropped out due to noncompliance had higher baseline DES scores and depression scores compared to the 43 patients (83%) who completed the study. Significant OCD symptom reduction at posttreatment was observed in study completers with a large effect size (d = 1.7). More severe OCD symptoms at posttreatment were associated with higher DES scores at baseline, and treatment nonresponders had significantly higher baseline DES scores compared to responders. These associations with outcome were mainly due to the DES subfactor absorption-imaginative involvement. In regression analyses, higher absorption-imaginative involvement scores at baseline predicted poorer CBT outcome, even after controlling for depressive symptoms, comorbid axis I disorders and concomitant psychotropic drugs. CONCLUSIONS: Results from this preliminary study suggest that higher levels of dissociation (particularly absorption-imaginative involvement) in patients with OCD might predict poorer CBT outcome. If our results can be replicated, treatment outcome might be improved by additional interventions for those patients with OCD who indicate high levels of dissociation, for example by using interventions aimed at improving coping with emotionally stressful situations.     

High expression of Sirt7 served as a predictor of adverse outcome in breast cancer

Objective: Sirt7, as one of the seven Sirtuin family members, which plays distinct roles in cancer progression, is bringing emerging attention due to its oncogenic characteristic. The expression of Sirt7 in breast cancer remained unclear, and the aim of this study was to elucidate its role in breast cancer. Methods: A total of 188 cases included in this study were immunohistochemically evaluated for Sirt7, and western blot assay was used to assess its expression in breast cell lines as well as 36 breast cancer tissues and 36 paired non-cancerous tissues. Results: Upregulation of Sirt7 was found in breast cancer cell lines and breast cancer tissues (P < 0.001) by western blot analysis. Sirt7 was highly expressed in breast cancer tissue samples (67.8%) compared to adjacent normal breast tissues (31.8%) by immunohistochemical assay. It was also observed that the high expression level of Sirt7 was significantly correlated with high histological grade (P = 0.039) and negatively related to overall survival (P = 0.006). Sirt7 proved to be an independent prognostic factor (P = 0.007) in breast cancer. Conclusions: Sirt7 expression was implicated with high histological grade and independently predicted poor clinical outcome in patients with breast cancer, suggesting that Sirt7 might play a role in the malignant progression of breast cancer.     

Alliance negotiation as a predictor of early treatment outcome

Aim

The therapeutic alliance is a robust predictor of treatment outcome. However, little is known about the way alliance negotiation contributes to psychotherapy outcome. The aim of the present study was to analyze the effects of alliance negotiation on treatment outcome in the first four sessions of psychotherapy.

Methods

Ninety-six patients diagnosed with emotional disorders received weekly Solution-Focused Brief Therapy. Each patient completed both the Alliance Negotiation Scale (ANS) and the Outcome Questionnaire 45 (OQ.45) after each of the first four sessions. Both between- and within-patients effects of alliance negotiation on symptom severity were analyzed using Hierarchical Linear Models.

Results

Results showed significant between and within patient effects of alliance negotiation on symptom severity. Patients with higher levels of alliance negotiation across treatment showed lower levels of symptom severity (between-patient effect). Also, in a session with higher alliance negotiation compared to the average session of this patient, symptom severity was lower than in the average session (within-patient effect).

Discussion

The results indicate that therapies characterized by higher alliance negotiation and sessions with higher alliance negotiation are beneficial for early outcome.

Conclusion

From a clinical point of view, the results suggest that alliance negotiation is a meaningful factor for therapy outcome and that therapists may benefit from training and monitoring alliance negotiation during the early stages of treatment.     

Fanconi anemia: myelodysplasia as a predictor of outcome

The adverse potential of the development of myelodysplastic syndrome (MDS) in Fanconi anemia (FA) was examined in a retrospective study of 41 FA patients who had bone marrow morphology and chromosomes reviewed by a single group. Thirty-three patients had adequate cytogenetic studies, and 16 (48%) had one or more abnormal studies: nine initially, and seven more on follow-up. Cytogenetic clonal variation was frequent, including disappearance of clones, clonal evolution, and appearance of new clones. The estimated five-year survival with a cytogenetic clone is 0.40, compared to 0.94 without a clone. Morphologic myelodysplasia (MDS), independent of a cytogenetic clone, was found in 13/41 patients (32%). The estimated five-year survival with MDS is 0.09, versus 0.92 without MDS. Leukemia developed in three patients whose initial cytogenetic clones prior to leukemia were t(1;18), t(5;22) and monosomy 7; the one with t(1;18) also had MDS. Our results focus on marrow morphology, and suggest that morphologic MDS may be more important than classical cytogenetics in prediction of an adverse outcome.     

Hypercholesterolaemia in pregnancy as a predictor of adverse pregnancy outcome

Background

Prevention of viable spontaneous preterm birth and low birth weight through screening is one of the key aims of antenatal care as these have implications for the child, mother and society. If women can be identified to be at high risk of these adverse birth outcomes in early pregnancy, they can be targeted for more intensive antenatal surveillance and prophylactic interventions.

Objectives

This study is therefore aimed to determine the association between elevated maternal serum cholesterol level in pregnancy and adverse pregnancy outcome.

Methods

It was a prospective observational cohort study in which eligible participants were enrolled at gestational age of 14 to 20 weeks. Blood samples were obtained to measure total serum cholesterol concentrations and the sera were then analyzed enzymatically by the cholesterol oxidase: p-aminophenazone (CHOD PAP) method. Pregnancy outcomes were obtained by extraction from medical records and the labour ward register.

Results

The incidences of the two adverse pregnancy outcomes examined in the study (preterm births and low birth weight (LBW) in term neonates) were 8.0% and 14.4% respectively. Preterm birth was 6.89-times more common in mothers with high cholesterol than in control mothers with normal total cholesterol level (38.5% versus 5.4%, P=0.029) while LBW was 7.99-times more common in mothers with high total maternal cholesterol than in mothers with normal cholesterol (87.5% versus 10.5%, P=0.019).

Conclusion

We can infer that the high maternal serum cholesterol (hypercholesterolaemia) is associated with preterm delivery/ low birth weight (LBW) in term infants. However, further validation of these findings with more robust prospective and longitudinal characterization of maternal serum cholesterol profiles is required in subsequent investigations.     

Serum bactericidal titer as a predictor of outcome in endocarditis

A study was conducted in 89 rabbits with experimental aortic valve endocarditis caused by three different strains of Staphylococcus aureus to determine whether there was a correlation between the peak serum bactericidal titer of the four drugs tested and the vegetation titer. After four days of therapy both the rabbits with and those without sterile vegetations had median peak bactericidal titers of 18. The mean vegetation titers did not correlate with the mean bactericidal titers. The serum bactericidal test does not measure the relative rate of killing of the bacteria by the drugs. Although the test remains clinically useful for documentation of bactericidal activity, the minimum level of activity necessary for the test to serve as a predictor of outcome remains to be defined.     

Therapeutic reactance as a predictor of outcome in the treatment of chronic depression

This study examined whether reactance would negatively influence treatment outcome in 347 patients diagnosed with chronic forms of depression and treated at 9 sites with either Nefazodone, cognitive-behavioral analysis system of psychotherapy (CBASP), or combination therapy. Contrary to our hypotheses, reactance positively predicted treatment outcome in CBASP on 2 of 4 scales. These effects were independent of the therapeutic alliance, which also positively predicted outcome. Reactance did not predict outcome in the groups receiving medication alone or in combination with CBASP. The findings suggest that reactance may be an asset in psychotherapy among chronically depressed individuals and that reactant patients can benefit from directive psychotherapy when therapists flexibly respond to perturbations in the therapeutic relationship. Results support the importance of Aptitude * Treatment interactions in psychotherapy outcome. The direction and significance of such interactions may vary with different forms of psychopathology.     

Expression of mdr-1/P-glycoprotein in human neuroblastoma.

Increased expression of the mdr-1 gene encoding the drug efflux pump P-glycoprotein is a well-established mediator of acquired drug resistance in vitro, and a similar role has been hypothesized in vivo in human malignancy. Because expression of mdr-1 is increased in neuroblastoma cell lines by differentiating agents, the authors hypothesized a similar correlation with differentiation in vivo in neuroblastomas. In 12 tumors from 11 patients, total RNA analysis demonstrated no correlation with differentiation, but a correlation could be detected in the cell-based methods of analysis. The very primitive 'stroma'-poor, poorly differentiated neuroblastomas had low levels of mdr-1/P-glycoprotein. The intermediate grades had higher levels of expression and although heterogeneity of differentiation appeared within these tumors, both primitive and more differentiated cells expressed the gene at comparable levels within the tumor. One very well-differentiated neuroblastoma, a ganglioneuroma, had no detectable expression in the neurofibrillary material, but demonstrated expression in adjacent large ganglionic cells. Thus mdr-1/P-glycoprotein expression increased with increasing differentiation among tumors, and was present in ganglionic cells in the most well-differentiated tumor. The three tumors with the highest levels of expression were obtained from patients who received preoperative chemotherapy.     

Readiness to change as a predictor of outcome in batterer treatment

The current study examined stage of change as a predictor of outcome in batterer treatment. Men (N=119) were classified into the transtheoretical model's stages of change and assessed 3 times over treatment. Hierarchical linear modeling revealed significant variation in men's progress, predictable from their stage of change. As hypothesized, men in the precontemplation stage showed little positive change in empathy, communication, or abusive behavior, whereas men in the contemplation and action stages showed positive growth in all of these domains. These effects occurred in the initial 10 weeks of treatment, after which men progressed at a more homogeneous rate. Interpretation is complicated by pretreatment differences that draw into question stage-related patterns in final outcome. Implications for general models of abuse cessation and for stage-specific trajectories are discussed.     

Rumination as a predictor of relapse in mindfulness-based cognitive therapy for depression

Objectives. In mindfulness-based cognitive therapy (MBCT), it is proposed that training in mindfulness should reduce the tendency of formerly depressed patients to enter into ruminative thinking, thus reducing their risk of depressive relapse. However, data showing that rumination is associated with depressive relapse are lacking. Method. In an uncontrolled study with 24 formerly depressed patients, rumination was assessed with the Ruminative Response Scale. To assess the occurrence of relapse or recurrence, the Structured Clinical Interview for DSM-IV was administered 12 months after the end of the MBCT. Results. Rumination significantly decreased during the MBCT course. Post-treatment levels of rumination predicted the risk of relapse of major depressive disorder in the 12-month follow-up period even after controlling for numbers of previous episodes and residual depressive symptoms. Conclusions. The results provide preliminary evidence that rumination is important in the process of depressive relapse.     

Early serum galactomannan trend as a predictor of outcome of invasive aspergillosis

The monitoring and prediction of treatment responses to invasive aspergillosis (IA) are difficult. We determined whether serum galactomannan index (GMI) trends early in the course of disease may be useful in predicting eventual clinical outcomes. For the subjects recruited into the multicenter Global Aspergillosis Study, serial GMIs were measured at baseline and at weeks 1, 2, and 4 following antifungal treatment. Clinical response and survival at 12 weeks were the outcome measures. GMI trends were analyzed by using the generalized estimation equation approach. GMI cutoffs were evaluated by using receiver-operating curve analyses incorporating pre- and posttest probabilities. Of the 202 study patients diagnosed with IA, 71 (35.1%) had a baseline GMI of ≥ 0.5. Week 1 GMI was significantly lower for the eventual responders to treatment at week 12 than for the nonresponders (GMIs of 0.62 ± 0.12 and 1.15 ± 0.22, respectively; P = 0.035). A GMI reduction of >35% between baseline and week 1 predicted a probability of a satisfactory clinical response. For IA patients with pretreatment GMIs of <0.5 (n = 131; 64.9%), GMI ought to remain low during treatment, and a rising absolute GMI to >0.5 at week 2 despite antifungal treatment heralded a poor clinical outcome. Here, every 0.1-unit increase in the GMI between baseline and week 2 increased the likelihood of an unsatisfactory clinical response by 21.6% (P = 0.018). In summary, clinical outcomes may be anticipated by charting early GMI trends during the first 2 weeks of antifungal therapy. These findings have significant implications for the management of IA.     

Loss of BCL2L10 protein expression as prognostic predictor for poor clinical outcome in gastric carcinoma

Xu J D, Furuya T, Cao X X, Liu X L, Li Q Q, Wang W J, Xu J W, Xu Z D, Sasaki K & Liu X P
(2010) Histopathology 57, 814–824 Loss of BCL2L10 protein expression as prognostic predictor for poor clinical outcome in gastric carcinoma Aims: BCL2L10 protein is an apoptosis‐related member of the Bcl‐2 protein family. The clinical significance of its expression in gastric carcinoma is poorly understood. The aim was to investigate BCL2L10 expression and its clinical and prognostic significance in gastric carcinoma patients. Methods and results: Immunohistochemistry, real–time polymerase chain reaction (PCR) and immunoblotting all revealed extensive loss of BCL2L10 expression in gastric cancer cells. The scaled BCL2L10 expression data was categorized into three groups (groups 0–2) to facilitate statistical analysis. A significant correlation was observed between the lower BCL2L10 expression group and shorter disease‐free survival (P = 1.956 × 10^?18). Multivariate regression analysis showed that loss of BCL2L10 protein expression [P = 4.883 × 10^?8, hazard ratio (HR) = 0.252] is an independent prognostic predictor of gastric carcinoma. The receiver operator characteristic (ROC) curve showed that the area for BCL2L10 protein was 0.817 (P = 8.331 × 10^?14), indicating that loss of BCL2L10 protein expression is an excellent prognostic predictor of gastric carcinoma. Conclusions: Loss of BCL2L10 protein expression predicts poor clinical outcome in gastric carcinoma.