Fast Relapse Research Articles

DIPG-40. LONG TERM SURVIVAL OF A 14 YEAR OLD GIRL WITH H3K27M MUTATED DIFFUSE MIDLINE GLIOMA FOLLOWING RADIOTHERAPY AND PROLONGED TUMOR TREATING FIELDS (TTFIELDS) -CASE REPORT

Abstract INTRODUCTION Pediatric diffuse midline H3K27M mutated glioma has a dismal prognosis. Most cases are treated by radiotherapy and oral chemotherapy, with surgical resection having a debatable role in some. Tumor-treating fields (TTFields) is a noninvasive modality in which alternating electrical fields exert biophysical force on charged and polarizable molecules known as dipoles. TTFields has been shown to extend survival for adult patients with newly diagnosed and recurrent GBM, and is FDA approved for these indications. There is sparse data about pediatric patients. CASE REPORT A 14-year-old girl presented with headache and vomiting. A large left thalamic tumor was diagnosed and underwent subtotal resection. Diagnosis was diffuse midline glioma, H3K27M positive, IDH negative. Molecular Panel: Tumor mutation burden low, microsatellite stable. Genomic findings: FGFR1, NF1, H3F3A -K28M, ATRX R666, MAP3K1 She was re-operated due to a fast tumor relapse within a few weeks, prior to radiotherapy, followed with radiotherapy with local field 59Gy. She then received temozolamide (12 months) concomitant with TTfields (Optune, Novocure). TTfields therapy was administered for 5 years without adverse effects and excellent compliance (above 85%). After 5 years, therapy was withheld, and she is now off therapy NED for another 15 months. DISCUSSION Diffuse midline H3K27M glioma harbors a poor prognosis in children. Children refrain from this treatment both for lack of evidence and because of the difficulty in adhering to a regimen that demands carrying a battery of 1.5-2kg all day and shaving all hair every 3 days. Our patient had a high compliance and as she wore a head scarf for religious customs, the device was not visible. To our knowledge this is the first pediatric reported case of long-term survival of H3K27mutatted midline glioma using TTFields. Further pediatric studies are warranted.

Bifurcations of a cancer immunotherapy model explaining the transient delayed response and various other responses

In this paper, we investigate the various responses in cancer immune therapy through bifurcation theory. Our results characterize the influence of key parameters on different treatment responses and illustrate the response regions through bifurcation diagrams using parameters tuned by therapy. In particular, we examine a periodic outcome with a delayed therapy response followed by a cancer relapse. The repetitive pattern in this periodic solution is formed by two quasi-steady cancer states connected by two fast transitions. Our results suggest that the transient behavior of the delayed response, which is the fast transition after the cancer progression state, is induced by a periodic solution exhibiting an exploding period near a saddle–node bifurcation. Another transient behavior, which shows as a fast relapse after a long period of dormancy state, is caused by the slow change near a saddle-type equilibrium. Our findings have the potential to guide and inform future therapeutic research.

Branched-chain amino acid transaminase 1 regulates glioblastoma cell plasticity and contributes to immunosuppression.

Glioblastoma is the most common malignant brain tumor in adults. Cellular plasticity and the poorly differentiated features result in a fast relapse of the tumors following treatment. Moreover, the immunosuppressive microenvironment proved to be a major obstacle to immunotherapeutic approaches. Branched-chain amino acid transaminase 1 (BCAT1) was shown to drive the growth of glioblastoma and other cancers;however, its oncogenic mechanism remains poorly understood. Using human tumor data, cell line models and orthotopic immuno-competent and -deficient mouse models, we investigated the phenotypic and mechanistic effects of BCAT1 on glioblastoma cell state and immunomodulation. Here, we show that BCAT1 is crucial for maintaining the poorly differentiated state of glioblastoma cells and that its low expression correlates with a more differentiated glioblastoma phenotype. Furthermore, orthotopic tumor injection into immunocompetent mice demonstrated that the brain microenvironment is sufficient to induce differentiation of Bcat1-KO tumors in vivo. We link the transition to a differentiated cell state to the increased activity of ten-eleven translocation demethylases and the hypomethylation and activation of neuronal differentiation genes. In addition, the knockout of Bcat1 attenuated immunosuppression, allowing for an extensive infiltration of CD8+ cytotoxic T-cells and complete abrogation of tumor growth. Further analysis in immunodeficient mice revealed that both tumor cell differentiation and immunomodulation following BCAT1-KO contribute to the long-term suppression of tumor growth. Our study unveils BCAT1's pivotal role in promoting glioblastoma growth by inhibiting tumor cell differentiation and sustaining an immunosuppressive milieu. These findings offer a novel therapeutic avenue for targeting glioblastoma through the inhibition of BCAT1.

A review on the protective role of selected Ayurveda herbs against skin cancer

Melanoma skin cancer (MSC) is considered the most aggressive among all skin cancers due to its tendency to fast growth, metastasis, and high relapse rate. Although MSC is treatable if identified early, several side effects and aesthetic issues associated with its treatment impose a psychological burden and compromise patients’ quality of life. Thus, there is a dire need for primary prevention by adopting alternative remedies, which are accessible, safe, and cost-effective. The present review emphasizes the role of selected Ayurveda herbs, viz.,Azadirachta indicaA. Juss,Ocimum tenuiflorumL.,Phyllanthus emblicaL.,Santalum albumL.,Tinospora cordifolia(Willd.) Hook. F. and Thoms., andWithania somniferaL. Dunal, which are long being utilized in the Indian traditional system to tackle diverse health problems in preventing MSCs. PubMed and Google Scholar were used to search various research articles on the anti-oncogenic and chemopreventive roles of Ayurveda herbs. This review emphasizes the beneficial effects of Ayurveda herbs so that the ordinary public includes these herbs in their routine to prevent MSC and other cancers. The available literature clearly states that these herbs are beneficial in preventing MSCs. However, the scarcity of clinical trials on these herbs warrants extensive research in this area to obtain an efficacious drug.

Novel dual LSD1/HDAC6 inhibitors for the treatment of multiple myeloma

Lysine specific demethylase 1 (LSD1) and HDAC6 are epigenetic proteins associated with several diseases, including cancer and combined inhibition of these proteins could be highly beneficial in treating some cancers such as AML, MM and solid tumors. Multiple myeloma (MM) is a challenging cancer with fast relapse rate where novel treatment options are the need of the hour. We have designed and developed novel, LSD1 and HDAC6 selective dual inhibitors to target MM. Our dual inhibitor compound 1 shows superior potency in multiple MM cell lines. In MM.1S xenograft model compound 1 shows superior efficacy compared to single agent LSD1 and HDAC6 inhibitors by oral administration and is well tolerated. Further evaluation of the molecule in other cancers is in progress.

Oncolytic viral therapies and the delicate balance between virus-macrophage-tumour interactions: a mathematical approach

The success of oncolytic virotherapies depends on the tumour microenvironment, which contains a large number of infiltrating immune cells. In this theoretical study, we derive an ODE model to investigate the interactions between breast cancer tumour cells, an oncolytic virus (Vesicular Stomatitis Virus), and tumour-infiltrating macrophages with different phenotypes which can impact the dynamics of oncolytic viruses. The complexity of the model requires a combined analytical-numerical approach to understand the transient and asymptotic dynamics of this model. We use this model to propose new biological hypotheses regarding the impact on tumour elimination/relapse/persistence of: (i) different macrophage polarisation/re-polarisation rates; (ii) different infection rates of macrophages and tumour cells with the oncolytic virus; (iii) different viral burst sizes for macrophages and tumour cells. We show that increasing the rate at which the oncolytic virus infects the tumour cells can delay tumour relapse and even eliminate tumour. Increasing the rate at which the oncolytic virus particles infect the macrophages can trigger transitions between steady-state dynamics and oscillatory dynamics, but it does not lead to tumour elimination unless the tumour infection rate is also very large. Moreover, we confirm numerically that a large tumour-induced M1$\to$M2 polarisation leads to fast tumour growth and fast relapse (if the tumour was reduced before by a strong anti-tumour immune and viral response). The increase in viral-induced M2$\to$M1 re-polarisation reduces temporarily the tumour size, but does not lead to tumour elimination. Finally, we show numerically that the tumour size is more sensitive to the production of viruses by the infected macrophages.

Hypogastric and Sacral Root Nerve Entrapment By Deep Infiltrating Endometriosis

Study Objective Raise awareness of rare presentations of Deep Infiltrating Endometriosis (DIE) and its treatment. Sacral root (S2-S3-S4) and inferior hypogastric nerve compromise is a usual component of parametrial (cardinal and uterosacral) DIE but entrapment is rarely observed. Design Discussion and case presentation along with histopathologic analysis of surgical findings. Setting Private tertiary care clinic in Chile Patients or Participants 32-year-old patient with progressive dysmenorrea, dyspareunia and dysquezia. Pelvic gel-contrasted ultrasound and MRI are consistent with DIE with a 2 cm right uterosacral/parametrial nodule and a 5 cm rectal nodule without mucosal involvement. She only had mild initial response with fast relapse of symptoms after a 2-month course of 2mg/day oral Dienogest. Interventions Radical excision of deep infiltrating endometriosis nodule that entrapped both right inferior hypogastric nerve and sacral roots. Measurements and Main Results After surgery the patient reported pelvic pain had completely disspeared. Postoperative urinary retention that required Foley´s catheterization for 30 hours. Also complained of total loss of rectal or vesical sensation. Progressively recovered and by POD 7 she reported having an almost normal bladder/micturition sensation. One month after surgery she has no autonomic pelvic visceral complaints. Histopathological analysis of the nodule showed endometriosis and intense fibrosis infiltrating the uterine smooth muscle fibers. It also included the deep uterine vein, with two nerves, the hypogastric nerve and a sacral root. Conclusion It is recommended to identify and preserve autonomic pelvic nerves whenever possible because it improves postoperative vegetative pelvic organ and specially voiding functions.

Can immune markers help identify fast relapse in patients with muscle invasive bladder cancer?

The aim of this pilot study was to assess the role of immune markers in fast relapse (<2 years) of high-grade muscle invasive urothelial carcinomas of the bladder (HGUC) treated by cystectomy. A series of 40 such cases was investigated for immune protein (CD3, CD4, CD8, CD20, CD68, CD163, FOXP3 and PD-1) status by immunohistochemistry. Decreased expression of all immune cell markers was observed in tumors of patients who relapsed quickly. In Kaplan-Meier (log-rank test) analysis, low CD3, CD4 and CD8 expression was associated with fast relapse (P = 0.005, 0.028, 0.036 respectively). Additional evaluation of the immune transcriptome by NanoString Human PanCancer Immune Panel v.1.1 has identified 5 differentially expressed genes significantly associated with fast relapse. Among these, KLRB1 and HLA-DQA1 were also significant on Kaplan-Meier analysis (log-rank test P = 0.007 and 0.006, respectively). These findings strengthen the potential clinical utility and, hence, the need for further evaluation of immune markers in HGUC prognostication.

Survival differences and associated molecular signatures of DNMT3A-mutant acute myeloid leukemia patients

Acute myeloid leukemia (AML) is a very heterogeneous and highly malignant blood cancer. Mutations of the DNA methyltransferase DNMT3A are among the most frequent recurrent genetic lesions in AML. The majority of DNMT3A-mutant AML patients shows fast relapse and poor survival, but also patients with long survival or long-term remission have been reported. Underlying molecular signatures and mechanisms that contribute to these survival differences are only poorly understood and have not been studied in detail so far. We applied hierarchical clustering to somatic gene mutation profiles of 51 DNMT3A-mutant patients from The Cancer Genome Atlas (TCGA) AML cohort revealing two robust patient subgroups with profound differences in survival. We further determined molecular signatures that distinguish both subgroups. Our results suggest that FLT3 and/or NPM1 mutations contribute to survival differences of DNMT3A-mutant patients. We observed an upregulation of genes of the p53, VEGF and DNA replication pathway and a downregulation of genes of the PI3K-Akt pathway in short- compared to long-lived patients. We identified that the majority of measured miRNAs was downregulated in the short-lived group and we found differentially expressed microRNAs between both subgroups that have not been reported for AML so far (miR-153-2, miR-3065, miR-95, miR-6718) suggesting that miRNAs could be important for prognosis. In addition, we learned gene regulatory networks to predict potential major regulators and found several genes and miRNAs with known roles in AML pathogenesis, but also interesting novel candidates involved in the regulation of hematopoiesis, cell cycle, cell differentiation, and immunity that may contribute to the observed survival differences of both subgroups and could therefore be important for prognosis. Moreover, the characteristic gene mutation and expression signatures that distinguished short- from long-lived patients were also predictive for independent DNMT3A-mutant AML patients from other cohorts and could also contribute to further improve the European LeukemiaNet (ELN) prognostic scoring system. Our study represents the first in-depth computational approach to identify molecular factors associated with survival differences of DNMT3A-mutant AML patients and could trigger additional studies to develop robust molecular markers for a better stratification of AML patients with DNMT3A mutations.

Cross-sectional analysis of circulating tumor DNA in primary colorectal cancer at surgery and during post-surgery follow-up by liquid biopsy

BackgroundLiquid biopsy (LB) in early-stage, non-metastatic colorectal cancer (CRC) must be sensitive enough to detect extremely low circulating tumor DNA (ctDNA) levels. This challenge has been seldom and non-systematically investigated.MethodsNext generation sequencing (NGS) and digital PCR (dPCR) were combined to test tumor DNAs (tDNAs) and paired ctDNAs collected at surgery from 39 patients, 12 of whom were also monitored during the immediate post-surgery follow up. Patients treated for metastatic disease (n = 14) were included as controls.ResultsNGS and dPCR concordantly (100% agreement) called at least one single nucleotide variant (SNV) in 34 tDNAs, estimated differences in allelic frequencies being negligible (±1.4%). However, despite dPCR testing, SNVs were only detectable in 15/34 (44.1%) ctDNAs from patients at surgery, as opposed to 14/14 (100%) metastatic patients. This was likely due to striking differences (average 10 times, up to 500) in ctDNA levels between groups. NGS revealed blood-only SNVs, suggesting spatial heterogeneity since pre-surgery disease stages, and raising the combined NGS/dPCR sensitivity to 58.8%. ctDNA levels at surgery correlated with neither tumor size, stage, grade, or nodal status, nor with variant abundance in paired tDNA. LB sensitivity reached 63.6% when ctDNA was combined with CEA. Finally, persistence and absence of ctDNA on the first conventional (month 3) post-surgery follow-up were associated with fast relapse and a disease-free status in 3 and 7 patients, respectively.ConclusionsA simple clinical NGS/dPCR/CEA combination effectively addresses the LB challenge in a fraction of non-metastatic CRC patients.

Transdermal siRNA delivery by pH-switchable micelles with targeting effect suppress skin melanoma progression

Melanoma is an aggressive disease with rapid progression and fast relapse, representing one of the formidable challenges in clinic. Current systemic therapies for melanoma exhibit limited anticancer potential due to the lack of specificity and limited efficacy. Herein, we design a cationic polymer (SCP-HA-PAE) by conjugating skin/cell penetrating peptide (SCP) and hyaluronic acid (HA) to the amphipathic polymer (poly β-amino esters, PAE), then fabricate the nanocarriers (SHP) composed by SCP-HA-PAE for delivering siRNA to skin melanoma by transdermal application. SHP not only manifests the excellent ability in penetrating through skin stratum corneum (SC), targeting melanoma and being sensitive to pH, but also expresses the advantages in compacting the vector/siRNAs nanocomplexes and stimulating their endosome escape inside cells, which ensure the enhanced siRNA delivery efficiency. SHP/siRNA induce the strong efficacy in retarding the progression and relapse of skin melanoma through the enhanced apoptosis effect both in vitro & in vivo. This study provides a proof-of-concept design of pH-switchable cationic micelles as transdermal gene delivery nanoplatforms with targeting effect for melanoma therapy, which may be adapted widely in the treatment of various superficial tumors and skin genetic diseases.

Rebiopsy in patients with or without prior TKIs revealed complicated histology of lung cancer.

e20525 Background: The important of rebiopsy is well known in lung adenocarcinomas (ADs) after acquiring resistant to TKIs, for they may transform to SCLC. But histology transformation in non-ADs or ADs without TKIs seems infrequent. Methods: We performed a retrospective collection of cases with changed histology after rebiopsy in patients presenting from January 2015 to April 2018 in a single center. Results: Among 188 patients who conducted rebiopsy, there were 20 cases presenting changed histologic type, which can be divided into two groups based on if TKIs were used before histology change. Group1 (TKIs used, N = 14) including ADs changing to SCLC (N = 9), squamous cell carcinoma (SQ) (N = 2), carcinosarcoma combined with few AD component (N = 1), SCLC combined AD (N = 1), and adenosquamous carcinoma changing to SCLC (N = 1). Four cases in group 1 went through surgery, and one of them who never smoke was diagnosed as AD (pT2N0M1a, EGFR exon 19del), with no small cell carcinoma (SCC) component found, but rebiopsy of metastasis revealed SCC without any AD component after 3 months of gefitinib. The disease continued to progress during the following chemotherapy (CT), and biopsies with other two metastases also presented SCC without AD component. Group 2 were 6 cases without TKIs before the rebiopsy (Table). Case 2, 4, 6 were all heavy smokers. Rebiopsy of case 2 was ALK+, so the patient took 4 months crizotinib and then 2 months alectinib, the disease was still stable on January 6, 2019. Case 5 was a classic extensive-stage SCLC with fast response to EP therapy, but fast relapse and resistance to the following CT, and the primary lesion at right upper lobe showed AD-like imaging, so rebiopsy was performed and carcinoma favor AD was found. EGFR exon 19del was detected in the plasma, and the lesion gain PR after one month of icotinib. The third biopsy of the progress lesion came back to SCC after resistance to TKI. Conclusions: Rebiopsy of lung cancers with or without TKIs therapy revealed diversity histology changes. This reminded us the important of rebiopsy, not only for TKIs resistant lung ADs. [Table: see text]

Cancer metabolism in a snapshot: MRS(I).

The contribution of MRS(I) to the in vivo evaluation of cancer-metabolism-derived metrics, mostly since 2016, is reviewed here. Increased carbon consumption by tumour cells, which are highly glycolytic, is now being sampled by 13 C magnetic resonance spectroscopic imaging (MRSI) following the injection of hyperpolarized [1-13 C] pyruvate (Pyr). Hot-spots of, mostly, increased lactate dehydrogenase activity or flow between Pyr and lactate (Lac) have been seen with cancer progression in prostate (preclinical and in humans), brain and pancreas (both preclinical) tumours. Therapy response is usually signalled by decreased Lac/Pyr 13 C-labelled ratio with respect to untreated or non-responding tumour. For therapeutic agents inducing tumour hypoxia, the 13 C-labelled Lac/bicarbonate ratio may be a better metric than the Lac/Pyr ratio. 31 P MRSI may sample intracellular pH changes from brain tumours (acidification upon antiangiogenic treatment, basification at fast proliferation and relapse). The steady state tumour metabolome pattern is still in use for cancer evaluation. Metrics used for this range from quantification of single oncometabolites (such as 2-hydroxyglutarate in mutant IDH1 glial brain tumours) to selected metabolite ratios (such as total choline to N-acetylaspartate (plain ratio or CNI index)) or the whole 1 H MRSI(I) pattern through pattern recognition analysis. These approaches have been applied to address different questions such as tumour subtype definition, following/predicting the response to therapy or defining better resection or radiosurgery limits.

Validation of Cyclic Adenosine Monophosphate Phosphodiesterase-4D7 for its Independent Contribution to Risk Stratification in a Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

BackgroundThe clinical metrics used to date to assess the progression risk of newly diagnosed prostate cancer patients only partly represent the true biological aggressiveness of the underlying disease. ObjectiveValidation of the prognostic biomarker phosphodiesterase-4D7 (PDE4D7) in predicting longitudinal biological outcomes in a historical surgery cohort to improve postsurgical risk stratification. Design, patients, and methodsRNA was extracted from biopsy punches of resected tumors from 550 patients. PDE4D7 was quantified using one-step quantitative reverse transcription-polymerase chain reaction. PDE4D7 scores were calculated by normalization of PDE4D7 to reference genes. Multivariate analyses were adjusted for clinical prognostic variables. Outcomes tested were: prostate-specific antigen relapse, start of salvage treatment, progression to metastases, overall mortality, and prostate cancer-specific mortality. The PDE4D7 score was combined with the clinical risk model Cancer of the Prostate Risk Assessment Postsurgical Score (CAPRA-S) using multivariate regression modeling; the combined score was tested in post-treatment progression free survival prediction. Outcome measurements and statistical analysisCorrelations with outcomes were analyzed using multivariate Cox regression and logistic regression statistics. Results and limitationsThe PDE4D7 score was significantly associated with time-to-prostate specific antigen failure after prostatectomy (hazard ratio [HR]: 0.53, 95% confidence interval [CI]: 0.41–0.67 for each unit increase, p<0.0001). After adjustment for postsurgical prognostic variables the HR was 0.56 (95% CI: 0.43–0.73, p<0.0001). The PDE4D7 score remained significant after adjusting the multi-variate analysis for the CAPRA-S model categories (HR=0.54, 95% CI=0.42–0.69, p<0.0001). Combination of the PDE4D7 score with the CAPRA-S demonstrated a significant incremental value of 4–6% in 2-yr (p=0.004) or 5-yr (p=0.003) prediction of progression free survival after surgery. The combined model of PDE4D7 and CAPRA-S improves patient selection with very high risk of fast disease relapse after primary intervention. ConclusionsThe PDE4D7 score has the potential to provide independent risk information and to restratify patients with clinical intermediate- to high-risk characteristics to a very low-risk profile. Patient summaryIn this report, we studied the potential of a novel biomarker to predict outcomes of a cohort of prostate cancer patients who underwent surgery more than 10 yr ago. We found that a gene called phosphodiesterase-4D7 added extra information to the available clinical data. We conclude that the measurement of this gene in tumor tissue may contribute to more effective treatment decisions.

Cell dynamics in tumour environment after treatments.

Most cancer treatments cause necrotic cell deaths in the tumour microenvironment. Necrotic cells send signals to immune cells to start the wound healing process in the tissue. Therefore, we assume after stopping treatments there is a wound that needs to be healed. We develop a simple computational model to investigate cell dynamics during the wound healing process after treatments. The model predicts that the involvement of high-fitness cancer cells in the wound healing leads to fast relapse, and cancer cells outside of the wound can cause a slow recurrence of the tumour. Therefore, the absence of relapse after treatments may imply a slow-developing tumour that might not reach an observable size in the patients' lifetime. Additionally, the model indicates that the location of remaining cancer cells after treatments is an important factor in the recurrence time. The fastest recurrence happens when high-fitness cancer cells remain inside of the wound. However, the longest time to recurrence corresponds to cancer cells located outside of the wound. Note that this model is the first attempt to study cell dynamics in the wound healing process after cancer treatments, and it has some limitations that might influence the results. Experiments are needed to validate the results.

Checkpoint Antibodies but not T Cell-Recruiting Diabodies Effectively Synergize with TIL-Inducing γ-Irradiation.

T cell-recruiting bispecific antibodies (bsAb) show promise in hematologic malignancies and are also being evaluated in solid tumors. In this study, we investigated whether T cell-recruiting bsAbs synergize with hypofractionated tumor radiotherapy (hRT) and/or blockade of the programmed death-1 (PD-1) immune checkpoint, both of which can increase tumor-infiltrating lymphocyte (TIL) numbers. Unexpectedly, large melanomas treated with hRT plus bsAb (AC133×CD3) relapsed faster than those treated with hRT alone, accompanied by massive TIL apoptosis. This fast relapse was delayed by the further addition of anti-PD-1. Mechanistic investigations revealed restimulation-induced cell death mediated by BIM and FAS as an additional cause of bsAb-mediated TIL depletion. In contrast, the double combination of hRT and anti-PD-1 strongly increased TIL numbers, and even very large tumors were completely eradicated. Our study reveals the risk that CD3-engaging bsAbs can induce apoptotic TIL depletion followed by rapid tumor regrowth, reminiscent of tolerance induction by CD3 mAb-mediated T-cell depletion, warranting caution in their use for the treatment of solid tumors. Our findings also argue that combining radiotherapy and anti-PD-1 can be quite potent, including against very large tumors. Cancer Res; 76(16); 4673-83. ©2016 AACR.

Concise Review: Stem Cells in Pancreatic Cancer: From Concept to Translation.

Pancreatic cancer stem cells (CSCs) have been first described in 2007 and since then have emerged as an intriguing entity of cancer cells with distinct functional features including self-renewal and exclusive in vivo tumorigenicity. The heterogeneous pancreatic CSC pool has been implicated in tumor propagation as well as metastatic spread. Clinically, the most important feature of CSCs is their strong resistance to standard chemotherapy, which results in fast disease relapse, even with today's more advanced chemotherapeutic regimens. Therefore, novel therapeutic strategies to most efficiently target pancreatic CSCs are being developed and their careful clinical translation should provide new avenues to eradicate this deadly disease.

High-dose benzodiazepine dependence: a qualitative study of patients' perception on cessation and withdrawal.

BackgroundBenzodiazepine withdrawal syndrome has been reported following attempts to withdraw even from low or therapeutic doses and has been compared to barbiturate and alcohol withdrawal. This experience is known to deter patients from future cessation attempts. Research on other psychotropic substances shows that the reasons and motivations for withdrawal attempts – as well as the experiences surrounding those attempts – at least partially predict future efforts at discontinuation as well as relapse. We therefore aimed to qualitatively explore what motivates patients to discontinue this medication as well as to examine their experiences surrounding previous and current withdrawal attempts and treatment interventions in order to positively influence future help-seeking behavior and compliance.MethodsTo understand these patients better, we conducted a series of 41 unstructured, narrative, in-depth interviews among adult Swiss patients with a long-term dependent use of benzodiazepines in doses equivalent to more than 40 mg diazepam per day and/or otherwise problematic use (mixing benzodiazepines, escalating dosage, recreational use or illegal purchase). Mayring’s qualitative content analysis was used to evaluate findings.ResultsThese high-dose benzodiazepine-dependent patients decision to change consumption patterns were affected by health concerns, the feeling of being addicted and social factors. Discontinuation attempts were frequent and not very successful with fast relapse. Withdrawal was perceived to be a difficult, complicated, and highly unpredictable process. The first attempt at withdrawal occurred at home and typically felt better than at the clinic. Inpatient treatment was believed to be more effective with long term treatment (approaches) than short term.Patients preferred gradual reduction of usage to abrupt cessation (and had experienced both). While no clear preferences for withdrawal were found for benzodiazepines with specific pharmacokinetic properties, participants frequently based their decision to participate in treatment on the availability of their preferred brand name and furthermore discarding equivalent dosage rationales.ConclusionsOur findings provide greater understanding of the factors that motivate high-dose benzodiazepine-dependent individuals to stop taking these medications, and how they experience withdrawal and treatment strategies. They underscore how patients’ perceptions of treatment approaches contribute to compliant or non-compliant behavior.

Frequently ABL kinase domain G:C→A:T mutation and uracil DNA glycosylase abnormal expression in TKI-resistant acute lymphoblastic leukemia of Chinese population

Most Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) patients often show rapid recurrence and development of ABL kinase domain (KD) mutation after tyrosine kinase inhibitor (TKI) treatment. To further investigate the mechanism of Ph(+) ALL fast relapse after TKI treatment, ABL KD mutation in 35 Chinese Ph(+) ALL with TKI resistance was detected by direct sequencing. The results showed that 77.1% (27/35) Ph(+) ALL patients with TKI resistance had ABL KD mutation and 55.6% (15/27) Ph(+) ALL patients with ABL KD mutation had T315I. Interestingly, 77.8% (21/27) Ph(+)ALL showed ABL mutation G: C→A:T, including T315I, E255K and E459K. Furthermore, all the Ph(+) ALL patients with two or more ABL KD mutations collaborated with complex chromosome abnormality and all the TKI-resistant Ph(+) ALL patients, whose karyotype progressed from simple t (9;22) into complex, developed ABL KD mutation. Moreover, the expression level of uracil-DNA glycosylase UNG2, which inhibits G:C→A:T transition in genomic DNA, decreased in Ph(+) ALL with TKI-resistance compared to that in newly diagnosis Ph(+) ALL. It is concluded that there is a high frequent ABL KD G:C→A:T mutation and a high genomic instability in Chinese TKI-resistant Ph(+) ALL. In addition, the decreased UNG2 expression in TKI-resistant Ph(+) ALL probably contributes to their high rate of ABL KD G:C→A:T mutation.

Toward an Understanding of the Neural Circuitry of Major Depressive Disorder Through the Clinical Response to Deep Brain Stimulation of Different Anatomical Targets

Deep brain stimulation has been proposed as a treatment for treatment-resistant depression. To date, multiple brain targets have been tested in single case studies and case series. The target regions with the most evidence to support their use are the subcallosal cingulate, ventral capsule/ventral striatum, nucleus accumbens, and medial forebrain bundle. Treatment effects of stimulation at each target share some commonalities, including similar response and remission rates, a relatively slow and progressive time course of treatment response, with a comparatively fast depressive relapse after discontinuation of stimulation. Response is maintained over time, and in some cases improves over years. Similarities may be at least partially attributable to overlap in white matter pathways between targets. Careful attention to mood and somatic effects seen with acute stimulation may differentiate primary vs. secondary treatment effects and mechanisms between the target regions. Understanding which symptoms are primarily affected, and the time course of response and relapse, will shed light on the biological mechanisms underlying DBS effects and depression pathology.