Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation

Abstract

Purpose

Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC).

Methods

117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed.

Results

Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5–11.6) vs 5.0 (4.2–5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8–12.9) vs. 5.8 (4.8–6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5–24.1) vs. 7.8 (5.2–10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation.

Conclusions

MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

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Metronomic capecitabine as second-line treatment for hepatocellular carcinoma after sorafenib discontinuation

Abstract

Purpose

Metronomic capecitabine (MC) is a well-tolerated systemic treatment showing promising results in one retrospective study, as second-line therapy after sorafenib failure, in patients with hepatocellular carcinoma (HCC).

Methods

117 patients undergoing MC were compared to 112 patients, eligible for this treatment, but undergoing best supportive care (BSC) after sorafenib discontinuation for toxicity or HCC progression. The two groups were compared for demographic and clinical features. A multivariate regression analysis was conducted to detect independent prognostic factors. To balance confounding factors between the two groups, a propensity score model based on independent prognosticators (performance status, neoplastic thrombosis, causes of sorafenib discontinuation and pre-sorafenib treatment) was performed.

Results

Patients undergoing MC showed better performance status, lower tumor burden, lower prevalence of portal vein thrombosis, and better cancer stage. Median (95% CI) post-sorafenib survival (PSS) was longer in MC than in BSC patients [9.5 (7.5–11.6) vs 5.0 (4.2–5.7) months (p < 0.001)]. Neoplastic thrombosis, cause of sorafenib discontinuation, pre-sorafenib treatment and MC were independent prognosticators. The benefit of capecitabine was confirmed in patients after matching with propensity score [PSS: 9.9 (6.8–12.9) vs. 5.8 (4.8–6.8) months, (p = 0.001)]. MC lowered the mortality risk by about 40%. MC achieved better results in patients who stopped sorafenib for adverse events than in those who progressed during it [PSS: 17.3 (10.5–24.1) vs. 7.8 (5.2–10.1) months, (p = 0.035)]. Treatment toxicity was low and easily manageable with dose modulation.

Conclusions

MC may be an efficient and safe second-line systemic therapy for HCC patients who discontinued sorafenib for toxicity or tumor progression.

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Comparison of TIVA with different combinations of ketamine–propofol mixtures in pediatric patients

Abstract

Purpose

Adding ketamine to propofol has been suggested to be useful for sedation and general anesthesia. This study aimed to determine the effect of TIVA with different ratios of ketofol on recovery in children.

Methods

Seventy-five children aged 3–12 years and undergoing adenoidectomy and/or tonsillectomy surgery were randomized into three groups. Ratios of 1:5, 1:6.7 and 1:10 ketamine–propofol mixture (ketofol) were prepared in the same syringe for groups I, II and III, respectively. Induction and maintenance of anesthesia were performed with 1:5, 1:6.7 and 1:10 ratios of ketofol in groups I, II and III, respectively. A McFarlan infusion dose regimen was used (15 mg/kg/h for 15 min, 13 mg/kg/h for 15 min, 11 mg/kg/h for 30 min) and infusion rates were decreased for the different ratios. Infusion rates were reduced to 67, 80 and 90% of the McFarlan dose regimen for groups I, II and III, respectively. Extubating time, length of stay in PACU, postoperative PAED and FLACC scores were recorded.

Results

Extubating time was significantly lower [mean 254.3 ± 92.7 s (95% CI 216.6–292.6, p = 0.001)] in group III than in groups I and II [371.3 ± 153 s (308.1–434.48) and 343.2 ± 123.7 s (292.2–394.3), respectively]. Length of stay in the PACU was lower in group III [median 15 min (interquartile range 15–20, p = 0.001)] than in groups I and II: 20 (15–27.5) and 20 min (20–27.5), respectively.

Conclusion

TIVA with a 1:10 ratio of ketofol admixture with a 90% reduction of McFarlan regimen can provide improved recovery conditions.

Trial registration

ClinicalTrials.gov identifier: NCT02848963.

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Human c-SRC kinase (CSK) overexpression makes T cells dummy

Abstract

Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide–MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regulator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Downstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis). Therefore, co-expression of CSK with a therapeutic TCR did not compromise target recognition and binding, but rendered T cells incapable of executing their effector functions. Consequently, we named these redirected T cells "dummy T cells" and propose to use them for safety validation of new TCRs prior to therapy.

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E-cadherin: Its dysregulation in carcinogenesis and clinical implications

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Sonia How Ming Wong, Chee Mun Fang, Lay-Hong Chuah, Chee Onn Leong, Siew Ching Ngai
E-cadherin is a transmembrane glycoprotein which connects epithelial cells together at adherens junctions. In normal cells, E-cadherin exerts its tumour suppressing role mainly by sequestering β-catenin from its binding to LEF (Lymphoid enhancer factor)/TCF (T cell factor) which serves the function of transcribing genes of the proliferative Wnt signaling pathway. Despite the ongoing debate on whether the loss of E-cadherin is the cause or effect of epithelial-mesenchymal transition (EMT), E-cadherin functional loss has frequently been associated with poor prognosis and survival in patients of various cancers. The dysregulation of E-cadherin expression that leads to carcinogenesis happens mostly at the epigenetic level but there are cases of genetic alterations as well. E-cadherin expression has been linked to the cellular functions of invasiveness reduction, growth inhibition, apoptosis, cell cycle arrest and differentiation. Studies on various cancers have shown that these different cellular functions are also interdependent. Recent studies have reported a rapid expansion of E-cadherin clinical relevance in various cancers. This review article summarises the multifaceted effect E-cadherin expression has on cellular functions in the context of carcinogenesis as well as its clinical implications in diagnosis, prognosis and therapeutics.



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Epigenetic regulation of the Hedgehog and Wnt pathways in cancer

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Leon J Wils, Maarten F Bijlsma
The Hedgehog (Hh) and wingless-Int1 (Wnt) pathways are important for tissue patterning in the developing embryo. In adult tissue, both pathways are typically dormant but are activated under certain conditions such as tissue damage. Aberrant activation of these pathways by mutations in key pathway regulators contributes to the genesis and progression of several cancer types. In addition, the impact of epigenetic regulation of the Hh and Wnt pathways on cancer is becoming increasingly clear. In this review, current knowledge on the epigenetic control of Hh and Wnt and the impact on tumor formation will be discussed. First, the role of epigenetic control on ligand production will be discussed, followed by the epigenetic regulation of the extra– and intracellular pathway members. Furthermore, the epigenetic control of pathway target genes will be highlighted. Lastly, an overview of current therapeutic strategies to target aberrant epigenetic control of the Hh and Wnt pathways is provided.



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Systematic review and survival meta-analysis of real world evidence on first-line pazopanib for metastatic renal cell carcinoma

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Miguel A. Climent, José Muñoz-Langa, Laura Basterretxea-Badiola, Carmen Santander-Lobera
A systematic review was conducted to identify real world studies reporting outcomes after first-line pazopanib in patients with metastatic renal cell carcinoma. Studies had to be observational and report survival data in terms of progression-free survival and overall survival in order to conduct meta-analysis techniques. These real-world data were compared to those obtained in the phase II and III randomized controlled trials of pazopanib. Real world evidence showed that the clinical and safety outcomes were consistent with those observed in the clinical trials despite the inclusion of unselected patients with a wide spectrum of prognostic features and comorbidities. Similarly to the results of the pivotal studies, good prognosis patients had the most benefit from pazopanib. Further investigation is needed to complement evidence from clinical trials, in particular focused on patient-centered outcomes.



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Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review

Publication date: Available online 23 November 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Marion Savina, Sophie Gourgou, Antoine Italiano, Derek Dinart, Virginie Rondeau, Nicolas Penel, Simone Mathoulin-Pelissier, Carine Bellera
BackgroundIn cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. We aimed at identifying meta-analyses evaluating surrogate endpoints and assessing the strength of evidence for each study.Materials and methodsWe performed a systematic review to identify meta-analyses of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema.Results53 publications reported on 164 meta-analyses, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival showed good surrogacy properties for OS in colorectal cancer, lung cancer and head and neck cancer. DFS was also highly correlated to OS in gastric cancer.Conclusion(s)Clinical settings with validated surrogate endpoints for OS remain limited. Harmonization of the statistical methodology used to evaluate surrogate endpoints is required.



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A review of the literature on the relationships between genetic polymorphisms and chemotherapy-induced nausea and vomiting

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Komal P. Singh, Anand A. Dhruva, Elena Flowers, Kord M. Kober, Christine Miaskowski
Despite current advances in antiemetic treatments, between 30% to and 60% of oncology patients experience chemotherapy-induced nausea (CIN) and 13% to 33% report chemotherapy-induced vomiting (CIV). Inter-individual differences are observed in the occurrence and severity of chemotherapy-induced nausea and vomiting (CINV). This review summarizes and critiques studies on associations between occurrence and severity of CINV and polymorphisms in serotonin receptor, drug metabolism, and drug transport pathway genes. Sixteen studies evaluated the associations between the occurrence and/or severity of CINV and single nucleotide polymorphisms (SNPs). Across these studies, three SNPs in 5-hydroxytryptamine receptor (5-HT3R) genes, two alleles of the cytochrome P450 family 2 subfamily D member 6 (CYP2D6) gene, and three SNPs in ATP binding cassette subfamily B member 1 (ABCB1) gene were associated with the occurrence and severity of CINV. Given the limited number of polymorphisms evaluated, additional research is warranted to identify new mechanisms to develop more targeted therapies.



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Anti-hypertensive drugs and skin cancer risk: a review of the literature and meta-analysis

Publication date: February 2018
Source:Critical Reviews in Oncology/Hematology, Volume 122
Author(s): Sara Gandini, Domenico Palli, Giuseppe Spadola, Benedetta Bendinelli, Emilia Cocorocchio, Ignazio Stanganelli, Lucia Miligi, Giovanna Masala, Saverio Caini
IntroductionSeveral anti-hypertensive drugs have photosensitizing properties, however it remains unclear whether long-term users of these drugs are also at increased risk of skin malignancies. We conducted a literature review and meta-analysis on the association between use of anti-hypertensive drugs and the risk of cutaneous melanoma and non-melanoma skin cancer (NMSC).MethodsWe searched PubMed, EMBASE, Google Scholar and the Cochrane Library, and included observational and experimental epidemiological studies published until February 28th, 2017. We calculated summary relative risk (SRR) and 95% confidence intervals (95% CI) through random effect models to estimate the risk of skin malignancies among users of the following classes of anti-hypertensive drugs: thiazide diuretics, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB) and β-blockers. We conducted sub-group and sensitivity analysis to explore causes of between-studies heterogeneity, and assessed publication bias using a funnel-plot based approach.ResultsNineteen independent studies were included in the meta-analysis. CCB users were at increased skin cancer risk (SRR 1.14, 95% CI 1.07–1.21), and β-blockers users were at increased risk of developing cutaneous melanoma (SRR 1.21, 95% CI 1.05–1.40), with acceptable between-studies heterogeneity (I² < 50%). There was no association between thiazide diuretics, ACEi or ARB use and skin cancer risk. We found no evidence of publication bias affecting the results.ConclusionFamily doctors and clinicians should inform their patients about the increased risk of skin cancer associated with the use of CCB and β-blockers and instruct them to perform periodic skin self-examination. Further studies are warranted to elucidate the observed associations.



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Long-term toxicity of the treatment for germ cell-cancer. A review

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): P. Maroto, G. Anguera, C. Martin
Testicular germ-cell cancer (GCC) is a curable disease. Stage I patients are mostly cured by surgery alone. For those with good prognosis advanced disease, radiotherapy in some patients with stage II Seminoma and chemotherapy for all other patients, are responsible for 95% of long-term survivors. Unfortunately, despite this high level of curability, overall survival has been reported lower for those patients receiving either radiotherapy or chemotherapy versus patients treated by surgery alone. Long-term survivors face a higher incidence of second neoplasms, and a higher risk of cardiovascular disease and metabolic syndrome than expected. Other non-life-threatening toxicities such as ototoxicity, neurotoxicity and fertility problems are common. This paper reviews the potential causes of the higher mortality among long-term survivors of testicular tumors, the incidence of them and some recommendations for the diagnoses and prevention of long-term sequelae in patients with GCC.



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The relationship between body mass index and short term postoperative outcomes in patients undergoing potentially curative surgery for colorectal cancer: A systematic review and meta-analysis

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Arwa S. Almasaudi, Stephen T. McSorley, Christine A. Edwards, Donald C. McMillan
BackgroundThe prevalence of obesity has increased worldwide over the last few decades, and is a well-recognized risk factor for colorectal cancer. Surgical site infection is the most frequent complication following surgery for colorectal cancer, and the main cause of postoperative morbidity. The aim of the present systematic review and meta-analysis was to examine the relationship between increasing BMI and postoperative surgical site infection following surgery for colorectal cancer.MethodsA systemic literature search was conducted using Medline, PubMed, Embase (Ovid) and Web of Science databases from inception to the end of August 2016. Studies examining the relationship between obesity and surgical site infection following surgery for colorectal cancer were included. Analysis of the data was performed using Review Manager version 5.3(The Nordic Cochrane Centre, The Cochrane Collaboration, Copen-hagen, Denmark,)ResultsIn this meta-analysis, a total of 9535 patients from 16 studies were included. BMI <30 vs ≥30kg/m² was used to examine the association of obesity and surgical site infection in patients from Western countries. The estimated pooled OR demonstrated that obesity increased the risk of surgical site infection by approximately 100% (OR=2.13; 95% CI 1.66-2.72, p<0.001).BMI <25 vs ≥25kg/m² was used to examine the association of obesity and surgical site infection from Asian countries. The estimated pooled OR demonstrated that obesity increased the risk of surgical site infection by approximately 60% (OR=1.63; 95% CI 1.29-2.06, p<0.001). There was little evidence of publication bias in the meta-analysis.ConclusionFrom this systematic review and meta-analysis there was good evidence that obesity was associated with a significantly higher risk of developing surgical site infection following surgery for colorectal cancer in both ethnic groups. The magnitude of the effect warrants further investigation.



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A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Gordon Cook, Sonja Zweegman, María-Victoria Mateos, Florence Suzan, Philippe Moreau
Multiple classes of agent with distinct mechanisms of action are now available for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM), including immunomodulatory agents, proteasome inhibitors, histone deacetylase inhibitors and monoclonal antibodies. Additionally, several different drugs may be available within each agent class, each with their own specific efficacy and safety profile. This expansion of the treatment landscape has dramatically improved outcomes for patients. However, as the treatment options for RRMM become more complex, choosing the class of agent or combination of agents to use in the relapsed setting becomes increasingly challenging. Furthermore, treatment options for specific patient populations such as the elderly, those with high-risk cytogenetic abnormalities and those with refractory disease are yet to be defined in the current treatment landscape. When choosing an appropriate treatment approach, physicians must consider multiple criteria including both patient-related and disease-related factors. The aim should be to provide patient-specific treatment in order to gain a clinical benefit while minimizing toxicity. This review provides an overview of the mechanism of action and efficacy and safety profiles of each class of agent and of treatment regimens that combine different classes of agent, with a special focus on treating specific patient populations.



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The Therapeutic use of human albumin in cancer patients’ management

Publication date: December 2017
Source:Critical Reviews in Oncology/Hematology, Volume 120
Author(s): Elissar Moujaess, May Fakhoury, Tarek Assi, Hanine Elias, Fadi El Karak, Marwan Ghosn, Joseph Kattan
Human albumin (HA) has been widely used in clinical practice due to its unique physiological characteristics and pharmacokinetics. However, with the absence of clear institutional recommendations, its uncontrolled prescription remains largely controversial. An extensive review on the albumin chemistry, pharmacology, physiology and pathology was performed, and data on commercially available HA, its cost, medical usage and the related available guidelines, particularly in oncology patients were gathered.Studies assessing the appropriate use and safety of HA in cancer patients are lacking. A retrospective survey of the appropriateness of HA infusions according to the SIMTI guidelines (2009) was performed in our department. Among 53 patients who received HA infusions, only 5.7% of the indications were appropriate for HA administration. Occasionally appropriate and inappropriate indications were considered in 10% and 84.3% of the prescriptions respectively with a relatively high cost. The adoption of strict guidelines may substantially reduce the inappropriate use and the subsequent healthcare costs.



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Physical activity reduces fatigue in patients with cancer and hematopoietic stem cell transplant recipients: A systematic review and meta-analysis of randomized trials

Publication date: Available online 16 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Sapna Oberoi, Paula D. Robinson, Danielle Cataudella, Nicole Culos-Reid, Hailey Davis, Nathan Duong, Faith Gibson, Miriam Götte, Pamela Hinds, Sanne L Nijhof, Deborah Tomlinson, Patrick van der Torre, Sandra Cabral, LLee Dupuis, Lillian Sung
PurposeObjective was to determine whether physical activity reduces the severity of fatigue in patients with cancer or hematopoietic stem cell transplant (HSCT) recipients.MethodsWe conducted a meta-analysis of randomized trials comparing physical activity with control interventions for the management of fatigue in patients with cancer or HSCT recipients.ResultsThere were 170 trials included. Physical activity reduced the severity of fatigue when compared to all control groups (standardized mean difference −0.49, 95% confidence interval −0.60 to −0.37; P < 0.00001). Aerobic, neuromotor, resistance and combination exercises were all effective in reducing fatigue although smaller effects were observed with resistance exercises (P interaction = 0.01). Other intervention and patient characteristics did not influence the effect of physical activity on the severity of fatigue.ConclusionsPhysical activity was effective at reducing fatigue in patients with cancer and HSCT recipients across patient sub-groups. Determining the best approaches for safe implementation should be a priority.



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The role of Stereotactic body radiotherapy (SBRT) in reirradiation of Head and Neck cancer recurrence

Publication date: Available online 15 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): A. Román A., C. Jodar, A. Perez-Rozos, Y. Lupiañez-Perez, JA Medina, J. Gomez-Millan
IntroductionHead and neck cancer recurrence is a therapeutic challenge due to the anatomical and functional constraints of the head and neck area. Stereotactic body radiotherapy (SBRT) is a high-precision technique of radiotherapy that consists of delivering a high ablative biological dose in 1–5 high-dose fractions, requiring a very high precision of the radiotherapy process with potential application in this clinical setting.MethodsDifferent studies that investigate the role of SBRT in the treatment of recurrent head and neck cancer have been reviewed. Indications to properly select patients for this treatment are presented.ResultsRetrospective studies and phase I–II trials with selected patients have shown low to moderate toxicity, with an efficacy at least similar to that of treatment with combinations of radiotherapy and chemotherapy. In selected patients, SBRT is a treatment option for recurrent head and neck cancer with low toxicity.DiscussionNew prospective studies should clarify data regarding the efficacy and toxicity of SBRT in head and neck cancer recurrence.



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Publishers Note - Tribute to Matti

Publication date: Available online 14 December 2017
Source:Critical Reviews in Oncology/Hematology





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Systemic treatment in adult uterine sarcomas

Publication date: Available online 14 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): I.M.E. Desar, P.B. Ottevanger, C. Benson, W.T.A. van der Graaf
Uterine sarcomas (US) are rare mesenchymal tumours of the uterus and are divided mainly into uterine leiomyosarcoma (uLMS), low grade endometrial stromal sarcoma (LG-ESS), high grade endometrial stromal sarcoma (HG-ESS), adenosarcomas and high grade undifferentiated sarcoma (HGUS). US are often high-grade tumours with a high local recurrence rate and metastatic risk. We here discuss the current standard of care and knowledge of systemic therapy for adult uterine sarcomas, in particular uLMS, LG-ESS, HG-ESS and HGUS, in both the adjuvant as well as the metastatic setting.



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Protective effects of curcumin against doxorubicin-induced toxicity and resistance: a review

Publication date: Available online 14 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Mohammad Mohajeri, Amirhossein Sahebkar
Doxorubicin (DOX)-induced toxicity and resistance are major obstacles in chemotherapeutic approaches. Despite effective in the treatment of numerous malignancies, some clinicians have voiced concern that DOX has the potential to cause debilitating consequences in organ tissues, especially the heart. The mechanisms of toxicity and resistance are respectively related to induction of reactive oxygen species (ROS) and up-regulation of ATP-binding cassette (ABC) transporter. Curcumin (CUR) with several biological and pharmacological properties is expected to restore DOX-mediated impairments to tissues. This review is intended to address the current knowledge on DOX adverse effects and CUR protective actions in the heart, kidneys, liver, brain, and reproductive organs. Coadministration of CUR and DOX is capable of ameliorating DOX toxicity pertained to antioxidant, apoptosis, autophagy, and mitochondrial permeability.



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An attempt to conceptualize the individual onco-functional balance: why a standardized treatment is an illusion for diffuse low-grade glioma patients

Publication date: Available online 13 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Emmanuel Mandonnet, Hugues Duffau
In the era of evidence-based medicine, clinicians aim to establish standards of care from randomized studies. Following, personalized medicine has emerged, as new individualized biomarkers could help to predict sensitivity to specific treatment.In this paper, we show that, for diffuse low-grade glioma, some specificities – dual goal of both survival and functional gain, long duration of the disease with multistep treatments, multiparametric evaluation of the onco-functional balance of each treatment modality – call for a change of paradigm. After summarizing how to weight the benefits and risks of surgery, chemotherapy and radiotherapy, we show that the overall efficacy of a treatment modality cannot be assessed per se, as it depends on its integration in the whole sequence. Then, we revisit the notion of personalized medicine: instead of decision-making based solely on molecular profile, we plead for a recursive algorithm, allowing a dynamic evaluation of the onco-functional balance, integrating many individual characteristics of the patient's tumor and brain function.



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Continuity and diversity

Publication date: Available online 7 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Matti Aapro




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Editorial Board

Publication date: December 2017
Source:Critical Reviews in Oncology/Hematology, Volume 120





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Mind and body practices for fatigue reduction in patients with cancer and hematopoietic stem cell transplant recipients: A systematic review and meta-analysis

Publication date: December 2017
Source:Critical Reviews in Oncology/Hematology, Volume 120
Author(s): Nathan Duong, Hailey Davis, Paula D. Robinson, Sapna Oberoi, Danielle Cataudella, S. Nicole Culos-Reed, Faith Gibson, Miriam Götte, Pamela Hinds, Sanne L. Nijhof, Deborah Tomlinson, Patrick van der Torre, Elena Ladas, Sandra Cabral, L. Lee Dupuis, Lillian Sung
PurposeTo determine whether non-physical activity mind and body practices reduce the severity of fatigue in patients with cancer or hematopoietic stem cell transplant (HSCT) recipients compared to control interventions.MethodsWe included randomized trials which compared non-physical activity mind and body practices compared with control interventions for the management of fatigue in cancer and HSCT patients.ResultsAmong 55 trials (4975 patients), interventions were acupuncture or acupressure (n=12), mindfulness (n=11), relaxation techniques (n=10), massage (n=6), energy therapy (n=5), energizing yogic breathing (n=3) and others (n=8). When combined, all interventions significantly reduced fatigue severity compared to all controls (standardized mean difference −0.51, 95% confidence interval −0.73 to −0.29). More specifically, mindfulness and relaxation significantly reduced fatigue severity.ConclusionsMindfulness and relaxation were effective at reducing fatigue severity in patients with cancer and HSCT recipients. Future studies should evaluate how to translate these findings into clinical practice across different patient groups.



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Human c-SRC kinase (CSK) overexpression makes T cells dummy

Abstract

Adoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide–MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on correct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the majority of the adverse events are due to TCR recognition of the wrong target, we tested if blocking the signalling would affect the binding. By over-expressing the c-SRC kinase (CSK), a negative regulator of LCK, in redirected T cells, we showed that peripheral blood T cells inhibited anti-CD3/anti-CD28-induced phosphorylation of ERK, whereas TCR proximal signalling was not affected. Similarly, overexpression of CSK together with a therapeutic TCR prevented pMHC-induced ERK phosphorylation. Downstream effector functions were also almost completely blocked, including pMHC-induced IL-2 release, degranulation and, most importantly, target cell killing. The lack of effector functions contrasted with the unaffected TCR expression, pMHC recognition, and membrane exchange activity (trogocytosis). Therefore, co-expression of CSK with a therapeutic TCR did not compromise target recognition and binding, but rendered T cells incapable of executing their effector functions. Consequently, we named these redirected T cells "dummy T cells" and propose to use them for safety validation of new TCRs prior to therapy.

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E-cadherin: Its dysregulation in carcinogenesis and clinical implications

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Sonia How Ming Wong, Chee Mun Fang, Lay-Hong Chuah, Chee Onn Leong, Siew Ching Ngai
E-cadherin is a transmembrane glycoprotein which connects epithelial cells together at adherens junctions. In normal cells, E-cadherin exerts its tumour suppressing role mainly by sequestering β-catenin from its binding to LEF (Lymphoid enhancer factor)/TCF (T cell factor) which serves the function of transcribing genes of the proliferative Wnt signaling pathway. Despite the ongoing debate on whether the loss of E-cadherin is the cause or effect of epithelial-mesenchymal transition (EMT), E-cadherin functional loss has frequently been associated with poor prognosis and survival in patients of various cancers. The dysregulation of E-cadherin expression that leads to carcinogenesis happens mostly at the epigenetic level but there are cases of genetic alterations as well. E-cadherin expression has been linked to the cellular functions of invasiveness reduction, growth inhibition, apoptosis, cell cycle arrest and differentiation. Studies on various cancers have shown that these different cellular functions are also interdependent. Recent studies have reported a rapid expansion of E-cadherin clinical relevance in various cancers. This review article summarises the multifaceted effect E-cadherin expression has on cellular functions in the context of carcinogenesis as well as its clinical implications in diagnosis, prognosis and therapeutics.



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Epigenetic regulation of the Hedgehog and Wnt pathways in cancer

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Leon J Wils, Maarten F Bijlsma
The Hedgehog (Hh) and wingless-Int1 (Wnt) pathways are important for tissue patterning in the developing embryo. In adult tissue, both pathways are typically dormant but are activated under certain conditions such as tissue damage. Aberrant activation of these pathways by mutations in key pathway regulators contributes to the genesis and progression of several cancer types. In addition, the impact of epigenetic regulation of the Hh and Wnt pathways on cancer is becoming increasingly clear. In this review, current knowledge on the epigenetic control of Hh and Wnt and the impact on tumor formation will be discussed. First, the role of epigenetic control on ligand production will be discussed, followed by the epigenetic regulation of the extra– and intracellular pathway members. Furthermore, the epigenetic control of pathway target genes will be highlighted. Lastly, an overview of current therapeutic strategies to target aberrant epigenetic control of the Hh and Wnt pathways is provided.



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Systematic review and survival meta-analysis of real world evidence on first-line pazopanib for metastatic renal cell carcinoma

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Miguel A. Climent, José Muñoz-Langa, Laura Basterretxea-Badiola, Carmen Santander-Lobera
A systematic review was conducted to identify real world studies reporting outcomes after first-line pazopanib in patients with metastatic renal cell carcinoma. Studies had to be observational and report survival data in terms of progression-free survival and overall survival in order to conduct meta-analysis techniques. These real-world data were compared to those obtained in the phase II and III randomized controlled trials of pazopanib. Real world evidence showed that the clinical and safety outcomes were consistent with those observed in the clinical trials despite the inclusion of unselected patients with a wide spectrum of prognostic features and comorbidities. Similarly to the results of the pivotal studies, good prognosis patients had the most benefit from pazopanib. Further investigation is needed to complement evidence from clinical trials, in particular focused on patient-centered outcomes.



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Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review

Publication date: Available online 23 November 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Marion Savina, Sophie Gourgou, Antoine Italiano, Derek Dinart, Virginie Rondeau, Nicolas Penel, Simone Mathoulin-Pelissier, Carine Bellera
BackgroundIn cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. We aimed at identifying meta-analyses evaluating surrogate endpoints and assessing the strength of evidence for each study.Materials and methodsWe performed a systematic review to identify meta-analyses of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema.Results53 publications reported on 164 meta-analyses, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival showed good surrogacy properties for OS in colorectal cancer, lung cancer and head and neck cancer. DFS was also highly correlated to OS in gastric cancer.Conclusion(s)Clinical settings with validated surrogate endpoints for OS remain limited. Harmonization of the statistical methodology used to evaluate surrogate endpoints is required.



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A review of the literature on the relationships between genetic polymorphisms and chemotherapy-induced nausea and vomiting

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Komal P. Singh, Anand A. Dhruva, Elena Flowers, Kord M. Kober, Christine Miaskowski
Despite current advances in antiemetic treatments, between 30% to and 60% of oncology patients experience chemotherapy-induced nausea (CIN) and 13% to 33% report chemotherapy-induced vomiting (CIV). Inter-individual differences are observed in the occurrence and severity of chemotherapy-induced nausea and vomiting (CINV). This review summarizes and critiques studies on associations between occurrence and severity of CINV and polymorphisms in serotonin receptor, drug metabolism, and drug transport pathway genes. Sixteen studies evaluated the associations between the occurrence and/or severity of CINV and single nucleotide polymorphisms (SNPs). Across these studies, three SNPs in 5-hydroxytryptamine receptor (5-HT3R) genes, two alleles of the cytochrome P450 family 2 subfamily D member 6 (CYP2D6) gene, and three SNPs in ATP binding cassette subfamily B member 1 (ABCB1) gene were associated with the occurrence and severity of CINV. Given the limited number of polymorphisms evaluated, additional research is warranted to identify new mechanisms to develop more targeted therapies.



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Anti-hypertensive drugs and skin cancer risk: a review of the literature and meta-analysis

Publication date: February 2018
Source:Critical Reviews in Oncology/Hematology, Volume 122
Author(s): Sara Gandini, Domenico Palli, Giuseppe Spadola, Benedetta Bendinelli, Emilia Cocorocchio, Ignazio Stanganelli, Lucia Miligi, Giovanna Masala, Saverio Caini
IntroductionSeveral anti-hypertensive drugs have photosensitizing properties, however it remains unclear whether long-term users of these drugs are also at increased risk of skin malignancies. We conducted a literature review and meta-analysis on the association between use of anti-hypertensive drugs and the risk of cutaneous melanoma and non-melanoma skin cancer (NMSC).MethodsWe searched PubMed, EMBASE, Google Scholar and the Cochrane Library, and included observational and experimental epidemiological studies published until February 28th, 2017. We calculated summary relative risk (SRR) and 95% confidence intervals (95% CI) through random effect models to estimate the risk of skin malignancies among users of the following classes of anti-hypertensive drugs: thiazide diuretics, angiotensin converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB) and β-blockers. We conducted sub-group and sensitivity analysis to explore causes of between-studies heterogeneity, and assessed publication bias using a funnel-plot based approach.ResultsNineteen independent studies were included in the meta-analysis. CCB users were at increased skin cancer risk (SRR 1.14, 95% CI 1.07–1.21), and β-blockers users were at increased risk of developing cutaneous melanoma (SRR 1.21, 95% CI 1.05–1.40), with acceptable between-studies heterogeneity (I² < 50%). There was no association between thiazide diuretics, ACEi or ARB use and skin cancer risk. We found no evidence of publication bias affecting the results.ConclusionFamily doctors and clinicians should inform their patients about the increased risk of skin cancer associated with the use of CCB and β-blockers and instruct them to perform periodic skin self-examination. Further studies are warranted to elucidate the observed associations.



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Long-term toxicity of the treatment for germ cell-cancer. A review

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): P. Maroto, G. Anguera, C. Martin
Testicular germ-cell cancer (GCC) is a curable disease. Stage I patients are mostly cured by surgery alone. For those with good prognosis advanced disease, radiotherapy in some patients with stage II Seminoma and chemotherapy for all other patients, are responsible for 95% of long-term survivors. Unfortunately, despite this high level of curability, overall survival has been reported lower for those patients receiving either radiotherapy or chemotherapy versus patients treated by surgery alone. Long-term survivors face a higher incidence of second neoplasms, and a higher risk of cardiovascular disease and metabolic syndrome than expected. Other non-life-threatening toxicities such as ototoxicity, neurotoxicity and fertility problems are common. This paper reviews the potential causes of the higher mortality among long-term survivors of testicular tumors, the incidence of them and some recommendations for the diagnoses and prevention of long-term sequelae in patients with GCC.



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The relationship between body mass index and short term postoperative outcomes in patients undergoing potentially curative surgery for colorectal cancer: A systematic review and meta-analysis

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Arwa S. Almasaudi, Stephen T. McSorley, Christine A. Edwards, Donald C. McMillan
BackgroundThe prevalence of obesity has increased worldwide over the last few decades, and is a well-recognized risk factor for colorectal cancer. Surgical site infection is the most frequent complication following surgery for colorectal cancer, and the main cause of postoperative morbidity. The aim of the present systematic review and meta-analysis was to examine the relationship between increasing BMI and postoperative surgical site infection following surgery for colorectal cancer.MethodsA systemic literature search was conducted using Medline, PubMed, Embase (Ovid) and Web of Science databases from inception to the end of August 2016. Studies examining the relationship between obesity and surgical site infection following surgery for colorectal cancer were included. Analysis of the data was performed using Review Manager version 5.3(The Nordic Cochrane Centre, The Cochrane Collaboration, Copen-hagen, Denmark,)ResultsIn this meta-analysis, a total of 9535 patients from 16 studies were included. BMI <30 vs ≥30kg/m² was used to examine the association of obesity and surgical site infection in patients from Western countries. The estimated pooled OR demonstrated that obesity increased the risk of surgical site infection by approximately 100% (OR=2.13; 95% CI 1.66-2.72, p<0.001).BMI <25 vs ≥25kg/m² was used to examine the association of obesity and surgical site infection from Asian countries. The estimated pooled OR demonstrated that obesity increased the risk of surgical site infection by approximately 60% (OR=1.63; 95% CI 1.29-2.06, p<0.001). There was little evidence of publication bias in the meta-analysis.ConclusionFrom this systematic review and meta-analysis there was good evidence that obesity was associated with a significantly higher risk of developing surgical site infection following surgery for colorectal cancer in both ethnic groups. The magnitude of the effect warrants further investigation.



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A question of class: Treatment options for patients with relapsed and/or refractory multiple myeloma

Publication date: January 2018
Source:Critical Reviews in Oncology/Hematology, Volume 121
Author(s): Gordon Cook, Sonja Zweegman, María-Victoria Mateos, Florence Suzan, Philippe Moreau
Multiple classes of agent with distinct mechanisms of action are now available for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM), including immunomodulatory agents, proteasome inhibitors, histone deacetylase inhibitors and monoclonal antibodies. Additionally, several different drugs may be available within each agent class, each with their own specific efficacy and safety profile. This expansion of the treatment landscape has dramatically improved outcomes for patients. However, as the treatment options for RRMM become more complex, choosing the class of agent or combination of agents to use in the relapsed setting becomes increasingly challenging. Furthermore, treatment options for specific patient populations such as the elderly, those with high-risk cytogenetic abnormalities and those with refractory disease are yet to be defined in the current treatment landscape. When choosing an appropriate treatment approach, physicians must consider multiple criteria including both patient-related and disease-related factors. The aim should be to provide patient-specific treatment in order to gain a clinical benefit while minimizing toxicity. This review provides an overview of the mechanism of action and efficacy and safety profiles of each class of agent and of treatment regimens that combine different classes of agent, with a special focus on treating specific patient populations.



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The Therapeutic use of human albumin in cancer patients’ management

Publication date: December 2017
Source:Critical Reviews in Oncology/Hematology, Volume 120
Author(s): Elissar Moujaess, May Fakhoury, Tarek Assi, Hanine Elias, Fadi El Karak, Marwan Ghosn, Joseph Kattan
Human albumin (HA) has been widely used in clinical practice due to its unique physiological characteristics and pharmacokinetics. However, with the absence of clear institutional recommendations, its uncontrolled prescription remains largely controversial. An extensive review on the albumin chemistry, pharmacology, physiology and pathology was performed, and data on commercially available HA, its cost, medical usage and the related available guidelines, particularly in oncology patients were gathered.Studies assessing the appropriate use and safety of HA in cancer patients are lacking. A retrospective survey of the appropriateness of HA infusions according to the SIMTI guidelines (2009) was performed in our department. Among 53 patients who received HA infusions, only 5.7% of the indications were appropriate for HA administration. Occasionally appropriate and inappropriate indications were considered in 10% and 84.3% of the prescriptions respectively with a relatively high cost. The adoption of strict guidelines may substantially reduce the inappropriate use and the subsequent healthcare costs.



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Physical activity reduces fatigue in patients with cancer and hematopoietic stem cell transplant recipients: A systematic review and meta-analysis of randomized trials

Publication date: Available online 16 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Sapna Oberoi, Paula D. Robinson, Danielle Cataudella, Nicole Culos-Reid, Hailey Davis, Nathan Duong, Faith Gibson, Miriam Götte, Pamela Hinds, Sanne L Nijhof, Deborah Tomlinson, Patrick van der Torre, Sandra Cabral, LLee Dupuis, Lillian Sung
PurposeObjective was to determine whether physical activity reduces the severity of fatigue in patients with cancer or hematopoietic stem cell transplant (HSCT) recipients.MethodsWe conducted a meta-analysis of randomized trials comparing physical activity with control interventions for the management of fatigue in patients with cancer or HSCT recipients.ResultsThere were 170 trials included. Physical activity reduced the severity of fatigue when compared to all control groups (standardized mean difference −0.49, 95% confidence interval −0.60 to −0.37; P < 0.00001). Aerobic, neuromotor, resistance and combination exercises were all effective in reducing fatigue although smaller effects were observed with resistance exercises (P interaction = 0.01). Other intervention and patient characteristics did not influence the effect of physical activity on the severity of fatigue.ConclusionsPhysical activity was effective at reducing fatigue in patients with cancer and HSCT recipients across patient sub-groups. Determining the best approaches for safe implementation should be a priority.



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The role of Stereotactic body radiotherapy (SBRT) in reirradiation of Head and Neck cancer recurrence

Publication date: Available online 15 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): A. Román A., C. Jodar, A. Perez-Rozos, Y. Lupiañez-Perez, JA Medina, J. Gomez-Millan
IntroductionHead and neck cancer recurrence is a therapeutic challenge due to the anatomical and functional constraints of the head and neck area. Stereotactic body radiotherapy (SBRT) is a high-precision technique of radiotherapy that consists of delivering a high ablative biological dose in 1–5 high-dose fractions, requiring a very high precision of the radiotherapy process with potential application in this clinical setting.MethodsDifferent studies that investigate the role of SBRT in the treatment of recurrent head and neck cancer have been reviewed. Indications to properly select patients for this treatment are presented.ResultsRetrospective studies and phase I–II trials with selected patients have shown low to moderate toxicity, with an efficacy at least similar to that of treatment with combinations of radiotherapy and chemotherapy. In selected patients, SBRT is a treatment option for recurrent head and neck cancer with low toxicity.DiscussionNew prospective studies should clarify data regarding the efficacy and toxicity of SBRT in head and neck cancer recurrence.



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Publishers Note - Tribute to Matti

Publication date: Available online 14 December 2017
Source:Critical Reviews in Oncology/Hematology





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Systemic treatment in adult uterine sarcomas

Publication date: Available online 14 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): I.M.E. Desar, P.B. Ottevanger, C. Benson, W.T.A. van der Graaf
Uterine sarcomas (US) are rare mesenchymal tumours of the uterus and are divided mainly into uterine leiomyosarcoma (uLMS), low grade endometrial stromal sarcoma (LG-ESS), high grade endometrial stromal sarcoma (HG-ESS), adenosarcomas and high grade undifferentiated sarcoma (HGUS). US are often high-grade tumours with a high local recurrence rate and metastatic risk. We here discuss the current standard of care and knowledge of systemic therapy for adult uterine sarcomas, in particular uLMS, LG-ESS, HG-ESS and HGUS, in both the adjuvant as well as the metastatic setting.



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Protective effects of curcumin against doxorubicin-induced toxicity and resistance: a review

Publication date: Available online 14 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Mohammad Mohajeri, Amirhossein Sahebkar
Doxorubicin (DOX)-induced toxicity and resistance are major obstacles in chemotherapeutic approaches. Despite effective in the treatment of numerous malignancies, some clinicians have voiced concern that DOX has the potential to cause debilitating consequences in organ tissues, especially the heart. The mechanisms of toxicity and resistance are respectively related to induction of reactive oxygen species (ROS) and up-regulation of ATP-binding cassette (ABC) transporter. Curcumin (CUR) with several biological and pharmacological properties is expected to restore DOX-mediated impairments to tissues. This review is intended to address the current knowledge on DOX adverse effects and CUR protective actions in the heart, kidneys, liver, brain, and reproductive organs. Coadministration of CUR and DOX is capable of ameliorating DOX toxicity pertained to antioxidant, apoptosis, autophagy, and mitochondrial permeability.



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An attempt to conceptualize the individual onco-functional balance: why a standardized treatment is an illusion for diffuse low-grade glioma patients

Publication date: Available online 13 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Emmanuel Mandonnet, Hugues Duffau
In the era of evidence-based medicine, clinicians aim to establish standards of care from randomized studies. Following, personalized medicine has emerged, as new individualized biomarkers could help to predict sensitivity to specific treatment.In this paper, we show that, for diffuse low-grade glioma, some specificities – dual goal of both survival and functional gain, long duration of the disease with multistep treatments, multiparametric evaluation of the onco-functional balance of each treatment modality – call for a change of paradigm. After summarizing how to weight the benefits and risks of surgery, chemotherapy and radiotherapy, we show that the overall efficacy of a treatment modality cannot be assessed per se, as it depends on its integration in the whole sequence. Then, we revisit the notion of personalized medicine: instead of decision-making based solely on molecular profile, we plead for a recursive algorithm, allowing a dynamic evaluation of the onco-functional balance, integrating many individual characteristics of the patient's tumor and brain function.



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Continuity and diversity

Publication date: Available online 7 December 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Matti Aapro




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Editorial Board

Publication date: December 2017
Source:Critical Reviews in Oncology/Hematology, Volume 120





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Mind and body practices for fatigue reduction in patients with cancer and hematopoietic stem cell transplant recipients: A systematic review and meta-analysis

Publication date: December 2017
Source:Critical Reviews in Oncology/Hematology, Volume 120
Author(s): Nathan Duong, Hailey Davis, Paula D. Robinson, Sapna Oberoi, Danielle Cataudella, S. Nicole Culos-Reed, Faith Gibson, Miriam Götte, Pamela Hinds, Sanne L. Nijhof, Deborah Tomlinson, Patrick van der Torre, Elena Ladas, Sandra Cabral, L. Lee Dupuis, Lillian Sung
PurposeTo determine whether non-physical activity mind and body practices reduce the severity of fatigue in patients with cancer or hematopoietic stem cell transplant (HSCT) recipients compared to control interventions.MethodsWe included randomized trials which compared non-physical activity mind and body practices compared with control interventions for the management of fatigue in cancer and HSCT patients.ResultsAmong 55 trials (4975 patients), interventions were acupuncture or acupressure (n=12), mindfulness (n=11), relaxation techniques (n=10), massage (n=6), energy therapy (n=5), energizing yogic breathing (n=3) and others (n=8). When combined, all interventions significantly reduced fatigue severity compared to all controls (standardized mean difference −0.51, 95% confidence interval −0.73 to −0.29). More specifically, mindfulness and relaxation significantly reduced fatigue severity.ConclusionsMindfulness and relaxation were effective at reducing fatigue severity in patients with cancer and HSCT recipients. Future studies should evaluate how to translate these findings into clinical practice across different patient groups.



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The key role of extracellular vesicles in the metastatic process

Publication date: Available online 24 November 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Hongyun Zhao, Abhinav Achreja, Elisabetta Iessi, Mariantonia Logozzi, Davide Mizzoni, Rossella Di Raimo, Deepak Nagrath, Stefano Fais
Extracellular vesicles (EVs), including exosomes, have a key role in the paracrine communication between organs and compartments. EVs shuttle virtually all types of biomolecules such as proteins, lipids, nucleic acids, metabolites and even pharmacological compounds. Their ability to transfer their biomolecular cargo into target cells enables EVs to play a key role in intercellular communication that can regulate cellular functions such as proliferation, apoptosis and migration. This has led to the emergence of EVs as a key player in tumor growth and metastasis through the formation of "tumor niches" in target organs. Recent data have also been shown that EVs may transform the microenvironment of primary tumors thus favoring the selection of cancer cells with a metastatic behavior. The release of EVs from resident non-malignant cells may contribute to the metastatic processes as well. However, cancer EVs may induce malignant transformation in resident mesenchymal stem cells, suggesting that the metastatic process is not exclusively due to circulating tumor cells. In this review, we outline and discuss evidence-based roles of EVs in actively regulating multiple steps of the metastatic process and how we can leverage EVs to impair metastasis.

Graphical abstract

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Genetic host factors in Helicobacter pylori-induced carcinogenesis: Emerging new paradigms

Publication date: January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1869, Issue 1
Author(s): Michiel C. Mommersteeg, Jun Yu, Maikel P. Peppelenbosch, Gwenny M. Fuhler
Helicobacter Pylori is a gram negative rod shaped microaerophilic bacterium that colonizes the stomach of approximately half the world's population. Infection with c may cause chronic gastritis which via a quite well described process known as Correas cascade can progress through sequential development of atrophic gastritis, intestinal metaplasia and dysplasia to gastric cancer. H. pylori is currently the only bacterium that is classified as a class 1 carcinogen by the WHO, although the exact mechanisms by which this bacterium contributes to gastric carcinogenesis are still poorly understood. Only a minority of H. pylori-infected patients will eventually develop gastric cancer, suggesting that host factors may be important in determining the outcome of H. pylori infection. This is supported by a growing body of evidence suggesting that the host genetic background contributes to risk of H. pylori infection and gastric carcinogenesis. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors, H. pylori incidence and cancer. Many of these genes influence cellular pathways leading to inflammatory signaling, inflammasome formation and autophagy. In this review we summarize known carcinogenic effects of H. pylori, and discuss recent findings that implicate host genetic pattern recognition pathways in the development of gastric cancer and their relation with H. pylori.



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Long pentraxin 3: A novel multifaceted player in cancer

Publication date: January 2018
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Volume 1869, Issue 1
Author(s): Arianna Giacomini, Gaia Cristina Ghedini, Marco Presta, Roberto Ronca
Since its discovery in 1992, long pentraxin 3 (PTX3) has been characterized as soluble patter recognition receptor, a key player of the innate immunity arm with non-redundant functions in pathogen recognition and inflammatory responses. As a component of the extra-cellular matrix milieu, PTX3 has been implicated also in wound healing/tissue remodeling, cardiovascular diseases, fertility, and infectious diseases. Consequently, PTX3 levels in biological fluids have been proposed as a fluid-phase biomarker in different pathological conditions.In the last decade, experimental evidences have shown that PTX3 may exert a significant impact also on different aspects of cancer biology, including tumor onset, angiogenesis, metastatic dissemination and immune-modulation. However, it remains unclear whether PTX3 acts as a good cop or bad cop in cancer. In this review, we will summarize and discuss the scientific literature data focusing on the role of PTX3 in experimental and human tumors, including its putative translational implications.



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'Mutiny on the crown: two cases of rare cephalic malformations

The presentation and management of two bizarre congenital cephalic curiosities at the two extremes of the clinical spectrum are discussed herewith. Case 1: presented to us as a neonate with a scalp swelling mirror-imaging her head and face. The journey from clinics to wards and to the operation theatre and to her home is introspected. Case 2: presented to us as dicephalous dibrachius dipus parapagus conjoined twins. The detailed work-up of individual organ systems, the multidisciplinary approach to management and the final outcome are discussed. This is an unsolved mystery for the anatomists, paediatric surgeons, radiologists and the medical fraternity at large.

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Constrictive bronchiolitis presenting with a mixed obstructive and restrictive pattern, associated with acid reflux

A previously healthy 55-year-old woman presented with worsening dyspnoea on exertion. The patient lived at altitude, did not smoke and had no exposure to occupational or environmental toxins. Her physical examination, including pulmonary, was unremarkable. Pulmonary function tests showed forced expiratory volume in 1 s/forced vital capacity ratio 74% predicted, diffusing capacity for carbon monoxide (DLCO) 92% predicted and residual volume 213% predicted. Rheumatological workup was negative. Chest radiograph showed hyperinflation without consolidation, and high-resolution chest CT showed mosaic attenuation with air trapping on expiratory imaging. A decreasing DLCO lead to transbronchial biopsies that were inconclusive. A video-assisted thoracic surgery lung biopsy showed small airway disease suggestive of constrictive bronchiolitis. Oesophagram and a barium swallow showed a hiatal hernia with large volume gastro-oesophageal reflux to the level of the clavicles. The development of constrictive bronchiolitis in this patient was possibly secondary to hiatal hernia and silent gastroesophageal reflux disease (GERD). In the face of presumably idiopathic lung disease, clinicians should perform a GERD workup even in the absence of GERD symptoms.

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Three-vessel coronary artery aneurysmal disease complicated by multivessel thrombosis and cardiogenic shock: the saving role of intracoronary thrombolysis

The benefit of intracoronary thrombolytics in ST-elevation myocardial infarction (STEMI) is not well established. Mainstays of STEMI management include intravenous thrombolytics, percutaneous coronary interventions and surgical revascularisation. However, in cases of STEMI secondary to coronary artery aneurysmal disease (CAAD), standard treatment options may not be suitable due to high thrombus burden, perioperative risk and factors unique to each patient. Thus, STEMI management in CAAD can represent a therapeutically challenging clinical scenario. Here, we describe a patient with severe three-vessel CAAD complicated by multivessel thrombosis and cardiogenic shock for whom traditional management options including placement of haemodynamic support devices were not feasible. As an alternative measure, the patient was treated with intracoronary thrombolysis with remarkable clinical stabilisation and angiographic resolution of thrombosis. He remains clinically stable several years later without recurrent events. This case serves to demonstrate the potential lifesaving benefit of intracoronary thrombolysis in complicated multivessel CAAD.

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Necrotising soft tissue infection without systemic toxicity in a patient with rheumatoid arthritis treated with tocilizumab

A Japanese woman aged 76 years with rheumatoid arthritis treated with prednisolone and tocilizumab presented with a 2-day history of redness and pain in her right thigh. She was hospitalised with a primary diagnosis of cellulitis and antimicrobial therapy was initiated. She had been stable until the fourth day of admission, when the swelling of her right thigh rapidly worsened and demonstrated purpura; she was subsequently unable to walk because of the pain. A diagnosis of necrotising soft tissue infection (NSTI) was made and extensive debridement was performed. Over the next 4 months, additional debridement was performed four times. Her condition improved significantly and she was able to walk later. Physicians should recognise that tocilizumab can mask systemic toxicities and inflammatory findings even in severe infections. To avoid delays in diagnosis and surgical intervention, clinicians should consider NSTIs when they encounter patients treated with tocilizumab, even if it mimics cellulitis.

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Enlarging hypermetabolic nodule: benign non-functional adrenocortical adenoma

Description

A 70-year-old woman with controlled type 2 diabetes mellitus and hypertension presented for evaluation of chronic abdominal discomfort. An incidental 3.2x3.5x3 cm left adrenal mass was identified on CT. Physical examination revealed obesity stage 2 without a Cushingoid appearance and controlled hypertension with a regular heart rate. Biochemical evaluations for Cushing syndrome, primary aldosteronism and pheochromocytoma were negative. A 1-year follow-up CT of the adrenal glands with washout showed a larger left-sided adrenal mass, measuring 4.3x3.4x3 cm (figure 1A). The attenuation values of the mass were indeterminate: non-contrast, 15 Hounsfield unit (HU); portal venous, 70 HU; delayed, 42 HU; absolute washout, 51%. MRI of the abdomen confirmed the left adrenal mass (figure 1B,C). Given the rapidly increasing size, malignancy was suspected and a whole-body positron emission tomography/CT scan using 18F-fluorodeoxyglucose (18F-FDG) was performed, which demonstrated (figure 1D,E) an 18F-FDG avid adrenal mass (standardized uptake...

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HCV load as a possible prognostic factor in patients with HCV-related DLBCL

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Immune thrombocytopenia induced by vonoprazan fumarate: a single center retrospective study

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Efficacy of antithymocyte globulin as first-line treatment for aplastic anemia—a single-center experience

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On/off dropped head syndrome: A severe adverse event after prolonged treatment with MEK inhibitor

Publication date: Available online 15 December 2017
Source:European Journal of Cancer
Author(s): C. Longvert, T. Maisonobe, P. Saiag, K. Auré




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Inhibition of EGR1 inhibits glioma proliferation by targeting CCND1 promoter

Gliomas are the most common primary tumors in central nervous system. The prognosis of the patients with glioma is poor regardless of the development of therapeutic strategies. Its aggressive behavior mainly d...

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Smoldering mantle cell lymphoma

Mantle cell lymphoma (MCL) is an aggressive disease, with poor prognosis and a limited survival. However, some patients with indolent MCL can survive beyond 7~10 years. These patients remain largely asymptomat...

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Changes of liver hemodynamic and elastography parameters in patients with colorectal liver metastases receiving preoperative chemotherapy: “a note of caution”

Abstract

Background

New systemic chemotherapy agents have improved prognosis in patients with colorectal liver metastases (CLM), but some of them damage the liver parenchyma and ultimately increase postoperative morbidity and mortality after liver resection. The aims of our study were to determine the degree of hemodynamic and pathological liver injury in CLM patients receiving preoperative chemotherapy and to identify an association between these injuries and postoperative complications after liver resection.

Methods

This is a prospective descriptive study of patients with CLM receiving preoperative chemotherapy before curative liver resection from November 2013 to June 2014. All patients had preoperative elastography and hepatic hemodynamic evaluation. We analyzed clinical preoperative data and postoperative outcomes after grouping the patients by chemotherapy type, development of sinusoidal obstructive syndrome (SOS), and development of major complications.

Results

Eleven from the 20 patients included in the study received preoperative oxaliplatin-based chemotherapy (OBC). Nine patients had SOS at pathological analysis and five patients developed major complications. Patients receiving preoperative OBC had higher values of hepatic venous pressure gradient (HVPG) and developed more SOS and major complications. Patients developing SOS had higher values of HVPG and developed more major complications. Patients with major complications had higher values of HVPG, and patients with a HVPG of 5 mmHg or greater had more major complications than those under 5 mmHg (20 vs 80%, p = 0.005).

Conclusions

OBC and SOS impair liver hemodynamics in CLM patients. An increase in major complications after liver resection in these patients develops at subclinical HVPG levels.

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Contemporary management of high-grade gliomas

CNS Oncology, Ahead of Print.


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Changes of liver hemodynamic and elastography parameters in patients with colorectal liver metastases receiving preoperative chemotherapy: “a note of caution”

Abstract

Background

New systemic chemotherapy agents have improved prognosis in patients with colorectal liver metastases (CLM), but some of them damage the liver parenchyma and ultimately increase postoperative morbidity and mortality after liver resection. The aims of our study were to determine the degree of hemodynamic and pathological liver injury in CLM patients receiving preoperative chemotherapy and to identify an association between these injuries and postoperative complications after liver resection.

Methods

This is a prospective descriptive study of patients with CLM receiving preoperative chemotherapy before curative liver resection from November 2013 to June 2014. All patients had preoperative elastography and hepatic hemodynamic evaluation. We analyzed clinical preoperative data and postoperative outcomes after grouping the patients by chemotherapy type, development of sinusoidal obstructive syndrome (SOS), and development of major complications.

Results

Eleven from the 20 patients included in the study received preoperative oxaliplatin-based chemotherapy (OBC). Nine patients had SOS at pathological analysis and five patients developed major complications. Patients receiving preoperative OBC had higher values of hepatic venous pressure gradient (HVPG) and developed more SOS and major complications. Patients developing SOS had higher values of HVPG and developed more major complications. Patients with major complications had higher values of HVPG, and patients with a HVPG of 5 mmHg or greater had more major complications than those under 5 mmHg (20 vs 80%, p = 0.005).

Conclusions

OBC and SOS impair liver hemodynamics in CLM patients. An increase in major complications after liver resection in these patients develops at subclinical HVPG levels.

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Contemporary management of high-grade gliomas

CNS Oncology, Ahead of Print.


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Ibrutinib and its use in the treatment of chronic lymphocytic leukemia

Future Oncology, Ahead of Print.


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Welcome to the 14th volume of Future Oncology

Future Oncology, Volume 14, Issue 1, Page 1-3, January 2018.


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Camellia euphlebia exerts its antidepressant-like effect via modulation of the hypothalamic-pituitary-adrenal axis and brain monoaminergic systems

Abstract

Camellia euphlebia (family, Theaceae) is a Chinese folk medicine, known for its multiple pharmacological properties. The present study aimed to provide further insights into the therapeutic basis of C. euphlebia using several animal behavioral tests and physiological indexes. Tail suspension test, forced swimming test, open-field test, chronic unpredictable mild stress (CUMS), reversal of reserpine-induced hypothermia and palpebral ptosis, and 5-hydroxytryptophane-induced head-twitch response were used to evaluate the antidepressant effect of aqueous extract of Camellia euphlebia (AEC) on mice. The possible underlying mechanism was explored by investigating the changes associated with several parameters of animal behavior, as well as the changes in monoamine neurotransmitter and stress hormone levels in these animals during the tests. Mice administered AEC at 100 and 200 mg/kg/day doses for 7 days showed significantly reduced immobility duration in forced swimming test and tail suspension test, whilst exhibiting no apparent changes in locomotor activity. Additionally, administration of AEC also effectively antagonized reserpine-induced palpebral ptosis and hypothermia and enhanced 5-hydroxytryptophane-induced head-twitch response. AEC significantly elevated the levels of serotonin, noradrenaline and dopamine in the blood and brain compared to non-treated mice. After 28 days of administration, the maximum AEC dose (100 mg/kg/day) significantly reversed CUMS-induced inhibition of weight gain and sucrose intake, while decreasing the levels of plasma adrenocorticotropic hormone and serum corticosterone. The antidepressant effect of AEC appeared to involve the alteration of hypothalamic-pituitary-adrenal axis and monoaminergic systems.

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Camellia euphlebia exerts its antidepressant-like effect via modulation of the hypothalamic-pituitary-adrenal axis and brain monoaminergic systems

Abstract

Camellia euphlebia (family, Theaceae) is a Chinese folk medicine, known for its multiple pharmacological properties. The present study aimed to provide further insights into the therapeutic basis of C. euphlebia using several animal behavioral tests and physiological indexes. Tail suspension test, forced swimming test, open-field test, chronic unpredictable mild stress (CUMS), reversal of reserpine-induced hypothermia and palpebral ptosis, and 5-hydroxytryptophane-induced head-twitch response were used to evaluate the antidepressant effect of aqueous extract of Camellia euphlebia (AEC) on mice. The possible underlying mechanism was explored by investigating the changes associated with several parameters of animal behavior, as well as the changes in monoamine neurotransmitter and stress hormone levels in these animals during the tests. Mice administered AEC at 100 and 200 mg/kg/day doses for 7 days showed significantly reduced immobility duration in forced swimming test and tail suspension test, whilst exhibiting no apparent changes in locomotor activity. Additionally, administration of AEC also effectively antagonized reserpine-induced palpebral ptosis and hypothermia and enhanced 5-hydroxytryptophane-induced head-twitch response. AEC significantly elevated the levels of serotonin, noradrenaline and dopamine in the blood and brain compared to non-treated mice. After 28 days of administration, the maximum AEC dose (100 mg/kg/day) significantly reversed CUMS-induced inhibition of weight gain and sucrose intake, while decreasing the levels of plasma adrenocorticotropic hormone and serum corticosterone. The antidepressant effect of AEC appeared to involve the alteration of hypothalamic-pituitary-adrenal axis and monoaminergic systems.

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Chemoprevention of preclinical breast and lung cancer with the bromodomain inhibitor I-BET 762

Breast cancer and lung cancer remain the top two leading causes of cancer death in women. Due to limited success in reducing the high mortality of these diseases, new drugs and approaches are desperately needed. Cancer prevention is one such promising strategy that is effective in both preclinical and clinical studies. I-BET 762 is a new bromodomain inhibitor that reversibly targets BET (bromodomain and extra-terminal) proteins and impairs their ability to bind to acetylated lysines on histones, thus interrupting downstream transcription. This inhibitor has anti-inflammatory effects and induces growth arrest in many cancers and is currently under clinical trials for treatment of cancer. However, few studies have investigated the chemopreventive effects of bromodomain inhibitors. Here, we found that I-BET 762 significantly delayed tumor development in preclinical breast and lung cancer mouse models. This drug not only induced growth arrest and downregulated c-Myc, pSTAT3 and pERK protein expression in tumor cells in vitro and in vivo but also altered immune populations in different organs. These results demonstrate the promising potential of using I-BET 762 for cancer prevention and suggest the striking effects of I-BET 762 are the result of targeting both tumor cells and the tumor microenvironment.

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A BET bromodomain inhibitor suppresses adiposity-associated malignant transformation

Almost half a million of all new cancers have been attributed to obesity and epidemiological evidence implicates visceral adipose tissue (VAT) and high-fat diets (HFD) in increasing cancer risk. We demonstrated that VAT-derived fibroblast growth factor 2 (FGF2) from mice fed a HFD or obese individuals stimulates the malignant transformation of epithelial cells. Mechanism-based strategies to prevent this VAT-enhanced tumorigenesis have not been explored. Clinical studies have indicated that bromodomain inhibitors have considerable potential as therapeutic agents for cancer by inhibiting the activity of several oncogenes including c-Myc however, their chemopreventive activity is unknown. We show herein that mice with visceral adiposity have elevated nuclear c-Myc expression in their epidermis. We hypothesized that the bromodomain inhibitor I-BET-762 (I-BET) would have efficacy in the prevention of malignant transformation by VAT and FGF2. We tested this hypothesis using our novel models of VAT-stimulated transformation in vitro and FGF2-stimulated tumor formation in vivo. We found that I-BET significantly attenuates VAT and FGF2-stimulated transformation and inhibits VAT-induced c-Myc protein expression in several skin and breast epithelial cell lines. Moreover, I-BET attenuated tumor growth significantly in FGF2-treated Nude mice. Work is ongoing to determine the role of visceral adiposity in c-Myc activity in several tissues and determine the inhibitory effect of I-BET on VAT-promoted tumors in vivo.

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Synergistic targeting of the regulatory and catalytic subunits of PI3K{delta} in mature B cell malignancies

Purpose: Aberrant activation of the B cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase delta). These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, towards identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to pre-clinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were employed to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted.

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Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden and improved survival

Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared to similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole exome sequence data was analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared to MCC-KP patients (HR 0.297, p < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR 0.296, p = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (p < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; p < 0.001). Additionally, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, p = 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. Additionally, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival.

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HSP27-mediated Extracellular and Intracellular Signaling Pathways Synergistically Confer Chemo-Resistance in Squamous Cell Carcinoma of Tongue

Purpose: Squamous cell carcinoma of tongue (SCCT) is the most common type of the oral cavity carcinoma. Chemo-resistance in SCCT is common and the underlying mechanism remains largely unknown. We aim to identify key molecules and signaling pathways mediating chemo-resistance in SCCT. Experimental Design: Using a proteomic approach we identify that the HSP27 was a potential mediator for chemo-resistance in SCCT cells. To further validate this role of HSP27, we performed various mechanistic studies using in vitro and in vivo models as well as serum and tissue samples of SCCT patients. Results: The HSP27 protein level was significantly increased in the multidrug-resistant SCCT cells and cell culture medium. Both HSP27 knockdown and anti-HSP27 antibody treatment reversed chemo-resistance. Inversely, both HSP27 overexpression and recombinant human HSP27 protein treatment enhanced chemo-resistance. Moreover, chemotherapy significantly induced HSP27 protein expression in both SCCT cells and their culture medium, so is that in tumor tissues and serum of SCCT patients. HSP27 overexpression predicts a poor outcome of SCCT patients receiving chemotherapy. Mechanically, extracellular HSP27 binds to TLR5 and then activates NF-B signaling to maintain SCCT cells survival. TLR5 knockdown or restored IBα protein level disrupts extracellular HSP27-induced NF-B transactivation and chemo-resistance. Moreover, Intracellular HSP27 binds to BAX and BIM to repress their translocation to mitochondrion and subsequent cytochrome C release upon chemotherapy, resulting into inhibition of the mitochondrial apoptotic pathway. Conclusions: HSP27 plays pivotal role in chemo-resistance of SCCT cells via a synergistic extracellular and intracellular signaling. HSP27 may represent a potential biomarker and therapeutic target for precision SCCT treatment.

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Ipilimumab plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies

Purpose: Prevention or treatment of relapsed lymphoid malignancies after hematopoietic stem cell transplantation (HSCT) requires novel strategies. We hypothesized that anti-tumor-cell responses could be enhanced by the addition of lenalidomide to the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab. Experimental Design: We conducted a phase 2 investigator-initiated trial to assess the safety and activity of ipilimumab and lenalidomide in patients with lymphoid malignancies that relapsed after allogeneic HSCT and in high-risk patients after autologous HSCT. Patients received 10 mg of oral lenalidomide daily for 21 days followed by intravenous ipilimumab at 3 mg/kg body weight. The regimen was repeated 4 weeks later for a total of 4 treatments. Results: We enrolled 17 patients (10 allogeneic and 7 autologous transplant recipients). Immune-mediated toxicity was limited to 1 patient with asymptomatic hypothyroidism and 1 with dermatitis in the allogeneic and autologous groups, respectively. One allogeneic transplant recipient had a flare of prior graft-versus-host disease (GVHD) while taking lenalidomide that precluded further treatment. All others finished treatment without GVHD. Four of 10 patients in the allogeneic group had complete responses (three of which were durable at 19+, 21+ and 32+ months), and 3 had partial responses. The disease in 6 of 7 patients in the autologous group remains in remission. The groups had similar immune responses; including a 2- to 3 -fold increases in inducible ICOS+CD4+FoxP3- T cells number. Conclusions:Our early-phase data suggested that ipilimumab plus lenalidomide is well tolerated after HSCT. Adverse events did not differ significantly between the allogeneic and autologous groups.

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Mitochondrial inhibition augments the efficacy of imatinib by resetting the metabolic phenotype of gastrointestinal stromal tumor

Purpose: Imatinib dramatically reduces GIST 18 F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown. Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered Kit V558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed. Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In Kit V558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib. Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST.

http://ift.tt/2kBsL6G

Synergistic targeting of the regulatory and catalytic subunits of PI3K{delta} in mature B cell malignancies

Purpose: Aberrant activation of the B cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase delta). These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, towards identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies. Experimental Design: We used in vitro and in vivo diffuse large B-cell lymphoma (DLBCL) cell lines and primary chronic lymphocytic leukemia (CLL) samples to pre-clinically evaluate the effects of the combination of the FDA-approved phosphodiesterase 4 (PDE4) inhibitor roflumilast and idelalisib on cell survival and tumor growth. Genetic models of gain- and loss-of-function were employed to map multiple signaling intermediaries downstream of the BCR. Results: Roflumilast elevates the intracellular levels of cyclic-AMP and synergizes with idelalisib in suppressing tumor growth and PI3K activity. Mechanistically, we show that roflumilast suppresses PI3K by inhibiting BCR-mediated activation of the P85 regulatory subunit, distinguishing itself from idelalisib, an ATP-competitive inhibitor of the catalytic P110 subunit. Using genetic models, we linked the PDE4-regulated modulation of P85 activation to the oncogenic kinase SYK. Conclusions: These data demonstrate that roflumilast and idelalisib suppress PI3K by distinct mechanisms, explaining the basis for their synergism, and suggest that the repurposing of PDE4 inhibitors to treat BCR-dependent malignancies is warranted.

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Merkel cell carcinoma patients presenting without a primary lesion have elevated markers of immunity, higher tumor mutation burden and improved survival

Purpose: Patients presenting with nodal Merkel cell carcinoma without an identifiable (unknown) primary lesion (MCC-UP) are nearly twice as likely to survive compared to similarly staged patients with known primary lesions (MCC-KP). The basis of this previously reported finding is unclear. Experimental Design: Survival analyses and markers of immunity were evaluated in 123 patients with advanced MCC. Whole exome sequence data was analyzed from 16 tumors. Results: As in prior studies, patients with nodal MCC-UP had strikingly improved MCC-specific survival as compared to MCC-KP patients (HR 0.297, p < 0.001). Surprisingly, patients presenting with distant metastatic MCC-UP also had significantly improved survival (HR 0.296, p = 0.038). None of the 72 patients with MCC-UP were immunosuppressed as compared to 12 of the 51 (24%) patients with MCC-KP (p < 0.001). Merkel polyomavirus oncoprotein antibody median titer was higher in MCC-UP patients (26,229) than MCC-KP patients (3,492; p < 0.001). Additionally, the median number of nonsynonymous exome mutations in MCC-UP tumors (688 mutations) was markedly higher than MCC-KP tumors (10 mutations, p = 0.016). Conclusions: This is the first study to our knowledge to explore potential underlying immune-mediated mechanisms of MCC-UP presentation. In this cohort, MCC-UP patients were never immune suppressed, had higher oncoprotein antibody titers, and higher tumor mutational burdens. Additionally, we show that nodal tumors identified in MCC-UP patients did indeed arise from primary skin lesions as they contained abundant UV-signature mutations. These findings suggest that stronger underlying immunity against MCC contributes to primary lesion elimination and improved survival.

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Ipilimumab plus Lenalidomide after Allogeneic and Autologous Stem Cell Transplantation for Patients with Lymphoid Malignancies

Purpose: Prevention or treatment of relapsed lymphoid malignancies after hematopoietic stem cell transplantation (HSCT) requires novel strategies. We hypothesized that anti-tumor-cell responses could be enhanced by the addition of lenalidomide to the cytotoxic T-lymphocyte-associated protein 4 inhibitor ipilimumab. Experimental Design: We conducted a phase 2 investigator-initiated trial to assess the safety and activity of ipilimumab and lenalidomide in patients with lymphoid malignancies that relapsed after allogeneic HSCT and in high-risk patients after autologous HSCT. Patients received 10 mg of oral lenalidomide daily for 21 days followed by intravenous ipilimumab at 3 mg/kg body weight. The regimen was repeated 4 weeks later for a total of 4 treatments. Results: We enrolled 17 patients (10 allogeneic and 7 autologous transplant recipients). Immune-mediated toxicity was limited to 1 patient with asymptomatic hypothyroidism and 1 with dermatitis in the allogeneic and autologous groups, respectively. One allogeneic transplant recipient had a flare of prior graft-versus-host disease (GVHD) while taking lenalidomide that precluded further treatment. All others finished treatment without GVHD. Four of 10 patients in the allogeneic group had complete responses (three of which were durable at 19+, 21+ and 32+ months), and 3 had partial responses. The disease in 6 of 7 patients in the autologous group remains in remission. The groups had similar immune responses; including a 2- to 3 -fold increases in inducible ICOS+CD4+FoxP3- T cells number. Conclusions:Our early-phase data suggested that ipilimumab plus lenalidomide is well tolerated after HSCT. Adverse events did not differ significantly between the allogeneic and autologous groups.

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Genome-wide association study identifies a new locus at 7q21.13 associated with hepatitis B virus-related hepatocellular carcinoma

Purpose: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In the present study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC. Experimental Design: GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls. Results: We identified a novel association signal within the CDK14 gene at 7q21.13 (index rs10272859, odds ratio = 1.28, P = 9.46 x 10-10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of CDK14 in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of CDK14 and the risk-associated SNPs in strong linkage disequilibrium with the index rs10273859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients. Conclusions: Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the CDK14 gene to be the functional target of the 7q21.13 locus.

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