A randomized double blinded placebo controlled trial of sildenafil for renoprotection prior to hilar clamping in patients undergoing robotic assisted laparoscopic partial nephrectomy

Objective

To perform a randomized control trial (RCT) assessing the effect of phosphodiesterase 5 inhibitor (PDE5i) used prior to hilar clamping during robot assisted partial nephrectomy (RAPN) for renoprotection.

Materials and Methods

We performed an institutional review board approved, placebo controlled, double blinded RCT evaluating a single 100 mg oral dose of sildenafil immediately prior to RAPN. Primary end point was accrual, participation and retention of patients with secondary endpoints assessing post-operative renal functional outcomes and safety. Exclusion criteria included history of coronary artery disease, solitary kidney, suspected benign pathology, PDE5i intolerance or pregnant females.

Results

Of 40 eligible consecutive patients undergoing RPN between 9/2013 and 12/2014, 30 (75%) were randomized to treatment and there was 100% participation and retention. The groups were well matched for all measured comorbidities. Intraoperative outcomes including warm ischemia time (median 15 vs. 16.5 min, P = 0.29) were similar. Change in eGFR demonstrated similar decrease between sildenafil versus placebo at 1 day (−8% vs. −10%, P = 0.53), 2 days (−9% vs. −9%, P = 0.77), and 1 month (−4% vs. −6%, P = 0.31) following RAPN. Intermediate follow up (median 183 days) demonstrated similar results (−8% vs. −1%, P = 0.16) between the two cohorts. Safety profiles were similar between the two cohorts without any adverse reactions to the sildenafil.

Conclusions

Successful retention of patients was achieved in this RCT. The secondary outcome of renoprotection was not identified. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Successful conservative management of diffuse cavernous hemangioma of the rectum

Abstract

Diffuse cavernous hemangioma of the rectum (DCHR) is a relatively rare disease. A 40-year-old man presented with long-standing lower abdominal discomfort and hematuria. At the time of hospitalization, his vital signs and hemoglobin level were normal. Colonoscopy showed markedly dilated blood vessels in the sigmoid mucosa, which was confirmed on magnetic resonance imaging and computed tomography as cavernous hemangioma. Without surgery, there have been no signs of progression of DCHR during a 3-year follow-up period.

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Alkaloid extracts from shea butter and breadfruit as potential inhibitors of monoamine oxidase, cholinesterases, and lipid peroxidation in rats’ brain homogenates: a comparative study

Abstract

Shea butter (Vitellaria paradoxa) and breadfruit (Treculia africana) are wild edible plants commonly consumed across the world. Unfortunately, these plants are currently going into extinction despite their potential biological properties. The actions of alkaloid extract from shea butter nut and breadfruit on some central nervous system biomarkers (monoamine oxidase (MAO), acetylcholinesterase (AChE), butyrylcholinesterase (BChE)) linked to some neurodegenerative diseases were investigated in this study. The radical scavenging and metal chelating abilities of the extract were also studied. Alkaloid extracts were obtained from shea butter and breadfruit via solvent extraction. The total alkaloid content of the extracts and their interactions on MAO, AChE, and BChE were determined. The ability of the extract to inhibit Fe²⁺-induced malondialdehyde (MDA) production in rats' brain homogenates including their radical scavenging and metal chelating abilities were also determined. Breadfruit (17.00 mg CE/g) had higher alkaloid content than shea butter (15.34 mg CE/g). Furthermore, a significant decrease in MAO, AChE, and BChE activities was exhibited by breadfruit compared to shea butter. However, shea butter had stronger antioxidant activity. The observed modulatory effects of the extracts on MAO, AChE, and BChE activities and their antioxidant properties give credence to the fact that they could be a novel multifunctional target for the treatment and management of some neurodegenerative diseases.

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Acquired EGFR-TKI and Met-TKI resistance mechanisms in NSCLC

Met-amplified epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation is responsive to concurrent EGFR-TKI and Met-TKI treatment in a preclinical model. Here, we determined that Met-amplified gefitinib-resistant cells acquire dual resistance to inhibition of EGFR and Met tyrosine kinase activities. PC-9 lung adenocarcinoma cells harboring 15-bp deletions (Del E746_A750) in EGFR exon 19 were treated with increasing concentrations of the Met-TKI PHA665752 and 1 μM gefitinib for 1 year; three resistant clones were established via Met amplification. The three dual-resistance cell lines (PC-9DR2, -9DR4, and -9DR6, designated as DR2, DR4, and DR6, respectively) exhibited different mechanisms for evading both EGFR and Met inhibition. None of the clones harbored a secondary mutation of EGFR T790M or a Met mutation. Insulin-like growth factor (IGF)/IGF1 receptor activation in DR2 and DR4 cells acted as a bypass signaling pathway. Met expression was attenuated to a greater extent in DR2 than in PC-9 cells, but was maintained in DR4 cells by overexpression of IGF-binding protein 3. In DR6 cells, Met was further amplified by association with heat shock protein (HSP) 90, which protected Met from degradation and induced SET and MYND domain-containing 3 (SMYD3)-mediated Met transcription. This is the first report describing the acquisition of dual resistance mechanisms in NSCLC harboring an activating EGFR mutation to Met-TKI and EGFR-TKI following previous EGFR-TKI treatment. These results might inform the development of more effective therapeutic strategies for NSCLC treatment.

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CXCL4 chemokines in tumor development

The CXCL4 paralog CXCL4L1 is a little studied chemokine that has been suggested to exert an anti-angiogenic function. However, CXCL4L1 is also expressed in patient tumors, tumor cell lines and murine xenografts, prompting a more detailed analysis of its role in cancer pathogenesis. We used genetic and antibody-based approaches to attenuate CXCL4L1 in models of pancreatic adenocarcinoma (PDAC). Mechanisms of expression were assessed in cell co-culture experiments, murine and avian xenotransplants, including through an evaluation of CpG methylation and mutation of critical CpG residues. CXCL4L1 gene expression was increased greatly in primary and metastatic PDAC. We found that myofibroblasts triggered cues in the tumor microenvironment which led to induction of CXCL4L1 in tumor cells. CXCL4L1 expression was also controlled by epigenetic modifications at critical CpG islands which were mapped. CXCL4L1 inhibited vasculogenesis but also affected tumor development more directly depending on the tumor cell type. In vivo administration of a monoclonal antibody against CXCL4L1, we demonstrated a blockade in the growth of tumors positive for CXCR3, a critical receptor for CXCL4 ligands. Our findings define a pro-tumorigenic role in PDAC development for endogenous CXCL4L1, which is independent of its anti-angiogenic function.

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TWEAK/Fn14 protects against colitis-associated cancer

Inflammatory bowel disease causes chronic, relapsing intestinal inflammation that can lead to the development of colorectal cancer. Members of the TNF superfamily are key regulators of intestinal inflammation. In particular, TNF-like weak inducer of apoptosis (TWEAK) and its receptor, Fn14, are involved in normal and pathologic intestinal tissue remodeling. In this study, we show that the TWEAK/Fn14 signaling complex plays a protective role during the acute stage of intestinal inflammation and contributes to the prevention of colitis-associated cancer during chronic inflammation through its pro-apoptotic effects. Colitis was in Fn14-/- and Fn14+/+ wild type littermates by administering 3% dextran sodium sulfate (DSS) for 7 days followed by 2 weeks recovery; azoxymethane (AOM) administration followed by 2 cycles of DSS/recovery was used to induce tumors. Reciprocal bone marrow chimeric mice were generated to compare hematopoietic and non-hematopoietic-specific effector tissues. Fn14-/- mice had enhanced susceptibility to colitis compared to Fn14+/+ controls as assessed by endoscopic and histological inflammatory scores, daily weight loss, and mortality rates during recovery after DSS administration. Bone marrow transfer experiments showed that both hematopoietic and non-hematopoietic components are involved in protection against colitis. Tumor lesions were found in the colons of most Fn14-/- mice, but not Fn14+/+ controls. AOM/DSS administration enhanced susceptibility to tumorigenesis in Fn14-/- mice. Overall, these findings show that Fn14 plays a protective role during the acute stages of intestinal inflammation, and its absence promotes the development of colitis-associated cancer.

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Agonistic anti-CD40 mAb reverses anti-PD1 mAb resistance

The durability and efficacy of anti-human PD1 monoclonal antibodies (PD1 mAb) vary across different malignancies. Although an absence of tumor-infiltrating cytotoxic T lymphocytes has been identified as a cause for resistance to PD1 mAb, the presence of intratumor exhausted PD1hi T cells also contributes to insensitivity to this immune checkpoint therapy. In this study, we used mouse tumor models of PD1 mAb resistance that harbored PD1hi T cells and flow cytometry analysis of tumor-infiltrating leukocytes immediately post-therapy as a screening platform to identify agents that could resensitize T cells to PD1 blockade. We showed that an agonistic anti-CD40 mAb converted PD1hi T cells into PD1lo T cells, reversing phenotypic T cell exhaustion and allowing the anti-PD1 refractory tumors to respond to anti-PD1 therapy. PD1 down-modulation by anti-CD40 mAb relied upon IL-12 but not IL-23, CD80/CD86/CD28 or CD70/CD27. Consistent with a role for regulatory T cells (Treg) in promoting T cell exhaustion, we also showed that intratumor Treg presented with a less activated and attenuated suppressive phenotype, marked by reductions in CTLA4 and PD1. Similar to anti-CD40 mAb, anti-CTLA4 mAb also lowered intratumor T cell PD1 expression. Our study provides a proof-of-principle framework to systematically identify immune conditioning agents able to convert PD1hi T cells to PD1lo T cells, with clinical implications in the management of anti-PD1 refractory patients.

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Vesigenurtacel-L (HS-410) in the management of high-grade nonmuscle invasive bladder cancer

Future Oncology Ahead of Print.


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A Systematic Analysis of 2 Monoisocentric Techniques for the Treatment of Multiple Brain Metastases

Background:

In this treatment planning study, we compare the plan quality and delivery parameters for the treatment of multiple brain metastases using 2 monoisocentric techniques: the Multiple Metastases Element from Brainlab and the RapidArc volumetric-modulated arc therapy from Varian Medical Systems.

Methods:

Eight patients who were treated in our institution for multiple metastases (3-7 lesions) were replanned with Multiple Metastases Element using noncoplanar dynamic conformal arcs. The same patients were replanned with the RapidArc technique in Eclipse using 4 noncoplanar arcs. Both techniques were designed using a single isocenter. Plan quality metrics (conformity index, homogeneity index, gradient index, and R_50%), monitor unit, and the planning time were recorded. Comparison of the Multiple Metastases Element and RapidArc plans was performed using Shapiro-Wilk test, paired Student t test, and Wilcoxon signed rank test.

Results:

A paired Wilcoxon signed rank test between Multiple Metastases Element and RapidArc showed comparable plan quality metrics and dose to brain. Mean ± standard deviation values of conformity index were 1.8 ± 0.7 and 1.7 ± 0.6, homogeneity index were 1.3 ± 0.1 and 1.3 ± 0.1, gradient index were 5.0 ± 1.8 and 5.1 ± 1.9, and R_50% were 4.9 ± 1.8 and 5.0 ± 1.9 for Multiple Metastases Element and RapidArc plans, respectively. Mean brain dose was 2.3 and 2.7 Gy for Multiple Metastases Element and RapidArc plans, respectively. The mean value of monitor units in Multiple Metastases Element plan was 7286 ± 1065, which is significantly lower than the RapidArc monitor units of 9966 ± 1533 (P < .05).

Conclusion:

For the planning of multiple brain lesions to be treated with stereotactic radiosurgery, Multiple Metastases Element planning software produced equivalent conformity, homogeneity, dose falloff, and brain V_{12 Gy} but required significantly lower monitor units, when compared to RapidArc plans.

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The growing world of CAR T cell trials: a systematic review

Abstract

In recent years, cancer treatment involving adoptive cell therapy with chimeric antigen receptor (CAR)-modified patient's immune cells has attracted growing interest. Using gene transfer techniques, the patient's T cells are modified ex vivo with a CAR which redirects the T cells toward the cancer cells through an antibody-derived binding domain. The T cells are activated by the CAR primary signaling and costimulatory domains. Such "second generation" CAR T cells induced complete remission of B cell malignancies in the long-term. In this fast-moving field with a growing number of engineered T cell products, we list about 100 currently ongoing trials here that involve CAR T cells targeting hematopoietic malignancies and solid cancer. Major challenges in the further development of the therapy are briefly discussed.

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Molecular cytogenetic characterization of two established ESFT cell lines

Abstract

Ewing's sarcoma/primitive neuroectodermal tumor/Askin's tumor (Ewing`s sarcoma family of tumors: ESFT) is the most common type of malignant tumor of bone and soft tissue in children and young adults, and morphologically is a member of a group of small round cell tumors. We report, here, on the establishment of two human ESFT cell lines, FU-PNET-3 and FU-PNET-4, from the iliac and the chest wall, respectively, the cells of both cell lines were tumorigenic in immunodeficient mice. Histologically, both original and xenograft tumors and cultured cells were composed of small round cells with positive immunoreactivity for CD99 and Nkx2.2. Molecular biological examination demonstrated chimeric transcripts of EWSR1 exon 7 to FLI1 exon 6 in FU-PNET-3 cells, and EWSR1 exon 10 to FLI1 exon 6 in FU-PNET-4 cells. Cytogenetic analysis revealed chromosome translocation t(11;22)(q24;q12) and some secondary changes in both cultured cells. These histological, molecular biological, and cytogenetical findings indicate ESFT in both cell lines. ESFT is well studied, but its recurrent fusion genes are heterogeneous and its biological behaviors are unclear. The FU-PNET-3 and FU-PNET-4 cell lines have been well examined and may become useful tools for studying the genetic and biological behavioral properties of ESFT.

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Classical risk factors, but not HPV status, predict survival after chemoradiotherapy in advanced head and neck cancer patients

Abstract

Purpose

Despite the advent of concomitant chemoradiotherapy (CCRT), the prognosis of advanced head and neck squamous cell carcinoma (HNSCC) patients remains particularly poor. Classically, HNSCC, especially oropharyngeal carcinomas, associated with human papillomavirus (HPV) exhibits better treatment outcomes than HNSCCs in non-infected patients, eliciting a call for the de-escalation of current therapies. To improve the management of HNSCC patients, we aimed to determine the impact of active HPV infection on patient response, recurrence and survival after CCRT in a population of heavy tobacco and alcohol consumers.

Methods

Paraffin-embedded samples from 218 advanced HNSCC patients, mostly smokers and/or drinkers treated by CCRT, were tested for the presence of HPV DNA by surrogate type-specific E6/E7 qPCR and p16 immunohistochemistry. Associations between the response to CCRT and patient outcomes according to HPV status and clinical data were evaluated by Kaplan–Meier analysis and both univariate and multivariate Cox regression.

Results

Type-specific E6/E7 PCR demonstrated HPV positivity in 20 % of HNSCC. Regarding HPV status, we did not find any significant relation with response to therapy in terms of progression-free survival or overall survival. However, we observed a significantly worse prognosis for consumers of alcohol and tobacco compared to nondrinkers (p = 0.003) and non-smokers (p = 0.03). Survival analyses also revealed that the outcome is compromised in stage IV patients (p = 0.007) and, in particular, for oral cavity, hypopharynx and oropharynx carcinoma patients (p = 0.001).

Conclusion

The risk of death from HNSCC significantly increases when patients are exposed to tobacco and alcohol during their therapy, regardless of HPV status.

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Telangiectatic osteosarcoma: a review of 87 cases

Abstract

Purposes

Telangiectatic osteosarcoma (TOS) is a rare subtype of osteosarcoma. We analyzed (1) oncologic outcome in a large homogeneous series and (2) the role of prognostic factors on prognosis, local recurrence and metastasis.

Methods

Eighty-seven patients (47 males, 54 %) were retrospectively analyzed. All except 4 had extracompartmental disease, and ten patients had lung metastasis at diagnosis. Pathologic fracture was present in 27 cases (31 %). Seventy-eight patients were treated with neoadjuvant chemotherapy; nine had surgery as first treatment. Limb-salvage surgery was performed in 71 cases, amputation in 14, and rotationplasty in one. One patient died before surgery. Possible prognostic factors were statistically evaluated.

Results

Overall survival was 60.7 % at 10 years of follow-up. Fifty-one patients were disease-free (58.6 %), 2 were alive with disease (2.3 %), 31 died with disease (35.6 %), and 3 died of other causes (3.4 %). Ten local recurrences were observed (11 %). Twenty-five patients (29 %) developed lung (22) or bone (3) metastases. No statistical difference was found considering age, metastases at diagnosis, gender, pathologic fracture, tumor volume, compartmental status, number of neoadjuvant chemotherapy agents and treatment. Induced necrosis was significant at both univariate and multivariate analysis (p < 0.0001).

Conclusions

TOS does not have a poor prognosis as previously reported in literature, with a survival of about 60 % at 10 years. Most of patients can be cured with neoadjuvant chemotherapy plus surgery (limb sparing surgery is possible and safe). Tumor response to chemotherapy as induced necrosis was the only significant prognostic factors on survival, even if small tumor volume at diagnosis correlates with better prognosis at univariate analysis.

Level of evidence

IV.

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Robot-assisted surgery versus conventional laparoscopic surgery for endometrial cancer: a systematic review and meta-analysis

Abstract

Purpose

To compare perioperative outcomes between robot-assisted surgery (RAS) and conventional laparoscopic surgery (CLS) for the treatment of endometrial cancer by conducting a meta-analysis.

Methods

We searched the Cochrane Central Register of Controlled Trials, PubMed, and EMBASE up to January 8, 2016. Studies clearly documenting a comparison between RAS and CLS for patients with endometrial cancer were included. The perioperative outcomes of interest included intraoperative visceral injuries, postoperative complications, operation time, estimated blood loss (EBL), blood transfusion, total lymph nodes harvested (TLNH), conversion to laparotomy, and length of hospital stay. The weighted mean difference (WMD) and odds ratio (OR) were pooled with either a fixed-effects or a random-effects model.

Results

A total of 19 studies were included in the analysis, involving 3056 patients. The pooled analysis showed that RAS was associated with lower EBL (WMD −77.65; 95 % confidence interval [CI] −105.58 to −49.72), lower conversion rate (OR 0.29; 95 % CI 0.18–0.46), and shorter hospital stay (WMD −0.48; 95 % CI −0.70 to −0.26) compared to CLS. The incidence of intraoperative visceral injuries, operation time, transfusion rate, and TLNH showed no significant differences between RAS and CLS.

Conclusions

RAS is a feasible and effective surgical approach that may be superior to CLS for the treatment of endometrial cancer, with lower EBL and lower conversion rate. Further prospective randomized trials are required to validate our findings.

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Hurdles in selection process of nanodelivery systems for multidrug-resistant cancer

Abstract

Purpose

Most of the nanomedicines for treatment of multidrug-resistant cancer do not reach Phase III trials and many are terminated or withdrawn or are in an indeterminate state since long without any study results being presented. Extensive perusal of nanomedicine development research revealed that one of the critical aspects influencing clinical outcomes and which requires diligent scrutiny is selection process of nanodelivery system.

Methods

Research papers and articles published on development of nanodelivery systems for treatment of multidrug-resistant cancer were analyzed. Observations and conclusions noted by these researchers which might shed some light on poor clinical performance of nanocarriers were collated and summarized under observation section. Further research articles were studied to find possible solutions which may be applied to these particular problems for resolving them. The inferences of these findings were composed in Result section.

Result

Plausible solutions for the observed obstacles were noted as examples of novel formulations that can yield the following: better in vivo imaging, precise targeting and dosing of a specific site and specific cell type in a particular cancer, modulation of tumor surroundings, intonation of systemic effects and high reproducibility.

Conclusion

The angle of approach to the development of best nanosystem for a specific type of tumor needs to be spun around. Some of these changes can be brought about by individual scientists, some need to be established by collated efforts of scientists globally and some await advent of better technologies. Regardless of the stratagem, it can be said decisively that the schematics of development phase need rethinking.

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Effects of Raf kinase inhibitor protein expression on pancreatic cancer cell growth and motility: an in vivo and in vitro study

Abstract

Purpose

Raf kinase inhibitor protein (RKIP) is a tumor suppressor that inhibits cell growth and metastasis of malignant tumors. Pancreatic cancer is a leading cause of cancer death with a low survival rate. RKIP expression and its role in tumorigenesis and metastasis in pancreatic cancer are poorly understood. The aims of our study were to assess the effects of RKIP on pancreatic carcinoma cells in vitro and in tumor tissues in vivo.

Methods

This study included 84 patients with histologically confirmed pancreatic adenocarcinoma. The expression levels of RKIP were measured in pancreatic cancer tissues and adjacent normal tissues using real-time PCR and immunohistochemistry. Overexpression plasmid of RKIP was transfected into SW1990 and AsPC-1 cell lines, and the effects on cell proliferation were studied using a Cell Counting Kit-8 assay. MEK1/2 and ERK1/2 were detected by Western blot and immunofluorescence assay.

Results

Results showed a reduced expression of RKIP in pancreatic carcinoma tissues compared with adjacent normal tissues, which closely correlated with patient outcomes. Overexpression of RKIP suppressed cell proliferation and promoted apoptosis in cultured SW1990 and AsPC-1 cell lines. Transwell assay showed RKIP can inhibit cell migration and invasion, and in vivo RKIP can suppress tumorigenesis by diminishing the volume of the tumors.

Conclusions

In conclusion, expression of RKIP is closely correlated with the survival of pancreatic cancer patients. RKIP can inhibit pancreatic adenocarcinoma cells proliferation, activities of migration and invasion, through downregulating Raf-1-MEK1/2-ERK1/2 signaling pathway.

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Vitamin C in synergism with cisplatin induces cell death in cervical cancer cells through altered redox cycling and p53 upregulation

Abstract

Purpose

Cervical cancer is the second most prevalent cancer in women worldwide. Survival of patients has been improved by cisplatin-based chemotherapy, but its effectiveness is limited due to its adverse effects on many tissues, especially nephrotoxicity. To optimize the efficacy of CDDP, we propose a combination therapy using natural products with minimal side effects. Vitamin C being a natural antioxidant is capable of selectively targeting cancer cells at pharmacological concentrations. Vitamin C synergistically enhances the activity of chemotherapeutic agents without increasing toxicity to normal cells. Therefore, we exploited co-therapy with cisplatin and vitamin C to kill cervical cancer cells.

Methods

We elucidated the role of CDDP and VC on cervical cancer cell line (SiHa) by using cell growth assays, DNA fragmentation analysis, comet assay, in vitro morphological assessment of apoptosis (AO/EB and DAPI staining), ROS analysis by DCFDA, flow cytometry, biochemical assays (GST, GSH, NO, catalase, TPA) and Western blotting.

Results

Our results clearly demonstrated that CDDP and VC treatment exhibited ameliorative effect on induction of cell death by p53 overexpression and generation of hydrogen peroxide in SiHa cells, thereby reducing the dosage of CDDP required to induce cell death in cancer cells.

Conclusions

These studies provide novel approaches to combat cisplatin resistance in cervical cancer.

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Iterative sorting reveals CD133+ and CD133- melanoma cells as phenotypically distinct populations

Abstract

Background

The heterogeneity and tumourigenicity of metastatic melanoma is attributed to a cancer stem cell model, with CD133 considered to be a cancer stem cell marker in melanoma as well as other tumours, but its role has remained controversial.

Methods

We iteratively sorted CD133+ and CD133- cells from 3 metastatic melanoma cell lines, and observed tumourigenicity and phenotypic characteristics over 7 generations of serial xeno-transplantation in NOD/SCID mice.

Results

We demonstrate that iterative sorting is required to make highly pure populations of CD133+ and CD133- cells from metastatic melanoma, and that these two populations have distinct characteristics not related to the cancer stem cell phenotype. In vitro, gene set enrichment analysis indicated CD133+ cells were related to a proliferative phenotype, whereas CD133- cells were of an invasive phenotype. However, in vivo, serial transplantation of CD133+ and CD133- tumours over 7 generations showed that both populations were equally able to initiate and propagate tumours. Despite this, both populations remained phenotypically distinct, with CD133- cells only able to express CD133 in vivo and not in vitro. Loss of CD133 from the surface of a CD133+ cell was observed in vitro and in vivo, however CD133- cells derived from CD133+ retained the CD133+ phenotype, even in the presence of signals from the tumour microenvironment.

Conclusion

We show for the first time the necessity of iterative sorting to isolate pure marker-positive and marker-negative populations for comparative studies, and present evidence that despite CD133+ and CD133- cells being equally tumourigenic, they display distinct phenotypic differences, suggesting CD133 may define a distinct lineage in melanoma.

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53BP1 depletion causes PARP inhibitor resistance in ATM-deficient breast cancer cells

Abstract

Background

Mutations in DNA damage response factors BRCA1 and BRCA2 confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors in breast and ovarian cancers. BRCA1/BRCA2-defective tumors can exhibit resistance to PARP inhibitors via multiple mechanisms, one of which involves loss of 53BP1. Deficiency in the DNA damage response factor ataxia-telangiectasia mutated (ATM) can also sensitize tumors to PARP inhibitors, raising the question of whether the presence or absence of 53BP1 can predict sensitivity of ATM-deficient breast cancer to these inhibitors.

Methods

Cytotoxicity of PARP inhibitor and ATM inhibitor in breast cancer cell lines was assessed by MTS, colony formation and apoptosis assays. ShRNA lentiviral vectors were used to knockdown 53BP1 expression in breast cancer cell lines. Phospho-ATM and 53BP1 protein expressions were determined in human breast cancer tissues by immunohistochemistry (IHC).

Results

We show that inhibiting ATM increased cytotoxicity of PARP inhibitor in triple-negative and non-triple-negative breast cancer cell lines, and depleting the cells of 53BP1 reduced this cytotoxicity. Inhibiting ATM abrogated homologous recombination induced by PARP inhibitor, and down-regulating 53BP1 partially reversed this effect. Further, overall survival was significantly better in triple-negative breast cancer patients with lower levels of phospho-ATM and tended to be better in patients with negative 53BP1.

Conclusion

These results suggest that 53BP1 may be a predictor of PARP inhibitor resistance in patients with ATM-deficient tumors.

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Are disseminated tumor cells in bone marrow and tumor-stroma ratio clinically applicable for patients undergoing surgical resection of primary colorectal cancer? The Leiden MRD study

Abstract

Purpose

Current TNM staging does not appropriately identify high-risk colorectal cancer (CRC) patients. The aim of this study was to evaluate whether the presence of disseminated tumor cells (DTCs) in the bone marrow (BM) and the presence of stroma in the primary tumor, i.e., the tumor-stroma ratio (TSR), in patients undergoing surgical resection of primary CRC provides information relevant for disease outcome.

Methods

Patients with primary CRC (n = 125), consecutively admitted for curative resection between 2001 and 2007, were included in the study. All patients underwent BM aspiration before surgery. Detection of tumor cells was performed using immunocytochemical staining for cytokeratin (CK-ICC). The TSR was determined on diagnostic H&E stained sections of primary tumors.

Results

DTCs were detected in the BM of 23/125 patients (18 %). No association was found between BM status and overall survival (HR 0.97 (95 % CI 0.45–2.09), p = 0.93). Also, no significant difference was found in their 5-year survival rate (resp. 72 % and 68 % for BM-positive versus BM-negative patients). The TSR was found to be associated with a worse overall survival (HR 2.16, 95 % CI 1.02–4.57, p = 0.04) with 5-year survival rates of 84 % versus 62 % for stroma-low and stroma-high patients, respectively. No relation was found between the presence of DTCs and TSR.

Conclusions

Our data indicate that the presence of DTCs in the BM of CRC patients is not associated with disease outcome. The TSR was, however, found to be associated with a worse overall survival, which indicates that for CRC the tumor microenvironment plays an important role in its behavior and prognosis.

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An Integrative Model of miRNA and mRNA Expression Signature for Patients of Breast Invasive Carcinoma with Radiotherapy Prognosis

Cancer Biotherapy & Radiopharmaceuticals Sep 2016, Vol. 31, No. 7: 253-260.


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Expression of Inhibitor of Differentiation-1 and Its Effects on Angiogenesis in Gastric Cancer

Cancer Biotherapy & Radiopharmaceuticals Sep 2016, Vol. 31, No. 7: 233-237.


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Interfering EZH2 Expression Reverses the Cisplatin Resistance in Human Ovarian Cancer by Inhibiting Autophagy

Cancer Biotherapy & Radiopharmaceuticals Sep 2016, Vol. 31, No. 7: 246-252.


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Abrogation of MUC5AC Expression Contributes to the Apoptosis and Cell Cycle Arrest of Colon Cancer Cells

Cancer Biotherapy & Radiopharmaceuticals Sep 2016, Vol. 31, No. 7: 261-267.


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Primary Leiomyosarcoma of the Pancreas—a Case Report and a Comprehensive Review

Abstract

Purpose

Primary mesenchymal tumors of the pancreas are rare, with leiomyosarcomas the most encountered entities among the pancreatic sarcomas. With few exceptions, single case reports published over the last six decades constitute the entire scientific literature on this topic. Thus, evidence regarding clinical decision-making is scant.

Methods

Based on a case report and an extensive literature search in PubMed, we discuss the clinical aspects and current management of this rare malignancy.

Results

We identified only two papers with more than a single case presentation; these institutional patient series were limited to five and nine patients. Additionally, a few papers sought to summarize the individual case reports published in the English and/or Chinese language. The clinical presentation is rather non-specific. Moreover, modern imaging modalities are insufficiently accurate to diagnose leiomyosarcoma of the pancreas. Treatment goals include a complete resection with free margins. Proper morphologic examination using immunohistochemistry and the application of a grading system are clinically important for prognostication. The efficacy of adjuvant treatments has not been established.

Conclusion

Primary pancreatic leiomyosarcoma is extremely rare, and the scientific literature is primarily based on single case reports. Conclusions on management and prognosis should be drawn with caution. A multidisciplinary team consultation is warranted to discuss a thorough individual treatment plan based on the available scientific literature, despite its low evidence level.

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CCL18 from ascites promotes ovarian cancer cell migration through proline-rich tyrosine kinase 2 signaling

Abstract

Background

Ovarian cancer (OC) ascites consist in a proinflammatory tumor environment that is characterized by the presence of various cytokines, chemokines and growth factors. The presence of these inflammatory-related factors in ascites is associated with a more aggressive tumor phenotype. CCL18 is a member of CCL chemokines and its expression has been associated with poor prognosis in some cancers. However, its role in OC progression has not been established. Therefore, the aim of the current study was to elucidate the role of ascites CCL18 in OC progression.

Methods

ELISA and tissue microarrays were used to assess CCL18 in ascites and phospho-Pyk2 expression in cancer tissues respectively. Cell migration was assessed using Boyden chambers. CCL18 and ascites signaling was examined in ovarian cancer cells utilizing siRNA and exogenous gene expression.

Results

Here, we show that CCL18 levels are markedly increased in advanced serous OC ascites relative to peritoneal effusions from women with benign conditions. Ascites and CCL18 dose-dependently enhanced the migration of OC cell lines CaOV3 and OVCAR3. CCL18 levels in ascites positively correlated with the ability of ascites to promote cell migration. CCL18 blocking antibodies significantly attenuated ascites-induced cell migration. Ascites and CCL18 stimulated the phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) in CaOV3 and OVCAR3 cells. Most importantly, the expression of phosphorylated Pyk2 in serous OC tumors was associated with shorter progression-free survival. Furthermore, enforced expression of Pyk2 promoted tumor cell migration while siRNA-mediated downregulation of Pyk2 attenuated cell migration. Downregulation of Pyk2 markedly inhibited ascites and CCL18-induced cell migration.

Conclusions

Taken together, our findings establish an important role for CCL18, as a component of ascites, in the migration of tumor cells and identify Pyk2 as prognostic factor and a critical downstream signaling pathway for ascites-induced OC cell migration.

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Partial splenic embolization to permit continuation of systemic chemotherapy

Abstract

Systemic chemotherapy treatments, commonly those that comprise oxaliplatin, have been linked to the appearance of distinctive liver lesions that evolves to portal hypertension, spleen enlargement, platelets sequestration, and thrombocytopenia. This outcome can interrupt treatment or force dosage reduction, decreasing efficiency of cancer therapy. We conducted a prospective phase II study for the evaluation of partial splenic embolization in patients with thrombocytopenia that impeded systemic chemotherapy continuation. From August 2014 through July 2015, 33 patients underwent partial splenic embolization to increase platelets count and allow their return to treatment. Primary endpoint was the accomplishment of a thrombocyte level superior to 130 × 10⁹/L and the secondary endpoints were the return to chemotherapy and toxicity. Partial splenic embolization was done 36 times in 33 patients. All patients presented gastrointestinal cancer and colorectal malignancy was the commonest primary site. An average of 6.4 cycles of chemotherapy was done before splenic embolization and the most common regimen was Folfox. Mean platelet count prior to embolization was 69 × 10⁹/L. A total of 94% of patients achieved primary endpoint. All patients in need reinitiated treatment and median time to chemotherapy return was 14 days. No grade 3 or above adverse events were identified. Aiming for a 50% to 70% infarction area may be sufficient to achieve success without the complications associated with more extensive infarction. Combined with the better safety profile, partial splenic embolization is an excellent option in the management of thrombocytopenia, enabling the resumption of systemic chemotherapy with minimal procedure-related morbidity.

Partial splenic embolization is an excellent option in the management of thrombocytopenia, enabling the resumption of systemic chemotherapy with minimal procedure-related morbidity.

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CD30 and CD30-Targeted Therapies in Hodgkin Lymphoma and Other B cell Lymphomas

Abstract

Evolution of cancer therapeutics has resulted in the development of agents with varying mechanisms of selective target inhibition. One such therapeutic approach is utilizing antibody-drug conjugates (ADCs), the combination of a cytotoxic agent linked with a monoclonal antibody, to achieve localization of the target and internalization of the cytotoxic agent in order to maximize efficacy with fewer toxicities. This review focuses on CD30 as a therapeutic target and the development and clinical activity of the ADC brentuximab vedotin in Hodgkin lymphoma (HL) and other B cell lymphomas.

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The Wide Experience of the Sequential Therapy for Patients with Metastatic Renal Cell Carcinoma

Abstract

Sequential targeted therapies are the standard of care for patients with metastatic renal cell carcinoma (mRCC). Several drugs are available for patients whose disease progresses while they receive initial tyrosine kinase inhibitor (TKI) therapy; these include nivolumab (an inhibitor of PD-1 receptor), everolimus (an inhibitor of the mechanistic target of rapamycin) or additional TKIs. Until now, there has been no clinical evidence to support the use of one strategy versus another, so investigators and physicians rely on experience, judgement and findings from molecular analyses to select the appropriate treatment. However, with the arrival of nivolumab and cabozantinib that provide an overall survival higher than other alternative treatments, therapeutic strategies may have changed. Here, we discuss findings from preclinical and clinical studies that might help clinicians to choose the optimal treatment approach for patients with mRCC who progress to initial therapy.

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Optimal Use of BRAF Targeting Therapy in the Immunotherapy Era

Abstract

Purpose of Review

The therapeutic landscape for metastatic melanoma has been revolutionized in recent years. This review will discuss existing evidence for therapeutic approaches for BRAF-mutated metastatic melanoma.

Recent Findings

Clinical trials involving combined BRAF/MEK inhibition with either vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown improved overall survival compared to monotherapy with BRAF inhibitors alone. In a subset of patients with good prognostic factors, long-term clinical benefit has been noted. Simultaneously, developments in immunotherapy have suggested long-lasting survival for some patients.

Summary

In advanced BRAF-mutated melanoma, both BRAF/MEK inhibition and immunotherapy agents show improved overall survival and, in a small population of patients, prolonged and long-term benefit as compared to standard chemotherapy. Trials are currently underway evaluating sequencing of these therapies and the safety of targeted therapy plus immunotherapy combinations.

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Incorporating Geriatric Medicine Providers into the Care of the Older Adult with Cancer

Abstract

A significant proportion of cancer patients and survivors are age 65 and over. Older adults with cancer often have more complex medical and social needs than their younger counterparts. Geriatric medicine providers (GMPs) such as geriatricians, geriatric-trained advanced practice providers, and geriatric certified registered nurses have expertise in caring for older adults, managing complex medical situations, and optimizing function and independence for this population. GMPs are not routinely incorporated into cancer care for older adults; however, their particular skill set may add benefit at many points along the cancer care continuum. In this article, we review the role of geriatric assessment in the care of older cancer patients, highlight specific case scenarios in which GMPs may offer additional understanding and insight in the care of older adults with cancer, and discuss specific mechanisms for incorporating GMPs into oncology care.

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The growing world of CAR T cell trials: a systematic review

Abstract

In recent years, cancer treatment involving adoptive cell therapy with chimeric antigen receptor (CAR)-modified patient's immune cells has attracted growing interest. Using gene transfer techniques, the patient's T cells are modified ex vivo with a CAR which redirects the T cells toward the cancer cells through an antibody-derived binding domain. The T cells are activated by the CAR primary signaling and costimulatory domains. Such "second generation" CAR T cells induced complete remission of B cell malignancies in the long-term. In this fast-moving field with a growing number of engineered T cell products, we list about 100 currently ongoing trials here that involve CAR T cells targeting hematopoietic malignancies and solid cancer. Major challenges in the further development of the therapy are briefly discussed.

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Accelerated reduction of serum thyroxine and hippocampal histone acetylation links to exacerbation of spatial memory impairment in aged CD-1 mice pubertally exposed to bisphenol-a

Abstract

Age-related cognitive decline has been associated with changes in endogenous hormones and epigenetic modification of chromatin, including histone acetylation. Developmental exposure to endocrine disrupting chemicals, such as bisphenol-A (BPA) that produces endocrine disruption and epigenetic changes, may be a risk factor for accelerating cognitive deficits during aging. Thus, we exposed CD-1 mice to BPA (0, 1, and 100 mg/l BPA in the drinking water) orally during puberty (from postnatal days 28 to 56) and investigated whether pubertal BPA exposure exacerbates the age-related impairment of spatial cognition in old age (18 months old) and whether serum sex and thyroid hormones or hippocampal histone acetylation (H3K9ac and H4K8ac) are associated with cognitive effects. A young control group (6 months old) was added to analyze the age effect. Results showed untreated aged mice had marked decline of spatial learning and memory in the novel location recognition and radial six-arm water maze tasks, with decreased levels of these hormones and hippocampal H3K9ac and H4K8ac compared to young controls. The BPA treatment exacerbated age-related spatial cognitive impairment and accelerated the reduction of free thyroxine (FT4), H3K9ac, and H4K8ac, and the 100 mg/l BPA group showed more significant impact. Additionally, correlation analyses revealed that lower levels of FT4, H3K9ac, and H4K8ac were accompanied by decreased spatial memory abilities. We concluded that accelerated reduction of serum FT4 and hippocampal H3K9ac and H4K8ac might be linked to exacerbation of age-related spatial cognitive impairment due to pubertal BPA exposure.

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Preventing weight gain in African American breast cancer survivors using smart scales and activity trackers: a randomized controlled pilot study

Abstract

Purpose

This study evaluated the feasibility and preliminary efficacy of two 6-month, self-regulation interventions that focused on daily self-weighing (DSW) and used objective monitoring and tailored feedback about weight (±activity), to prevent weight gain among African American breast cancer survivors.

Methods

Participants (n = 35) were randomized to an intervention + activity monitoring (INT+), intervention (INT), or control (CON) group. Interventions included a wireless scale (±activity tracker) that transmitted objective data to a mobile app/website, emailed lessons, and tailored feedback based on objective weight (±activity data). Participants completed in-person and online assessments at baseline, 3 months, and 6 months.

Results

Ninety-four percent of participants completed assessments at 3 months, and 97 % at 6 months. Median (IQR) weight change after 6 months was −0.9 % (−4.4–0.1) in the INT+ (p = 0.075; p = 0.067 vs. CON) and −0.2 % (−4.2–1.3) in the INT groups (p = 0.463; p = 0.357 vs. CON), versus a 0.2 % (−0.7–1.7) gain in the CON group. The proportion of INT+, INT, and CON participants that were at or below baseline weight was 72.7, 53.8, and 45.5 %, respectively (effect sizes d = 0.64, d = 0.18). Most INT+ participants weighed and wore trackers ≥5 days/week (INT+, 81.9 % vs. INT, 38.5 % vs. CON, 0 %; p < 0.0005; INT+, 72.7 %). Both intervention groups perceived DSW as positive, and 100 % would recommend the program to other breast cancer survivors.

Conclusion

An intervention focused on DSW as a self-monitoring strategy shows promise for preventing weight gain in breast cancer survivors.

Implications for cancer survivors

Daily self-monitoring of weight and activity may be a feasible and accessible approach to promote weight gain prevention in breast cancer survivors.

Clinical trial registration

ClinicalTrials.gov, NCT02030353

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Issue Information – UICC

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Issue Information – Table of Contents

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Issue Information – Information for Authors

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An initial report on the intraoperative use of indocyanine green fluorescence imaging in the surgical management of liver tumorss

Background

There has been a recent interest in the use of Indocyanine green (ICG) imaging. The aim of this study is to review our initial experience in liver surgery.

Methods

ICG fluorescent imaging was used in 15 patients undergoing surgical treatment of their liver tumors between 2015 and 2016. ICG imaging was initially performed, followed by intraoperative ultrasound (IOUS). Findings on fluorescence were compared with preoperative cross-sectional imaging and IOUS.

Result

Sixty-two lesions were identified, with 34 located superficially and 28 deeply in the liver. While 13 patients underwent surgery for malignant liver metastases, two patients had operations for benign liver diseases. Seven patients underwent open or robotic liver resections, five laparoscopic microwave liver ablation, and three diagnostic laparoscopy. ICG identified all of the superficial lesions. IOUS identified 98% of all lesions. The most benefit of ICG was in showing the margins of the superficial lesions in real-time and guiding surgical treatment, which was limited by IOUS.

Conclusion

This is the first North American study to evaluate the potential utility of ICG during liver surgery. Its major benefit seems to be in providing real-time feedback to the surgeon about the margins of superficial tumors for resection or ablation. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Estimation of Mineral and Trace Element Profile in Bubaline Milk Affected with Subclinical Mastitis

Abstract

The milk samples from buffaloes of Murrah breed at mid lactation stage, reared at an organised dairy farm, were screened for subclinical mastitis based on bacteriological examination and somatic cell count following International Dairy Federation criteria. Milk samples from subclinical mastitis infected and healthy buffaloes were analysed to evaluate physicochemical alterations in terms of protein, fat, pH, electrical conductivity, chloride, minerals (sodium, potassium and calcium) and trace elements (iron, zinc, copper and selenium). In the present study, protein, fat, zinc, iron, calcium and selenium content was significantly lower (P < 0.001), while pH and electrical conductivity were significantly higher in mastitic milk as compared to normal milk. Concentration of electrolytes mainly sodium and chloride significantly increased with higher somatic cell count in mastitic milk and to maintain osmolality; potassium levels decreased proportionately. Correlation matrix revealed significantly positive interdependences of somatic cell count with pH, electrical conductivity, sodium and chloride. However, protein, fat, calcium and potassium were correlated negatively with elevated somatic cell count in mastitic milk. It is concluded that udder infections resulting in elevated somatic cells may alter the mineral and trace element profile of milk, and magnitude of changes may have diagnostic and prognostic value.

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LINC00312 inhibits the migration and invasion of bladder cancer cells by targeting miR-197-3p

Abstract

To investigate the influence of the long non-coding RNA LINC00312 on bladder cancer (BC) cell invasion and metastasis by targeting miR-197-3p. BC and corresponding adjacent tissues were collected. LINC00312 and miR-197-3p were measured, and their correlation was detected through quantitative real-time PCR (qRT-PCR). BC cell line T24 was transfected and grouped (five groups) according to different transfection conditions. A scratch test was applied to analyze cell migration, and a Transwell assay was used to test cell invasion ability. Western blotting was to measure matrix metalloproteinase (MMP)-2, MMP-9, and the tissue inhibitor of metalloproteinase 2 (TIMP2) protein levels. qRT-PCR indicated that LINC00312 expression was lower but miR-197-3p expression was higher in BC tissues compared with adjacent tissues; LINC00312 was negatively correlated with miR-197-3p. The migration test revealed that the downregulation of miR-197-3p and overexpression of LINC00312 inhibited cell migration and invasion abilities, while the overexpression of miR-197-3p and the upregulation of LINC00312 promoted cell migration and invasion. BC cells with downregulated miR-197-3p or upregulated LINC00312 had low MMP-2 and MMP-9 levels but high TIMP2. LINC00312 inhibited BC cell invasion and metastasis through mediating miR-197-3p.

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Reevaluating stereotactic radiosurgery for glioblastoma: new potential for targeted dose-escalation

Abstract

Countless therapeutic strategies have been explored over many decades to prevent or slow the progression of glioblastoma. Despite radical changes in radiation management in other malignancies, there have been no major advances in the radiotherapeutic approach to glioblastoma in over 30 years. Past hopes to overcome inherent radioresistance with escalating doses have been met with frustration. However, prior clinical trials were performed before temozolomide, a radiosensitizer, altered the standard of care and this has renewed interest in dose escalation. Immunotherapy has led to further excitement, given the substantial responses that have been observed in other cancers when combined with high-dose radiation. In addition, advances in molecular profiling and neuroimaging have created new opportunities to improve patient selection for the most appropriate course of treatment. In this review, we outline past attempts to utilize radiosurgery in glioblastoma and focus on the potential to reintroduce this modality of dose escalation in the setting of modern and emerging systemic agents, molecular studies and imaging analyses.

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Differential receptor dependencies: expression and significance of muscarinic M1 receptors in the biology of prostate cancer.

Recent reports on acetylcholine muscarinic receptor subtype 3 (CHRM3) have shown its growth-promoting role in prostate cancer. Additional studies report the proliferative effect of the cholinergic agonist carbachol on prostate cancer by its agonistic action on CHRM3. This study shows that the type 1 acetylcholine muscarinic receptor (CHRM1) contributes toward the proliferation and growth of prostate cancer. We used growth and cytotoxic assays, the prostate cancer microarray database and CHRM downstream pathways' homology of CHRM subtypes to uncover multiple signals leading to the growth of prostate cancer. Growth assays showed that pilocarpine stimulates the proliferation of prostate cancer. Moreover, it shows that carbachol exerts an additional agonistic action on nicotinic cholinergic receptor of prostate cancer cells that can be blocked by tubocurarine. With the use of selective CHRM1 antagonists such as pirenzepine and dicyclomine, a considerable inhibition of proliferation of prostate cancer cell lines was observed in dose ranging from 15-60 [micro]g/ml. The microarray database of prostate cancer shows a dominant expression of CHRM1 in prostate cancer compared with other cholinergic subtypes. The bioinformatics of prostate cancer and CHRM pathways show that the downstream signalling include PIP3-AKT-CaM-mediated growth in LNCaP and PC3 cells. Our study suggests that antagonism of CHRM1 may be a potential therapeutic target against prostate cancer. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Ameliorative effect of kolaviron, a biflavonoid complex from Garcinia kola seeds against scopolamine-induced memory impairment in rats: role of antioxidant defense system

Abstract

In Alzheimer's disease (AD) basal forebrain cholinergic neurons appear to be targeted primarily in early stages of the disease. Scopolamine (muscarinic receptor antagonist) has been used for decades to induce working and reference memory impairment in rodents. In this study, we evaluated the protective effect of kolaviron, a biflavonoid complex isolated from Garcinia kola seeds extract against scopolamine-induced memory impairment/oxidative stress. Rats were pretreated with kolaviron (25, 50 or 100 mg/kg p.o.) for 3 consecutive days, scopolamine (3 mg/kg, i.p.) was administered 1 h post-treatment on day 3. Five minutes post-scopolamine injection, memory function was assessed using the Y-maze or Morris water maze tests (MWM) in rats. The rats were sacrificed and brains isolated on the 8th day after the MWM test for estimation of acetylcholinesterase activity and nitrosative/oxidative stress status. Scopolamine injection induced deficit (P < 0.05) in percentage alternation behaviour in the Y-maze test indicating memory impairment which was ameliorated by kolaviron in a dose-dependent manner. Also, pre-training treatment with kolaviron significantly improved spatial learning evidenced in the session-dependent and more efficient localization of the hidden platform in the MWM test. Moreover, scopolamine injection induced significant increase in lipid peroxidation (prefrontal cortex), nitrite generation (striatum and hippocampus) and a decrease in glutathione (prefrontal cortex, striatum and hippocampus) and superoxide dismutase (striatum and hippocampus) level which was attenuated by kolaviron pre-treatment. These findings showed that kolaviron possesses cognition enhancing effect through enhancement of antioxidant defense and cholinergic systems.

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