Repetitive transcranial magnetic stimulation in the treatment of resistant depression: changes of specific neurotransmitter precursor amino acids.

Repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depression offers an alternative therapy, since more than every third patient is not responding to adequate antidepressive treatment. In this interventional study safety, symptom development and changes of serum concentrations of neurotransmitter precursor amino acids, of immune activation and inflammation markers, of brain-derived neurotrophic factor (BDNF), nitrite as well as of salivary amylase were measured before and after a frontal polar cortex stimulation using rTMS as add-on treatment in 38 patients with treatment-resistant depression. Out of these, 17 patients received sham stimulation as a control. Treatment was well tolerated: with the exception of one patient of the verum group, who described discomfort during the second treatment, no serious adverse effects were observed. Improvement of depression with a significant decrease in the HAMD-7 scale (p = 0.001) was found in patients treated with rTMS, but not in sham-treated patients. Furthermore, serum phenylalanine and tyrosine dropped significantly (p = 0.03 and p = 0.027, respectively) in rTMS-treated patients. The kynurenine to tryptophan ratio (Kyn/Trp) tended to decrease under rTMS (p = 0.07). In addition, associations between concentrations of BDNF and neopterin as well as serum nitrite levels were found in patients after rTMS treatment, which indicates an influence of immune regulatory circuits on BDNF levels. In the sham-treated patients, no changes of biomarker concentrations were observed. Results show that rTMS is effective in the treatment of resistant depression. rTMS appears to influence the enzyme phenylalanine hydroxylase, which plays a central role in the biosynthesis of neurotransmitter precursors tyrosine and dihydroxyphenylalanine (DOPA).

Bone regeneration induced by a 3D architectured hydrogel in a rat critical-size calvarial defect.

Bone regeneration can be stimulated by implantation of biomaterials, which is especially important for larger bone defects. Here, healing potency of the porous ArcGel was evaluated in a critical-size calvarial bone defect in rats in comparison with clinical standard autologous bone and Bio-Oss® Collagen (BioOss), a bone graft material frequently used in clinics. Bone healing and metabolic processes involved were monitored longitudinally by [18F]-fluoride and [18F]-FDG µ-PET/CT 1d, 3d, 3w, 6w, and 12w post implantation. Differences in quality of bone healing were assessed by ex vivo µ-CT, mechanical tests and histomorphometry. The amount of bone formed after implantation of ArcGel was comparable to autologous bone and superior to BioOss (histomorphometry). Furthermore, microarchitecture of newly formed bone was more physiological and better functional in case of ArcGel (push-out tests). [18F]-FDG uptake increased until 3d after implantation, and decreased until 12w for both ArcGel and BioOss. [18F]-fluoride uptake increased until 3w post implantation for all materials, but persisted significantly longer at higher levels for BioOss, which indicates a prolonged remodelling phase. The study demonstrates the potential of ArcGel to induce restitutio ad integrum comparable with clinical standard autologous bone and better bone regeneration in large defects compared to a commercial state-of-the-art biomaterial.

Clozapine administration in clinical practice: once-daily versus divided dosing.

OBJECTIVE: While it is recommended that clozapine be administered in a divided dosing regimen, it is unclear whether this recommendation is followed in real-world clinical practice. In two large datasets, we examined clozapine dosing frequency and patient characteristics across different dosing regimens. METHOD: We conducted a cross-sectional survey, collecting data on patients receiving clozapine in August/September 2015 from the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, and The Zucker Hillside Hospital (ZHH) in New York, United States. RESULTS: Of 676 and 308 patients included in CAMH and ZHH datasets, clozapine was prescribed once daily in 75.1% and 74.4%, even though doses exceeding 200 mg/day were administered in 88.6% and 84.4% of the respective samples. No significant difference was found in the rates of positive symptom remission between once-daily vs. divided dosing (79.7% vs. 80.5%, P = 1.00). Higher clozapine dose and use of anticholinergic medications were significantly associated with divided dosing in both datasets. Older age or male gender was related to divided dosing in CAMH or ZHH dataset respectively. CONCLUSION: Despite the product monograph recommendation, clozapine is frequently prescribed once daily in North America. Further studies are needed to compare clinical outcomes between once-daily vs. divided clozapine dosing.

Levels in neurotransmitter precursor amino acids correlate with mental health in patients with breast cancer.

Breast cancer is the most common cancer among females. Approximately 30% of cancer patients develop depression or depressive adaptation disorder within 5 years post diagnosis. Low grade inflammation and subsequent changes in neurotransmitter levels could be the pathophysiological link. In the current study we investigated the association of neurotransmitter precursor amino acids with a diagnosis of depression or state anxiety in 154 subjects suffering from breast cancer (BCA(+)), depression (DPR(+)), both or neither. Sociodemographic parameters, severity of depressive symptoms, and state anxiety (ANX) were recorded. Neopterin, kynurenine/tryptophan and phenylalanine/tyrosine were analysed by HPLC or ELISA. Significantly higher serum neopterin values were found in DPR(+) patients (p = 0.034) and in ANX(+) subjects (p = 0.008), as a marker of Th1-related inflammation. The phenylalanine/tyrosine ratio (index of the catecholamine pathway) was associated with the factors "breast cancer" and "depression" and their interaction (all p < 0.001); it was highest in the DPR(+)BCA(+) group. The kynurenine/tryptophan ratio (index of the serotonin pathway) was significantly associated with the factors "breast cancer" and "state anxiety" and their interaction (p < 0.001, p = 0.026, p = 0.02, respectively); it was highest in the ANX(+)BCA(+) group. In BCA(+) patients kynurenine/tryptophan ratios correlated with severity of state anxiety (r = 0.226, p = 0.048, uncorrected) and phenylalanine/tyrosine ratios with severity of depressive symptoms (r = 0.376, p < 0.05, corrected). In conclusion, levels of neurotransmitter precursor amino acids correlate with mental health, an effect which was much more pronounced in BCA(+) patients than in BCA(-) subjects. Aside from identifying underlying pathophysiological mechanisms, these results could be the basis for future treatment studies: in BCA(+) patients with depression the use of serotonin-noradrenaline reuptake inhibitors might be recommended while in those with predominant anxiety selective serotonin reuptake inhibitors might be the treatment of choice.

[Renal masses and indication to nephrectomy: preoperative assessment and clinical presentation of five cases]. / Masses rénales et indication à la néphrectomie. Clinique et bilan préopératoire de cinq cas.

In Switzerland, renal cancer represents 2% of adult neoplasia and its incidence is 8,2 cases per 100000 people. Small renal masses (< 4 cm) are mostly found incidentally during ultrasound or CT-scan evaluations. Differentiation between benign lesions (20% of renal masses < 4 cm), cancer and pseudotumors may be difficult. CT-scan plays a central role in the preoperative assessment, but the use of renal biopsy seems to have a growing importance in this assessment. This article summarizes the different diagnostic approaches in the preoperative assessment and describes five cases of nephrectomy for renal masses incidentally discovered.

Modulation of follistatin and myostatin propeptide by anabolic steroids and gender.

The purpose of this pilot study was to investigate the impact of training, anabolic steroids and endogenous hormones on myostatin-interacting proteins in order to identify manipulations of myostatin signalling. To identify whether analysis of the myostatin interacting proteins follistatin and myostatin propeptide is suitable to detect the abuse of anabolic steroids, their serum concentrations were monitored in untrained males, bodybuilders using anabolic steroids and natural bodybuilders. In addition, we analysed follistatin and myostatin propeptide serum proteins in females during menstrual cycle. Our results showed increased follistatin concentrations in response to anabolic steroids. Furthermore, variations of sex steroid levels during the menstrual cycle had no impact on the expression of follistatin and myostatin propetide. In addition, we identified gender differences in the basal expression of the investigated proteins. In general, follistatin and myostatin propeptide concentrations were relatively stable within the same individual both in males and females. In conclusion, the current findings provide an insight into gender differences in myostatin-interacting proteins and their regulation in response to anabolic steroids and endogenous hormones. Therefore our data provide new aspects for the development of doping prevention strategies.

Training alters the skeletal muscle antioxidative capacity in non-insulin-dependent type 2 diabetic men.

The present study analyzes the oxidative stress situation in the skeletal muscle of overweight/obese men suffering from non-insulin-dependent type 2 diabetes mellitus [T2DM, n=16, years=61±7, body mass index (BMI)=31±4 kg/m(2) ] and BMI-matched non-diabetic male control subjects (CON, n=7, years=53±6, BMI=30±4 kg/m(2) ). Furthermore, it investigates whether physical training can alter the skeletal muscle antioxidative capacity of T2DM patients at rest. Molecule content analyses (immunohistochemical stainings) of 8-iso-prostaglandin-F2α (8-Iso-PGF), superoxide dismutase-2 (SOD2), glutathione peroxidase-1 (GPX1), peroxiredoxin isoforms (PRDX 1-6) and heat-shock-protein-70 (HSP70) were performed in biopsies taken from the vastus lateralis muscle. Under basal conditions, 8-Iso-PGF was significantly decreased in T2DM patients (-35.7%), whereas PRDX2 and PRDX6 were significantly increased relative to CON (+82.6%; +82.3%). Differences were neither observed in SOD2 nor in GPX1 or PRDX1, 3, 4, 5 density. Regular physical activity (moderate endurance or resistance training twice a week for 3 months) did not alter PRDX1, 2, 3, 4, 6 in the skeletal muscle of T2DM patients, but significantly increased SOD2 (+65.9%), GPX1 (+62.4%), PRDX5 (+37.5%), and HSP70 (+48.5%). Overweight/obese men with non-insulin-dependent T2DM exhibit up-regulated cytosolic peroxiredoxin contents relative to BMI-matched controls. Regular training further up-regulates cytosolic and mitochondrial antioxidative enzymes in T2DM patients and improves their cellular protection systems. This may contribute to a retardation of the disease's progression.

MSTN mRNA after varying exercise modalities in humans.

The aim of this study was to examine the effects of strength and endurance training on myostatin mRNA in the vastus lateralis muscle of healthy and physically active humans. 21 healthy and physically active sports students (static and dynamic knee extensor strength 33 ± 4.5 N/kgBW; 1 185 ± 170 W, respectively; maximum oxygen uptake 52.5 ± 8 ml/kgBW/min) were recruited and randomly assigned to a moderate endurance training group (n=7), a strength training group (n=7) and a control group (n=7). Muscle biopsies were taken from the vastus lateralis muscle 3-5 days before the start as well as at the end of the 12 weeks' training period. Exercise-specific functional improvements after moderate endurance training and strength training were measured for submaximal endurance and for static and dynamic strength of the knee extensor muscles. None of the myostatin mRNA values showed significant pre-post differences or group-specific differences. These results are in contrast to data with sedentary subjects, suggesting that myostatin is necessary for adaptations of skeletal muscle to exercise stress. We conclude that functional improvements after moderate endurance training and strength training can occur without alterations in myostatin mRNA in physically active humans.

Glomeruloid microvascular proliferation is associated with lack of response to chemotherapy in breast cancer.

BACKGROUND: Glomeruloid microvascular proliferation (GMP), a novel histology-based angiogenesis marker, has been associated with decreased survival in several human cancers. METHODS: In this study, we evaluated the ability of GMP to predict clinical response to neoadjuvant chemotherapy in a series of locally advanced breast cancers (n=112). RESULTS: Presence of GMP (21% of the cases) was significantly associated with high-grade tumours and TP53 mutations in addition to the basal-like and HER2 subtypes of breast cancer as defined by gene expression data. GMP was correlated to a gene expression signature for tumour hypoxia response. The GMP pattern was also significantly associated with lack of treatment response and progressive disease (P=0.004). INTERPRETATION: The findings suggest that GMP might be able to predict the lack of response to neoadjuvant chemotherapy in locally advanced breast cancer. Whether GMP may be an independent predictor compared with other factors including TP53 mutation status and tumour grade needs confirmation in larger studies.

Screening for tuberculosis in asylum seekers: comparison of chest radiography with an interview-based system.

SETTING: Mandatory initial screening of asylum seekers for tuberculosis (TB) in Switzerland, 2004-2005 and 2007-2008. OBJECTIVE: To compare the yield of screening by chest radiography with an individual assessment based on geographic origin, personal history and symptoms. DESIGN: Cross-sectional retrospective comparison of two 2-year periods. RESULTS: The prevalence of detected TB cases was defined as the proportion of screenees starting anti-tuberculosis treatment for culture-confirmed pulmonary TB within 90 days. TB prevalence was 14.3 per 10,000 asylum seekers screened (31/21,727) using chest radiography and 12.4 (29/23,402) using individual assessment. The sensitivity of radiography was 100% vs. 55% for individual assessment, but its specificity was lower (89.9% vs. 96.0%, respectively). The higher sensitivity of radiography meant shorter delays between screening and start of treatment (median 6 vs. 25 days). Its lower specificity led to a larger proportion of screenees needing further investigations for suspicion of TB (12% vs. 4%). CONCLUSION: The interview-based system initially missed more cases, but the ultimate 90-day yield was comparable for the two periods. The main difference is the delay until start of treatment, which potentially increases transmission and secondary cases. The radiograph system was more burdensome to both the health care system and the screenees, as more suspects required further investigations.

Glutamatergic axons from the lateral habenula mainly terminate on GABAergic neurons of the ventral midbrain.

The concept of cortical-subcortical loops emphasizes the importance of the basal ganglia for motor, psychomotor, and emotional cortical functions. These loops are bidirectionally controlled by the midbrain dopaminergic system, predominantly but not exclusively at the level of the striatum including the accumbens nucleus. Successful behaviors increase the activities of the mesostriatal (arising in the complex part of the substantia nigra) and mesolimbic (arising in the ventral tegmental area, VTA) neurons, thereby reinforcing the corresponding actions. In contrast, unsuccessful behaviors result in an increased activation of the lateral habenular complex (LHb), thereby decreasing the activities of mesolimbic neurons. Correspondingly, electrical stimulation of the LHb effectively blocks neuronal activity in the VTA. Whether this block is due to an inhibitory projection from the LHb to the VTA, or whether axons from excitatory LHb neurons target inhibitory neurons within the VTA, is presently not known. Here we show, using in situ hybridization and immunocytochemical double labeling at the light and electron microscopic level, that GABAergic neurons are scarce in the LHb and that glutamatergic axons from the LHb mostly target GABAergic neurons in the VTA and the mesopontine rostromedial tegmental nucleus (RMTg), also known as tail of the VTA (tVTA). These data explain the inhibitory effect of LHb activation on the VTA. In addition, however, a small number of LHb terminals in the VTA actually contacts dopaminergic neurons. The biological importance of these terminals requires further investigation.

Predictive value of tumour cell proliferation in locally advanced breast cancer treated with neoadjuvant chemotherapy.

We previously reported that defects in apoptotic pathways (mutations in the TP53 gene) predicted resistance to doxorubicin monotherapy. The aim of this study was to evaluate whether cell proliferation, as assessed by mitotic frequency and Ki-67 levels, may provide additional predictive information in the same tumours and to assess any potential correlations between these markers and mutations in the TP53 gene and erbB-2 overexpression. Surgical specimens were obtained from ninety locally advanced breast cancers before commencing primary chemotherapy consisting of weekly doxorubicin (14 mg/m2) for 16 weeks. 38% of the patients had a partial response (PR) to therapy, 52% had stable disease (SD) while 10% had progressive disease (PD). Univariate analysis showed a significant association between a high cell proliferation rate (expressed as a high mitotic frequency) and resistance to doxorubicin (P = 0.001). Further analyses revealed this association to be limited to the subgroup of tumour expressing wild-type TP53 (P = 0.016), and TP53 mutation status was the only factor predicting drug resistance in the multivariate analyses. The finding that a high mitotic frequency, as well as a high Ki-67 staining, correlated to TP53 mutations (P = 0.001 for both), suggests TP53 mutations are the key predictor of drug resistance, although cell proliferation may play an additional role in tumours harbouring wild-type TP53. Regarding overall (OS) and relapse-free survival (RFS), multivariate analyses (Cox' proportional hazards regression) revealed a high histological grade and negative oestrogen receptor (ER) status to be the variables that were most strongly related to breast cancer death (P = 0.001 and P = 0.001, respectively). A key reason for this difference with respect to the factors predicting chemotherapy resistance could be due to the adjuvant use of tamoxifen in all patients harbouring ER-positive tumours.

Apolipoprotein E polymorphism and lithogenic factors in gallbladder bile.

BACKGROUND: Associations between the polymorphism of apolipoprotein E, which plays an important role in cholesterol metabolism and cholesterol gallstone formation, have been reported recently. Patients with the apo E4 isoform showed increased numbers and cholesterol contents of their stones, a higher frequency of cholesterol crystals in bile, increased susceptibility to gallstone fragmentation by extracorporeal shock-wave lithotripsy and an increase in recurrence rate after dissolution. A recent study, however, showed that fast cholesterol crystallization in bile is associated with multiple stones but not with apo E4. Therefore the mechanism for an increased risk of gallstone formation in patients with the apo E4 isoform still remains under debate. DESIGN: To clarify this issue we investigated 37 patients with gallstones (10 with the apo E4 allele and 27 without the allele). Gallbladder biles were examined for total cholesterol and other lipids, cholesterol saturation index, crystal observation time, crystal mass, total protein and mucin. Moreover, number of gallstones and cholesterol in gallstones was compared in both groups. RESULTS: The crystal observation time (2.5 vs. 2.0 days, median) and the cholesterol saturation index (1.34 +/- 0.45 vs. 1.43 +/- 0.74) did not differ significantly between the apo E4 and the non apo E4 group. Total biliary lipids (11.6 +/- 3.8 vs. 9.3 +/- 3.9 g 100 mL-1, P = 0.126) and total biliary cholesterol (21.8 +/- 9.7 vs. 15.7 +/- 7 mmol L-1, P = 0.067) tended to be elevated in the apo E4 group. Crystal mass (3.60 +/- 4.10 vs. 2.38 +/- 2.70 mmol L-1), biliary total protein (8.6 +/- 3.5 vs. 8.3 +/- 6.6 mg mL-1) and mucin (0.55 +/- 0.38 vs. 0.66 +/- 0.67 mg mL-1), number (solitary/multiple) of gallstones and cholesterol in gallstones were not different in both groups of patients. CONCLUSIONS: In comparison to the non apo E4 patients the apo E4 group showed a trend to elevated biliary cholesterol whereas crystal observation time, cholesterol saturation index, crystal mass, number of gallstones, cholesterol content of gallstones and total protein and mucin were not different. These findings do not suggest an association of the apo E isoform and the formation of cholesterol gallstones

Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications.

The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome. A total of 85 cDNA microarray experiments representing 78 cancers, three fibroadenomas, and four normal breast tissues were analyzed by hierarchical clustering. As reported previously, the cancers could be classified into a basal epithelial-like group, an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression. A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups, each with a distinctive expression profile. These subtypes proved to be reasonably robust by clustering using two different gene sets: first, a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and, second, a gene set that highly correlated with patient outcome. Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospective study showed significantly different outcomes for the patients belonging to the various groups, including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups.

Plasma insulin-like growth factor binding protein-3 proteolysis is increased in primary breast cancer.

Fasting blood samples were obtained before definitive surgery or biopsy in 128 patients referred to the department of surgery with suspected or manifest breast cancer. Insulin-like growth factor (IGF)-I, IGF-II and free IGF-I were measured by radioimmunoassay/immunoradiometric assay, while IGFBP-3 proteolysis was evaluated by Western immunoblot. 12 patients had ductal carcinoma in situ benign conditions, while staging revealed metastatic disease in 15 of 16 patients with invasive cancers. IGFBP-3 proteolysis above the normal range was recorded in 19 patients with invasive cancers, but in none of the patients suffering from DCIS/benign conditions. Increased IGFBP-3 proteolysis was most frequently recorded in patients harbouring large tumours and metastatic disease (Stage I: 0/19, 0%; Stage II: 3/45, 7%, Stage III: 9/37, 24%, and Stage IV: 7/15, 47%). IGFBP-3 proteolysis was significantly higher in Stage III (P =0.01) and IV (P< 0.001) patients compared to the other stage groups (P = 0.001). IGF-I and IGF-II correlated negatively to IGFBP-3 proteolysis and age. Plasma levels of IGF-I and -II were significantly lower in patients with elevated IGFBP-3 proteolysis compared to those within the normal range. Our findings reveal alterations in the IGF-system among a substantial number of patients with large primary breast cancers.

GSTM1, GSTT1, and the risk of squamous cell carcinoma of the head and neck: a mini-HuGE review.

Squamous cell carcinoma of the head and neck (SCCHN) is a group of cancers of epithelial origin that may provide an ideal model for the study of gene-environment interaction. SCCHN includes squamous cell carcinomas of the oral cavity, pharynx, and larynx. Approximately 90% of the attributable risk for oral cancer and 80% of the attributable risk for larynx cancer results from tobacco use. Tobacco smoking has been demonstrated to increase the risk of SCCHN in a dose-response fashion. Polymorphisms of carcinogen-metabolizing enzymes, known to be involved in metabolism of carcinogens found in tobacco smoke, are relatively common in most populations. This paper provides a concise review of the 24 published studies that evaluated the risk of SCCHN in relation to two deletion polymorphisms of the glutathione S-transferase family: GSTM1 and GSTT1. Patterns of risk based on the site of the tumor and on nationality are presented, as are some methodological weaknesses of the studies. The results of these studies are inconsistent, with some reporting weak-to-moderate associations and others finding no elevation in risk for the main effect of the gene. Few studies have directly evaluated the interaction with tobacco. Well-designed, population-based studies of adequate size are needed.

[Biosurgical methods tested in 10 patients. Maggots into the wound--do they promote healing?]. / Biochirurgisches Verfahren an zehn Patienten getestet. Maden in die Wunde--beschleunigt das die Heilung?

Between 07.04.1999 and 06.07.1999 we used sterile maggots for the treatment of 10 patients having acute infections as well as chronic wounds. All patients had had unsuccessful treatment for more than six weeks before we started our regime. Patients with acute infections and most diabetics had the best short-term results. In some diabetics, in chronic arterial occlusive disease (stage 4) and in rare cases of chronic infections like steroid associated wounds or thrombangitis obliterans The treatment had no success or there were complications. The etiologically broad range of wounds and our limited experience with biosurgery limit the result of our study. In spite of that we regard biosurgery to be a very promising part of the range of surgical wound treatment.

Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast cancer.

TP53 status [mutations, immunostaining, and loss of heterozygosity (LOH)], expression of c-erbB-2, bcl-2, and histological grading were correlated to the response to doxorubicin monotherapy (14 mg/m2) administered weekly to 90 patients with locally advanced breast cancer. Mutations in the TP53 gene, in particular those affecting or disrupting the loop domains L2 or L3 of the p53 protein, were associated with lack of response to chemotherapy (P = 0.063 for all mutations and P = 0.008 for mutations affecting L2/L3, respectively). Similarly, expression of c-erbB-2 (P = 0.041), a high histological grade (P = 0.023), and lack of expression of bcl-2 (P = 0.018) all predicted chemoresistance. No statistically significant association between either p53 immunostaining or TP53 LOH and response to therapy was recorded, despite the finding that both were associated with TP53 mutation status (p53 immunostaining, P < 0.001; LOH, P = 0.021). Lack of immunostaining for p53 despite mutation of the TP53 gene was particularly seen in tumors harboring nonsense mutations or deletions/splices (7 of 10 negative for staining compared with 4 of 16 with missense mutations). TP53 mutations (total/affecting L2/L3 domains) were associated with expression of c-erbB-2 (P < 0.001 for both), high histological grade (P = 0.001 and P = 0.025), and bcl-2 negativity (P = 0.003 and P = 0.002). TP53 mutations, histological grade, and expression of bcl-2 (but not LOH or c-erbB-2 expression) all predicted for relapse-free as well as breast cancer-specific survival in univariate analysis (Ps between <0.0001 and 0.0155), but only tumor grade was found to be predictive in multivariate analysis (P = 0.01 and P = 0.0007, respectively). Our data are consistent with the hypothesis that certain TP53 mutations predict for resistance to doxorubicin in breast cancer patients. However, the observation that the majority of patients with TP53 mutations affecting or disrupting the L2/L3 domains with LOH in addition (n = 12) obtained a partial response (n = 4) or stabilization of disease (n = 5) during chemotherapy suggests redundant mechanisms to compensate for loss of p53 function. Our findings are consistent with the hypothesis that other defects may act in concert with loss of p53 function, causing resistance to doxorubicin in breast cancers.