Cancers, Vol. 9, Pages 111: Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features

Cancers, Vol. 9, Pages 111: Translocation Renal Cell Carcinoma: An Update on Clinicopathological and Molecular Features

Cancers doi: 10.3390/cancers9090111

Authors: Kentaro Inamura

Microphthalmia-associated transcription (MiT) family translocation renal cell carcinoma (tRCC) comprises Xp11 tRCC and t(6;11) RCC. Due to the presence of fusion genes, Xp11 tRCC and t(6;11) RCC are also known as TFE3- and TFEB-rearranged RCC, respectively. TFE3 and TFEB belong to the MiT family, which regulates melanocyte and osteoclast differentiation, and TFE3- and TFEB-rearranged RCC show characteristic clinicopathological and immunohistochemical features. Recent studies identified the fusion partner-dependent clinicopathological and immunohistochemical features in TFE3-rearranged RCC. Furthermore, RCC with chromosome 6p amplification, including TFEB, was identified as a unique subtype of RCC, along with ALK-rearranged RCC. This review summarizes these recent advancements in our tRCC-related knowledge.

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Clonality and mutational profiling of a case of composite hairy cell leukemia and chronic lymphocytic leukemia

Abstract

We report a unique case of composite hairy cell leukemia (HCL) and monoclonal B-cell lymphocytosis with chronic lymphocytic leukemia (CLL) phenotype evaluated comprehensively through cell sorting and deep sequencing. The patient presented with decreased exercise tolerance and complete blood count revealed neutropenia, monocytopenia, and thrombocytopenia. The peripheral blood film was suggestive of HCL. However, a bone marrow evaluation was suspicious for composite HCL and CLL. Flow cytometry not only confirmed monoclonal kappa light chain restricted HCL and CLL populations, but also identified a kappa restricted population with co-expression of bright CD20, bright CD22, and CD11c without CD25 or CD103. Each population was isolated by cell sorting and subsequent B-cell receptor gene rearrangement analysis showed distinct rearrangements in each population. Likewise, next-generation sequencing (NGS) showed distinct mutation patterns in each of the monoclonal B-cell populations. The HCL clone harbored the signature BRAF V600E mutation, the CLL clone harbored an RB1 (L343fs*6) mutation, and the third clone was essentially negative for either mutation. In HCL, the BRAF V600E has been found in hematopoietic stem cells, raising the possibility of a common stem cell origin for composite HCL/CLL. However, our findings suggest a process of independent clonal development of multiple neoplastic B-cell populations in composite lymphoma, likely occurring somewhere after the common lymphoid progenitor stage.

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The 150 most important questions in cancer research and clinical oncology series: questions 50–56

Abstract

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and potential collaborations among researchers all over the world. In this article, seven more questions are presented as followed. Question 50. When tumor cells spread from primary site to distant sites, are they required to be "trained" or "armed" in the bone marrow niche prior to colonizing soft tissues? Question 51. Are there tipping points during cancer progression which can be identified for manipulation? Question 52. Can we replace molecular biomarkers by network biomarkers? Question 53. Are conventional inhibitors of key cellular processes such as cell proliferation and differentiation more effective than targeted chemotherapeutics that antagonize the downstream cell signaling network via cell-surface receptors such as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR) and c-Met, or intracellular receptors such as androgen receptor (AR) and estrogen receptor (ER), by drugs like erlotinib, sunitinib and cabozantinib, or enzalutamide and tomoxifen? Question 54. How can we robustly identify the candidate causal event of somatic genome alteration (SGA) by using computational approach? Question 55. How can we systematically reveal the immune evasion mechanism exploited by each tumor and utilize such information to guide targeted therapy to restore immune sensitivity? Question 56. Can the nasopharyngeal carcinoma (NPC) patients with sarcomatoid carcinoma (SC) subtype benefit from more specific targeted therapy?

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Minimal Residual Disease Eradication in CML: Does It Really Matter?

Abstract

BCR-ABL1 tyrosine kinase inhibitors (TKIs) have improved the prognosis of chronic phase chronic myeloid leukemia (CP-CML) to an extent that survival is largely determined by non-CML mortality. Monitoring for minimal residual disease by measuring BCR-ABL1 messenger RNA is a key component of CML management. CP-CML patients who achieve a stable deep molecular response may discontinue (TKIs) with an ~ 50% chance of entering treatment-free remission (TFR). So far discontinuation of TKIs has largely been limited to clinical trials, but is on the verge of becoming a part of wider clinical practice. Careful patient selection, dense molecular monitoring, and prompt reinstitution of treatment in the event of relapse are all vital to reproduce the same level of success. Much effort has been dedicated to identifying therapeutic strategies to eliminate CML stem cells and enable to TFR in more patients. Unfortunately, despite promising preclinical data, as yet, none of the various approaches have entered clinical practice.

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Ganglioneuroblastoma in a newborn with multiple metastases: a case report

Ganglioneuroblastoma is a tumor of peripheral neuroblastic tissue which occurs predominantly in the pediatric age group; it is a rare occurrence in the newborn period with only one case reported at birth to date.

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Takayasu arteritis presenting as embolic stroke

A 52-year-old Caucasian woman presented to the emergency department with symptoms of acute ischaemic stroke (right-side weakness, confusion and aphasia) that resolved completely after administration of tissue plasminogen activator. During stroke work-up, she was found to have an enhancing infiltrate of the aorta at the level of the take-off of the great vessels, most consistent with early Takayasu arteritis. After being discharged home on steroids and dual antiplatelet therapy, she returned 2 days later with re-presentation of weakness and aphasia. Further work-up revealed two intraluminal clots in the left common carotid and left internal carotid arteries that had not been discovered during previous testing. This case illustrates the need to screen for sources of embolic stroke in patients with Takayasu arteritis, especially those with recurring symptoms.

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Oesophageal mastocytosis: eosinophilic oesophagitis without eosinophils?

A 59-year-old male with a history of lifelong asthma, allergic rhinitis and hypercholesterolaemia presented to the emergency department for management of severe substernal chest pain with radiating pain to his left arm, nausea and diaphoresis. Physical examination was unrevealing and a cardiac workup including cardiac enzymes, ECG, chest radiographs were negative for an underlying ischaemic event. A subsequent gastrointestinal workup including oesophageal manometry and oesophagogastroduodenoscopy revealed elevated lower oesophageal pressures and histopathology suggestive of mast cell proliferation, respectively. These findings were suggestive of oesophageal mastocytosis. Treatment with omeprazole-sodium bicarbonate, cetirizine, montelukast and oral budesonide promptly ameliorated his symptoms which have not recurred.

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Continuous remission of renal cell carcinoma with tumour thrombus after severe adverse events following short-term treatment with sunitinib

A 64-year-old Japanese man with renal cell carcinoma (RCC) and tumour thrombus in the inferior vena cava was treated with sunitinib. Two weeks after treatment, he was hospitalised for disturbance of consciousness. Laboratory tests revealed high-grade hypoglycaemia, hyponatraemia, liver dysfunction and thrombocytopaenia with disseminated intravascular coagulation. Sunitinib was discontinued and the patient recovered after a protracted platelet transfusion. At 5 months after treatment, CT revealed that the tumour thrombus had disappeared and other lesions had regressed. MRI at 15 months revealed further regression and suggested the possibility of histological remission according to the signal intensity of fibrosis. A partial response persisted at 20 months after treatment, despite residual accumulation in the renal tumour evident on positron emission tomography. In summary, we present a case of locally advanced RCC accompanied by severe adverse events that showed a significant and durable response to treatment with sunitinib for just 2 weeks.

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The 150 most important questions in cancer research and clinical oncology series: questions 50–56

Since the beginning of 2017, Chinese Journal of Cancer has published a series of important questions in cancer research and clinical oncology, which sparkle diverse thoughts, interesting communications, and poten...

http://ift.tt/2wdWZmV

Intraoperative Radiation Therapy for Locally Advanced or Locally Recurrent Rectal Cancer

Abstract

Colorectal cancer is a major cause of morbidity and mortality across the world. Although surgery alone is very effective for patients with early stage disease, patients with more advanced disease required a combined modality approach. Standard doses of radiation therapy are usually ineffective in controlling localized disease that cannot be widely resected. Radiation dose escalation with intraoperative radiation therapy (IORT) has been investigated for many years as a component of a trimodality strategy in patients at high risk for local recurrence. This paper reviews the evidence supporting inclusion of IORT in addition to external beam radiation, surgery, and chemotherapy in patients with very locally advanced primary rectal cancer and patients with locally advanced recurrent rectal cancer.

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Immunotherapy in Colorectal Cancer: Where Are We Now?

Abstract

Purpose of Review

This review examines the current state of colorectal cancer (CRC) immunotherapy across multiple treatment modalities and discusses some of the most promising approaches.

Recent Findings

CRC immunotherapy involving viral vector and dendritic cell vaccines, checkpoint blockade, and adoptive cell therapy has been explored from preclinical to clinical studies. Despite successes in other malignancies, including melanoma, leukemia, lung, and renal cancers, immunotherapies have been FDA approved for only a small subset of CRCs. Recent studies leveraging greater understanding of cellular and molecular mechanisms underlying colorectal tumorigenesis and immunotherapeutic mechanism of action may be exploited in upcoming trials.

Summary

While immune infiltration of CRC has been an established indicator of patient outcomes, immunotherapeutic strategies to date have not exploited its potential immunogenicity to benefit patients. New vaccine, checkpoint inhibitor, and CAR-T cell therapy paradigms promise to change that. With continued research, we could see a rapid increase in the number of FDA-approved immunotherapies for CRC in the coming years.

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Synthetic lethality interaction between Aurora kinases and CHEK1 inhibitors in ovarian cancer

Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair (HR) genes, so they rely on DNA-damage checkpoint proteins, like the Checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 and mitotic Aurora Kinase A (AURKA) inhibitors.  Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1 and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA inhibitor and LY2603618 as CHEK1 inhibitor.  Analyses of cell cycle and intracellular mediators were performed by flow cytometry and Western blot. Impact on stem cell properties was evaluated by flow cytometry analysis of surface markers  and sphere formation assays. Gene expression analyses followed by functional annotation identified a series of deregulated genes which belonged to cell cycle, including AURKA/B, TTK kinase and CHEK1.  AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. AURKA and CHEK1 inhibitors showed a synergistic interaction in different cellular models.  Combination of Alisertib and LY2603618 triggered apoptosis, reduced the stem cell population and increased the effect of taxanes and platinum compounds. Finally, expression of AURKA and CHEK1 was linked with detrimental outcome in patients. Our data describes a synthetic lethality interaction between CHEK1 and AURKA inhibitors with potential translation to the clinical setting.

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Oncolytic Reactivation of KSHV as a Therapeutic Approach for Primary Effusion Lymphoma

Primary effusion lymphoma (PEL) is an aggressive subtype of non-Hodgkin lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Currently treatment options for patients with PEL are limited. Oncolytic viruses have been engineered as anti-cancer agents and have recently shown increased therapeutic promise. Similarly, lytic activation of endogenous viruses from latently infected tumor cells can also be applied as a cancer therapy. In theory, such a therapeutic strategy would induce oncolysis by viral replication, while simultaneously stimulating an immune response to viral lytic cycle antigens. We examined the combination of the FDA-approved drug PEP005 (ingenol-3-angelate) with epigenetic drugs as a rational therapeutic approach for KSHV-mediated malignancies. JQ1, a bromodomain and extra terminal protein (BET) inhibitor, in combination with PEP005, not only robustly induced KSHV lytic replication, but also inhibited IL-6 production from PEL cells. Using the dosages of these agents that was found to be effective in reactivating HIV (as a means to clear latent virus with HAART therapy), we were able to inhibit PEL growth in vitro and delay tumor growth in a PEL xenograft tumor model. KSHV reactivation was mediated by activation of NF-B pathway <br />by PEP005, which led to increased occupancy of RNA polymerase II onto the KSHV genome. RNA-sequencing analysis further revealed cellular targets of PEP005, JQ1, and the synergistic effects of both. Thus, combination of PEP005 with a BET inhibitor may be considered as a rational therapeutic approach for the treatment of PEL.

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Trp53 Mutants Drive Neuroendocrine Lung Cancer through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response

Lung cancer is the leading cause of cancer deaths with small cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53 mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common Trp53 mutations in lung cancer, combined with Rb1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and Trp53 loss result in similar phenotypes demonstrating that Trp53 mutants promote lung carcinogenesis through loss-of-function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for Trp53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease.

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MITF-high and MITF-low cells and a novel subpopulation expressing genes of both cell states contribute to intra and inter-tumoral heterogeneity of primary melanoma.

Purpose. Understanding tumour heterogeneity is an important challenge in current cancer research. Transcription and epigenetic profiling of cultured melanoma cells have defined at least two distinct cell phenotypes characterised by distinctive gene expression signatures associated with high or low/absent expression of Microphthalmia-associated transcription factor (MITF). Nevertheless, heterogeneity of cell populations and gene expression in primary human tumours is much less well characterised. Experimental design. We performed single cell gene expression analyses on 472 cells isolated from needle biopsies of 5 primary human melanomas, 4 superficial spreading and one acral melanoma. The expression of MITF-high and MITF-low signature genes was assessed and compared to investigate intra and inter-tumoural heterogeneity and correlated gene expression profiles. Results. Single cell gene expression analyses revealed varying degrees of intra and inter-tumour heterogeneity conferred by the variable expression of distinct sets of genes in different tumours. Expression of MITF partially correlated with that of its known target genes while SOX10 expression correlated best with PAX3 and ZEB2. Nevertheless, cells simultaneously expressing MITF-high and MITF-low signature genes were observed both by single cell analyses and RNAscope. Conclusions. Single cell analyses can be performed on limiting numbers of cells from primary human melanomas revealing their heterogeneity. While tumours comprised variable proportions of cells with the MITF-high and MITF-low gene expression signatures characteristic of melanoma cultures, primary tumours also comprised cells expressing markers of both signatures defining a novel cell state in tumours in vivo.

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Timing of PD-1 Blockade Is Critical to Effective Combination Immunotherapy with Anti-OX40

Purpose: Antibodies specific for inhibitory checkpoints PD-1 and CTLA-4 have shown impressive results against solid tumors. This has fueled interest in novel immunotherapy combinations to affect patients who remain refractory to checkpoint blockade monotherapy. However, how to optimally combine checkpoint blockade with agents targeting T-cell costimulatory receptors, such as OX40, remains a critical question.

Experimental Design: We utilized an anti-PD-1–refractory, orthotopically transplanted MMTV-PyMT mammary cancer model to investigate the antitumor effect of an agonist anti-OX40 antibody combined with anti-PD-1. As PD-1 naturally aids in immune contraction after T-cell activation, we treated mice with concurrent combination treatment versus sequentially administering anti-OX40 followed by anti-PD-1.

Results: The concurrent addition of anti-PD-1 significantly attenuated the therapeutic effect of anti-OX40 alone. Combination-treated mice had considerable increases in type I and type II serum cytokines and significantly augmented expression of inhibitory receptors or exhaustion markers CTLA-4 and TIM-3 on T cells. Combination treatment increased intratumoral CD4⁺ T-cell proliferation at day 13, but at day 19, both CD4⁺ and CD8⁺ T-cell proliferation was significantly reduced compared with untreated mice. In two tumor models, sequential combination of anti-OX40 followed by anti-PD-1 (but not the reverse order) resulted in significant increases in therapeutic efficacy. Against MMTV-PyMT tumors, sequential combination was dependent on both CD4⁺ and CD8⁺ T cells and completely regressed tumors in approximately 30% of treated animals.

Conclusions: These results highlight the importance of timing for optimized therapeutic effect with combination immunotherapies and suggest the testing of sequencing in combination immunotherapy clinical trials. Clin Cancer Res; 1–13. ©2017 AACR.

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Evaluation of high dose volumetric CT to reduce inter-observer delineation variability and PTV margins for prostate cancer radiotherapy

The aim was to determine whether the enhanced soft tissue contrast provided by high-dose volumetric CT (HDVCT) can reduce inter-observer variability in delineating prostate compared to helical conventional CT (CCT) scans and 3T MRI scans for patients undergoing radical prostate cancer radiotherapy. Secondly, to quantify the potential PTV reduction with decreased inter-observer variability.

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The role of radical radiotherapy in the management of malignant pleural mesothelioma: A systematic review

Malignant pleural mesothelioma (MPM) is a devastating disease with limited treatment options and a dismal prognosis. Attempts to employ radical radiotherapy in this disease have been limited by the complex shape of the pleura and the dose restrictions necessitated by the close proximity of radiosensitive structures. Recent shifts towards a 'lung sparing' surgical approach in MPM have further heightened these challenges. The aim of this systematic review is to assess recent advances in radiotherapy planning and delivery, to ascertain how these developments have impacted on the feasibility of delivering photon-based, high-dose radiotherapy with radical intent in MPM.

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Curcumin-supplemented diets improve antioxidant enzymes and alter acetylcholinesterase genes expression level in Drosophila melanogaster model

Abstract

Curcumin, a bioactive polyphenolic compound in turmeric (Curcuma longa) rhizomes has been shown to exert anti-aging properties with limited scientific basis. Hence, this study sought to examine the antioxidant and anti-cholinesterase activities of curcumin-supplemented diets as well as their molecular effect on superoxide dismutase (SOD) and acetylcholinesterase (AChE) genes expression level associated with lifespan extension in Drosophila melanogaster model. In this experiment, D. melanogaster (both genders) of 1 to 3 days old were fed diets either containing no curcumin (control) or supplemented with curcumin at 0.2 and 1.0 mg/g of diet for 7 days. Subsequently, the survival and locomotor activities were determined. In addition, we evaluated RT-PCR expressions of SOD and AChE mRNA genes. Furthermore, catalase, SOD and AChE activities were determined. Curcumin-supplemented diet improves survival ability but did not affect locomotor activity when compared with the control. In addition, there was a significant increase in SOD and catalase with a concomitant decrease of AChE activities when compared with the control. Furthermore, curcumin-supplemented diets suppress AChE mRNA expression but no alteration on SOD gene expression level was observed when compared with control. In conclusion, our present results suggest that a down-regulation of AChE gene expression with a concomitant decrease of AChE activity as well as improving antioxidant status could be some possible mechanism in which curcumin exert anti-aging potential and increases lifespan of D. melanogaster.

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Durability of Protection Afforded by Fewer Doses of the HPV16/18 Vaccine: The CVT Trial

Abstract

Background: Previously, we demonstrated similar human papillomavirus (HPV)16/18 vaccine efficacy estimates and stable HPV16/18 antibody levels four years postvaccination in a nonrandomized analysis of women who received a varying number of doses of the bivalent HPV16/18 vaccine. Here we extend data to seven years following initial vaccination.Methods: We evaluated HPV16/18-vaccinated women who received one (n = 134), two (n_0/1 = 193, n_0/6 = 79), or three doses (n = 2043) to a median of 6.9 years postvaccination. Cervical HPV DNA was measured with the SPF10- DEIA-LiPA PCR system; HPV16/18-specific antibody levels were measured using enzyme-linked immunosorbent assays (n = 486). Infection and immunological measures were compared across vaccine dose groups. Prevalent HPV infection at year 7 was also compared with an unvaccinated control group (UCG). All statistical tests were two-sided.Results: Among women in the three-dose, two-dose_0/6, two-dose_0/1, and one-dose groups, cumulative incident HPV16/18 infection rates (No. of events/No. of individuals) were 4.3% (88/2036, 95% confidence interval [CI] = 3.5% to 5.3%), 3.8% (3/78, 95% CI = 1.0% to 10.1%), 3.6% (7/192, 95% CI = 1.6% to 7.1%), and 1.5% (2/133, 95% CI = 0.3% to 4.9%; P = 1.00, .85, .17 comparing the two-dose_0/6, two-dose_0/1, and one-dose groups to the three-dose group, respectively). The prevalence of other carcinogenic and noncarcinogenic HPV types, excluding HPV16/18/31/33/45, were high and not statistically different among all dose groups, indicating that the low incidence of HPV16/18 in the one- and two-dose groups was not due to lack of exposure. At seven years, 100% of participants in all dose groups remained HPV16 and HPV18 seropositive. A non–statistically significant decrease in the geometric mean of the HPV16 antibody levels between years 4 and 7 was observed among women in the three-dose group: –10.8% (95% CI = –25.3% to 6.6%); two-dose (0/6 months) group: –17.3% (95% CI = –39.3% to 12.8%), two-dose (0/1 month) group: –6.9% (95% CI = –22.1% to 11.2%), and one-dose group: –5.5% (95% CI = –29.7% to 27.0%); results were similar for HPV18.Conclusions: At an average of seven years of follow-up, we observed similar low rates of HPV16/18 infections and slight, if any, decreases in HPV16/18 antibody levels by dose group.

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Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway

Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway

Oncogenesis 6, e375 (August 2017). doi:10.1038/oncsis.2017.74

Authors: Q Chen, D Yang, H Zong, L Zhu, L Wang, X Wang, X Zhu, X Song & J Wang

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E6/E7 oncogenes in epithelial suprabasal layers and estradiol promote cervical growth and ear regeneration

E6/E7 oncogenes in epithelial suprabasal layers and estradiol promote cervical growth and ear regeneration

Oncogenesis 6, e374 (August 2017). doi:10.1038/oncsis.2017.73

Authors: C García, D Hernández-García, C Valencia, V Rojo-León, J-R Pérez-Estrada, M Werner & L Covarrubias

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Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

Oncogenesis 6, e373 (August 2017). doi:10.1038/oncsis.2017.72

Authors: T Avril, E Vauléon & E Chevet

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Two New Therapies Approved for Acute Myeloid Leukemia

FDA has approved two new treatments for some adult patients with acute myeloid leukemia (AML): enasidenib (Idhifa®), which targets the IDH2 protein; and liposomal cytarabine-daunorubicin CPX-351 (Vyxeos®), a two-drug chemotherapy combination encapsulated in liposomes.

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Determination of Follicular Localization in Human Ovarian Cortex for Vitrification

Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.


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Endothelial Growth Factor Receptors in Angiogenesis

Abstract

It is hard to underestimate the role of endothelial growth factor receptors in the generation of new blood vessels. This axis is involved in vascular development in embryos and angiogenesis in adults. As the signaling of these tyrosine kinase receptors has been elucidated, we have gained an appreciation of the complex interactions with other receptors, co-receptors, and downstream pathways.

Its involvement in pathology makes it a particularly tempting therapeutic target with its manipulation offering several theoretical benefits. The most intensely studied is the role of anti-VEGFR drugs in cancer chemotherapy. Initial trials were disappointing but a decade ago the first drug targeting the vascular endothelial growth factor (VEGF) axis was approved, providing a vital proof of concept. Therapies specifically targeting the receptor are in early development for prevention of neovascular diseases of the eye. Conversely, promotion of revascularization following vascular occlusion is another possible application being studied.

While these therapies show promise, the manipulation of VEGF receptors themselves remains a relatively small niche in the therapeutic armory. A deeper understanding of the receptor, its co-receptors, and the downstream web of signaling is required to complete the pieces of the puzzle and unlock the potential of this receptor pathway.

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Therapeutic effect of cisplatin administered with a lymphatic drug delivery system on false-negative metastatic lymph nodes

Abstract

Systemic administration of drugs into the blood circulation is a standard treatment for the prevention of metastasis. However, systemic delivery cannot maintain sufficiently high concentrations of anticancer drugs in lymphatic nodes (LNs). Here, we show that administering cisplatin (CDDP) using a lymphatic drug delivery system (LDDS) has the potential to treat false-negative metastatic LNs. We found that in MXH10/Mo-lpr/lpr mice, which develop systemic swelling of LNs up to 10 mm in diameter, the accumulation of indocyanine green (ICG, which has a similar molecular weight to CDDP) in a target LN was greater for lymphatic delivery of ICG than for systemic (intravenous) administration. Furthermore, CDDP administration with a LDDS inhibited tumor growth in false-negative metastatic LNs and produced fewer adverse effects than systemically administered CDDP. We anticipate that drug delivery using a LDDS will, in time, replace systemic chemotherapy for the treatment of false-negative metastatic LNs.

This article is protected by copyright. All rights reserved.

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Correction: Cerebral venous sinus thrombosis during superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for maxillary squamous cell carcinoma

Okamura S, Saito Y, Mori H, Yamasoba T. Cerebral venous sinus thrombosis during superselective intra-arterial infusion of cisplatin and concomitant radiotherapy for maxillary squamous cell carcinoma. BMJ Case Rep. Published Online First: 12 May 2017. doi:10.1136/bcr-2017-220591

The line '(1) the indwelling catheter in;' should read:

(1) the indwelling catheter in the common carotid artery decreased brain venous flow;

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Correction: Vitamin A deficiency due to chronic malabsorption: an ophthalmic manifestation of a systemic condition

Cheshire J, Kolli S. Vitamin A deficiency due to chronic malabsorption: an ophthalmic manifestation of a systemic condition. BMJ Case Rep. Published Online First: 10 May 2017. doi:10.1136/bcr-2017-220024

In this article, the author affiliations are incorrect; the correct affiliations are listed below.

James Cheshire: Heart of England NHS Foundation Trust, Birmingham, UK

Sai Kolli: Department of Ophthalmology, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK

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ERAS: Safety checklists, antibiotics, and VTE prophylaxis

The concept rested on several components that many of us have now tried to adopt or improve on, inclusive of a multidisciplinary team, a multimodal approach to anesthesia and preoperative preparedness, evidence-based approach to care protocols; and a change in management using interactive and continuous audit prior to and post-procedure. This article describes the development of ERAS protocols relative to checklist implementation, antibiotic use, and venous thromboembolism (VTE) prevention, how these ideas are developed and operationalized as well as how they are evolving and spreading across the care continuum to achieve sustained outcome improvements.

http://ift.tt/2iEviPM

Enhanced recovery after surgery—Preoperative fasting and glucose loading—A review

In this review, we explore the rationale and history behind the practice of preoperative fasting in elective surgery including the gradual move toward longer fasting and the more recent change in direction of practice. Gastric emptying physiology and the metabolic effects of prolonged fasting and carbohydrate loading are examined. Most recent guidelines related to these topics are discussed and practical recommendations for implementing these guidelines are suggested.

http://ift.tt/2gjoVjW

Combined surgical and endovascular approach to treat a carotid cavernous fistula with associated brainstem venous congestion

Endovascular embolization is the standard approach for management of carotid cavernous fistulas (CCFs) due to the ease of access and reduced level of risk associated with the procedure compared with open surgery. We present here a case of a CCF that eventually led to the development of brainstem venous congestion from perimedullary venous drainage. This fistula was not amenable to endovascular embolization due to lack of either ophthalmic vein or petrosal sinus drainage. Therefore, a craniotomy with direct puncture of the cavernous sinus was performed, followed by coil embolization to completely treat this fistula. This case demonstrates an uncommon progression of venous drainage to Cognard grade V, rare development of symptomatic brainstem venous congestion and a unique method to combine an open surgical approach with endovascular embolization to treat CCFs.

http://ift.tt/2xr3D8j

ERAS: Safety checklists, antibiotics, and VTE prophylaxis

The concept rested on several components that many of us have now tried to adopt or improve on, inclusive of a multidisciplinary team, a multimodal approach to anesthesia and preoperative preparedness, evidence-based approach to care protocols; and a change in management using interactive and continuous audit prior to and post-procedure. This article describes the development of ERAS protocols relative to checklist implementation, antibiotic use, and venous thromboembolism (VTE) prevention, how these ideas are developed and operationalized as well as how they are evolving and spreading across the care continuum to achieve sustained outcome improvements.

http://ift.tt/2iEviPM

Enhanced recovery after surgery—Preoperative fasting and glucose loading—A review

In this review, we explore the rationale and history behind the practice of preoperative fasting in elective surgery including the gradual move toward longer fasting and the more recent change in direction of practice. Gastric emptying physiology and the metabolic effects of prolonged fasting and carbohydrate loading are examined. Most recent guidelines related to these topics are discussed and practical recommendations for implementing these guidelines are suggested.

http://ift.tt/2gjoVjW

Synergistic activity of sorafenib and betulinic acid against clonogenic activity of non-small cell lung cancer cells

Summary

The highly selective multi-targeted agent – sorafenib – is an inhibitor of a number of intracellular signaling kinases with anti-proliferative, anti-angiogenic and pro-apoptotic effects in various types of tumors, including human non-small cell lung cancer (NSCLC). Betulin displays a broad spectrum of biological and pharmacological properties, including the anticancer and chemopreventive activity. Combination of drugs with different targets is a logical approach to overcome multilevel cross-stimulation among key signaling pathways in NSCLC progression. NSCLC cell lines: A549, H358 and A427, with different KRAS mutations, and normal human PBL cells, were treated with sorafenib and betulinic acid alone and in combination. We examined the effect of different combined treatments on viability (MTS test), proliferation and apoptotic susceptibility analyzed by flow cytometry, alterations in signaling pathways by Western blotting and colony-forming ability. The combination of sorafenib with betulinic acid had a strong effect on the induction of apoptosis of different non-small cell lung cancer cell lines. Also, this combination was not toxic for human peripheral blood lymphocytes (PBL). Combination treatment changed the expression of proteins involved in the mitochondrial apoptosis pathway and induced apoptotic death by caspase activation. Importantly, combination treatment with low drug concentrations tremendously reduced colony-forming ability of A549, H358 and A427 cells, as compared to both compounds alone. In this study, we showed that combination therapy with low concentrations of sorafenib and betulinic acid had the capacity to induce high levels of cell death and abolish clonogenic activity in some non-small cell lung cancer cell lines independently on KRAS mutations.

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Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway

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E6/E7 oncogenes in epithelial suprabasal layers and estradiol promote cervical growth and ear regeneration

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Endoplasmic reticulum stress signaling and chemotherapy resistance in solid cancers

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A retrospective study of amrubicin monotherapy for the treatment of relapsed small cell lung cancer in elderly patients

Abstract

Purpose

Amrubicin is one of the most active chemotherapeutic drugs for small cell lung cancer (SCLC). Previous studies reported its effectiveness and severe hematological toxicity. However, the efficacy of amrubicin monotherapy in elderly patients with SCLC has not been described. The objective of this study was to investigate the feasibility of amrubicin monotherapy in elderly patients and its efficacy for relapsed SCLC.

Methods

A retrospective cohort study design was used. We retrospectively evaluated the clinical effects and adverse events of amrubicin treatment in elderly (≥70 years) SCLC patients with relapsed SCLC.

Results

Between November 2003 and September 2015, 86 patients (aged ≥70 years) received amrubicin monotherapy for relapsed SCLC at four institutions. There were 42 cases of sensitive relapse (S) and 44 of refractory relapse (R). S cases with median age of 75 years (range 70–85 years) and R cases with median age of 74 years (range 70–84 years) were included in our analysis. The median number of treatment cycles was three (range 1–9), and the response rate was 33.7% (40.5% in the S and 27.2% in the R cases). Median progression-free survival time was 4.0 months in the S and 2.7 months in the R patients (p = 0.013). Median survival time from the start of amrubicin therapy was 7.6 months in the S and 5.5 months in the R cases (p = 0.26). The frequencies of grade ≥3 hematological toxicities were as follows: leukopenia, 60.4%; neutropenia, 74.4%; anemia, 11.6%; thrombocytopenia, 16.2%; and febrile neutropenia, 17.4%. Treatment-related death was observed in one patient.

Conclusion

Although hematological toxicities, particularly neutropenia, were severe, amrubicin showed favorable efficacy, not only in the S but also in the R cases, as shown in previous studies. Amrubicin could be a preferable standard treatment in elderly patients with relapsed SCLC. These results warrant further evaluation of amrubicin in elderly patients with relapsed SCLC by a prospective trial.

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Survival data for postoperative adjuvant chemotherapy comprising cisplatin plus vinorelbine after complete resection of non-small cell lung cancer

Abstract

Purpose

Despite the efficacy of postoperative adjuvant cisplatin (CDDP)-based chemotherapy for patients who have undergone surgical resection of non-small cell lung cancer (NSCLC), few reports have presented survival data for Asian patients treated with adjuvant chemotherapy involving a combination of CDDP and vinorelbine (VNR). This study was performed to evaluate the survival of patients with NSCLC who received postoperative adjuvant chemotherapy comprising CDDP + VNR.

Methods

We retrospectively evaluated patients with NSCLC who received adjuvant chemotherapy comprising CDDP + VNR at the Shizuoka Cancer Center between February 2006 and October 2011.

Results

One hundred patients who underwent surgical resection of NSCLC were included in this study. The patients' characteristics were as follows: median age 63 years (range 36–74 years), female 34%, never-smokers 20%, and non-squamous NSCLC 73%. Pathological stages IIA, IIB, and IIIA were observed in 31, 22, and 47% of patients, respectively. The 5- and 2-year overall survival rates were 73 and 93%, respectively. The 5- and 2-year relapse-free survival rates were 53 and 62%, respectively. Univariate analysis of prognostic factors showed that patient characteristics (sex, histology, and pathological stage) and CDDP dose intensity were not significantly associated with survival. In 48 patients who developed NSCLC recurrence, the 5-year survival rate after recurrence was 29%, and the median survival time after recurrence was 37 months.

Conclusions

Our results suggest that the prognosis after surgical resection of NSCLC and adjuvant chemotherapy comprising CDDP + VNR might be improving compared with previous survival data of adjuvant chemotherapy for NSCLC.

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sIL-24 peptide, a human interleukin-24 isoform, induces mitochondrial-mediated apoptosis in human cancer cells

Abstract

Purpose

Interleukin-24 (IL-24) is a unique cytokine in the IL-10 family that reveals tumor-suppressive activity against a broad range of cancers. Alternative splicing of human IL-24 generates several isoforms with different pro-apoptotic activities. In the current study, we aimed to investigate the cytotoxic properties of a recombinant smallest isoform of IL-24 (sIL-24) and the underlying molecular mechanisms in PC-3, A549, U937, and Raji cancer cells as well as normal cell line MRC-5.

Methods

Following treatment of the cells with recombinant sIL-24 peptide and full-length IL-24 protein, cytotoxicity was determined by MTT assay. Apoptosis induction was evaluated using annexin-V/PI double staining flow cytometry and Hoechst 33342 staining. The expression of Bax, Bcl-2, cytochrome c, and caspase-3 was analyzed by Western blotting.

Results

MTT assay exhibited that sIL-24 dose and time dependently inhibited the proliferation of IL-24 receptor-positive PC-3, U937, and Raji cells more effectively than full-length IL-24. In contrast, sIL-24 had little cytotoxic effect on A549 cells lacking the IL-24 receptor, or on MRC-5 normal cells. Flow cytometric analysis and morphological observation revealed an efficient apoptosis induction in the receptor-positive cells. Furthermore, Western blot assay demonstrated that cell death induced by sIL-24 was associated with upregulation of the Bax/Bcl-2 ratio, cytochrome c release, and the expression of cleaved caspase-3, suggesting that sIL-24 induced apoptosis mainly through the mitochondrial pathway. Notably, among the tested cells, induction of apoptosis was more significant in PC-3 cells.

Conclusion

Our results suggest that the sIL-24 peptide is a promising candidate for potential treatment of human cancers.

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AMP-activated protein kinase and cAMP response element-binding protein activity are associated with distinct postoperative behavioral changes in rats

Abstract

Purpose

To explore the association of AMP-activated protein kinase (AMPK) and cAMP response element-binding protein (CREB) activity with distinct postoperative behavioral changes in rats.

Methods

We performed partial hepatolobectomy in adult rats and aged rats. The learning and memory ability of rats was evaluated by the Barnes maze test on postoperative days 1–4. The expressions of AMPK and phosphorylated CREB (p-CREB) in the CA1 and DG regions of the hippocampus were detected by immunohistochemical assay at 3, 6, 12 and 24 h postoperatively.

Results

Surgery impaired the memory of aged rats but not that of adult rats on postoperative days 2 and 3 (both p < 0.05). Surgery synergistically increased the expressions of AMPK and p-CREB in the CA1 region of hippocampus in aged rats but not in adult rats at 3 and 6 h postoperatively.

Conclusion

Our data suggest that surgery induces cognitive impairment in aged rats. Surgery-induced expression of AMPK and p-CREB in the CA1 region of hippocampus may be involved in this cognitive impairment.

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Invading beyond bounds: extraintestinal Clostridium difficile infection leading to pancreatic and liver abscesses

Clostridium difficile has become a common healthcare-associated infection over the past few years and gained more attention. C. difficile was estimated to cause almost half a million infections in USA in 2011 and 29 000 died within 30 days of the initial diagnosis. Although colitis due to C. difficile is the most common presentation, there have been reported cases of extraintestinal infections. As per our review of literature, this is the third reported case of liver abscess due to the organism.

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Elephantiasis nostras verrucosa: a rare complication of lower limb lymphoedema

We reported a case of a 49-year-old man who had chronic lymphoedema of bilateral lower limbs for 30 years, but he did not seek treatment. His disease was complicated with irreversible changes of elephantiasis nostras verrucosa and had recurrent admissions due to infection. He was not keen for surgical intervention. This case report illustrated a rare and non-reversible complication of a common skin disease, lymphoedema and also the importance of identifying and treating it early.

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Dilemma of diagnosing sulphonylurea overdose in children: deliberations and considerations before reaching a diagnosis

A 15-year-old non-diabetic Caucasian girl presented with sudden onset of seizures, unrecordable blood glucose readings and acute renal failure. She denied any medication ingestion and no other precipitating factors were encountered for this acute presentation. She was treated with intravenous glucose infusion and hydrocortisone injection. Investigations showed a non-ketotic hypoglycaemia with high C-peptide and insulin levels. It took several days and multiple investigations to establish the exact cause of her persistent hypoglycaemia before it was concluded to be secondary to gliclazide overdose in a suicide attempt by the young girl. She made a complete recovery in a week with no apparent lasting neurological or renal impairment.

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Hypertensive bipolar: chronic lithium toxicity in patients taking ACE inhibitor

A patient with bipolar I disorder has been treated with lithium and haloperidol for the last 20 years and received an ACE inhibitor for his hypertension since 9 years ago. Despite regular clinic follow-ups and blood monitoring, he recently developed tremors and delirium. On hospital admission, serum level of lithium was far above toxic level. Mental state examination revealed an anxious and disorientated man with irrelevant speech. Immediate discontinuation of lithium resulted in slow reduction of serum lithium levels and gradual resolution of tremor but his delirium persisted for 2 weeks. His condition took a turn for the worse when he developed acute renal failure and arm abscess. We discussed about lithium toxicity and the vulnerability factors which have induced delirium and renal failure in this patient.

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Novel oral anticoagulant and kidney injury: apixaban-related acute interstitial nephritis

Non-vitamin K oral anticoagulants (NOACs) are being increasingly prescribed. These drugs act rapidly, have predictable dose-related anticoagulation effect and require no routine laboratory monitoring, making them attractive for both patients and healthcare providers. All NOACs are at least partially excreted thought the kidneys. Renal injury related to NOAC use is being increasingly reported. NOAC-related acute interstitial nephritis (AIN) has only been reported once and that was in context of dabigatran use. We describe the first case of apixaban-related AIN. This case adds an important differential diagnoses that should be considered for any patient presenting with renal injury while being treated with NOACs.

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Abdominal tuberculosis and spontaneous miscarriage

We present a case report of a 23-year-old Pakistani woman who had a second trimester spontaneous miscarriage while visiting her family in the Kingdom of Saudi Arabia. A dilatation and curettage (D&C) was done after the miscarriage. She developed sepsis and acute respiratory distress syndrome, requiring intensive care unit admission a few days after the D&C. An exploratory laparotomy was done and she was found to have a pelvic abscess. Despite adequate broad spectrum antimicrobial cover, she continued to drain a copious amount of serous fluid from the peritoneal cavity, with persistent fever and a stiff lung with difficult weaning off mechanical ventilation. Tuberculosis PCR of the peritoneal fluid came back positive. A histological finding of necrotising granuloma from the postoperative omental specimen and a positive culture from the ascitic fluid confirmed the diagnosis of Mycobacterium tuberculosis. Antituberculous treatment was started and she made a speedy recovery.

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Multiple sclerotic fibromas of the skin: an important clue for the diagnosis of Cowden syndrome

Cowden syndrome is a rare autosomal dominant condition characterised by mucocutaneous hamartomas and, most importantly, predisposition to various extracutaneous benign and malignant tumours. This disorder is associated with a germline mutation in the phosphatase and tensin homologue gene, a tumour suppressor gene, located on 10q23 chromosome. The expressivity of this genodermatosis is highly variable, therefore many of the cases remain undiagnosed. Skin and mucous findings are very common in Cowden syndrome and may represent the initial clinical manifestation leading to the diagnosis. The authors describe a case of a 58-year-old man with multiple cutaneous sclerotic fibromas associated with a previously unrecognised Cowden syndrome.

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Clinical applications of dendritic cells–cytokine-induced killer cells mediated immunotherapy for pancreatic cancer: an up-to-date meta-analysis

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Improved survival using specialized multidisciplinary board in sarcoma patients

Abstract:

BackgroundSarcomas are rare but aggressive diseases. Specialized multidisciplinary management is not implemented for all patients in most countries. We investigated the impact of a multidisciplinary tumor board (MDTB) presentation prior to treatment in a nationwide study over 5 years.Patients and methods:NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized MDTB, funded by the French National Cancer Institute to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma patients in France. Patients' characteristics and follow-up are collected in a database regularly monitored and updated. The management and survival of patients presented to these MDTB before versus after initial treatment were analyzed.ResultsOut of the 12,528 patients aged > =15, with a first diagnosis of soft tissue and visceral sarcoma obtained between 1/1/2010 and 31/12/2014, 5,281 (42.2%) and 7,247 (57.8%) were presented to the MDTB before and after the initiation of treatment respectively. The former group had generally worse prognostic characteristics. Presentation to a MDTB before treatment was associated with a better compliance to clinical practice guidelines, e.g. biopsy before surgery, imaging, quality of initial surgery, and less reoperations (all p < 0.001). Local relapse-free survival and relapse-free survival were significantly better in patients presented to a MDTB before initiation of treatment, both in univariate and multivariate analysis.ConclusionThe compliance to clinical practice guidelines and relapse-free survival of sarcoma patients are significantly better when the initial treatment is guided by a pre-therapeutic specialized MDTB.

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Survivin: a novel marker and potential therapeutic target for human angiosarcoma

Summary

Human angiosarcoma is a rare malignant vascular tumor associated with extremely poor clinical outcome and generally arising in the skin of head and neck. However, little is known about the molecular pathogeneses and useful immunohistochemical markers of angiosarcoma. To investigate the mechanisms of angiosarcoma progression, we collected 85 cases of human angiosarcoma specimens with clinical records and used ISO-HAS-B patient derived angiosarcoma cells. As control subjects, 54 cases of hemangioma and 34 of pyogenic granuloma were collected. Remarkably, consistent with our recent observations regarding the involvement of Survivin expression following Hippo pathway inactivation in the neoplastic proliferation of murine hemangioendothelioma cells and human infantile hemangioma, nuclear Survivin expression was observed in all cases of angiosarcoma but not in hemangiomas and pyogenic granulomas and Hippo pathway was inactivated in 90.3% of YAP-positive angiosarcoma cases. However, Survivin expression modes and YAP localization (Hippo pathway activation modes) were not correlated with survival. In addition, we confirmed that Survivin small interference RNA (siRNA) transfection and YM155, an anti-Survivin drug, elicited decreased nuclear Survivin expression and cell proliferation in ISO-HAS-B cells which expressed Survivin consistently. Conclusively, these findings support the importance of Survivin as a good marker and critical regulator of cellular proliferation for human angiosarcoma and YM155 as a potential therapeutic agent.

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Mutational analysis using Sanger and Next Generation Sequencing in sporadic spindle cell hemangiomas: A study of 19 cases

Abstract

Spindle cell hemangioma (SCH) is a distinct vascular soft tissue lesion characterized by cavernous blood vessels and a spindle cell component mainly occurring in the distal extremities of young adults. The majority of cases harbor heterozygous mutations in IDH1/2 sporadically or rarely in association with Maffucci syndrome. However, based on mosaicism and accordingly a low percentage of lesional cells harboring a mutant allele, detection can be challenging. We tested 19 sporadic SCHs by Sanger sequencing, Multiplex Ligation-dependent Probe Amplification (MLPA), conventional Next Generation Sequencing (NGS) and NGS using a Single Molecule Molecular Inversion Probes (smMIP) based library preparation in order to compare their diagnostic value. Four out of ten cases tested by Sanger sequencing and one of the two cases analyzed using MLPA revealed a mutation in IDH1 (p.R132C). The seven remaining negative cases and additional six cases were investigated using smMIP/NGS, showing hot spot mutations in IDH1 (p.R132C) (eight cases) and IDH2 (three cases; twice p.R172S and once p.R172G, respectively). One case was negative. Due to insufficient DNA quality and insufficient coverage, two cases were excluded. In total, in 16 out of 17 cases successfully tested an IDH1/2 mutation was found. Given that IDH1/2 mutations were absent in 161 other vascular lesions tested by smMIP/NGS, the mutation can be considered as highly specific for SCH. This article is protected by copyright. All rights reserved.

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A phase II study of modified docetaxel, cisplatin, and S-1 (mDCS) chemotherapy for unresectable advanced gastric cancer

Abstract

Purpose

Triplet therapy using docetaxel, cisplatin, and S-1 (DCS) against unresectable gastric cancer as previously reported by us showed high clinical efficacy, with a 87.1% total response rate; however, it also showed a high incidence of grade 3/4 toxicity. With the aim of reducing toxicities, we conducted a phase II study of modified DCS (mDCS), using a reduced dose of docetaxel, and evaluated the clinical efficacy and adverse events of this regimen.

Methods

Patients with unresectable gastric cancer received chemotherapy with S-1 (40 mg/m² b.i.d) on days 1–14, and docetaxel (50 mg/m²) plus cisplatin (60 mg/m²) on day 8 every 3 weeks. The primary endpoint was the response rate (RR). Overall (OS) and progression-free survival (PFS), and toxicities were also evaluated.

Results

Forty-nine patients were enrolled from November 2011 to April 2014, and 43 were eligible. The overall RR was 79.1%, including two cases of a complete response (4.7%), and 32 cases of a partial response (74.4%). Nine cases had stable disease (20.9%) but none showed progressive disease. Of the 43 cases, 15 cases (34.9%) underwent curative conversion surgery. The median PFS was 350 days (95% CI 240–416 days) and median OS was 722 days (95% CI 411 days–not reached). Grade 3/4 neutropenia developed in 79.1%, and febrile neutropenia in 34.9%, of patients. Non-hematological grade 3/4 adverse events were anorexia (25.6%), nausea (4.7%), and diarrhea (9.3%).

Conclusion

Modified DCS therapy showed high clinical efficacy sufficient enough to attempt conversion therapy against unresectable gastric cancer. Modified DCS showed fewer toxicities, but careful management of these is still essential.

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The insufficient prognostic power of stenosis in patients with esophageal cancer

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Disparities in cancer incidence by area-level socioeconomic status in the French West Indies

Abstract

Purpose

Social inequalities in cancer incidence and mortality have been reported in France, but no data are available for the French overseas territories. Our objective was to explore the association between cancer incidence and the socioeconomic level of the residence area in the French West Indies.

Methods

Cancer incidence data were obtained from the cancer registries of Guadeloupe and Martinique (2009–2010). To assess socioeconomic status, we developed a specific index of social deprivation from census data at a small area level. We used Bayesian methods to evaluate the association between cancer incidence and the deprivation index, for all cancers combined and for the major cancer sites.

Results

There was no clear association between area-based deprivation and the incidence of all cancers combined. In men, higher area deprivation was associated with a higher incidence of prostate cancer (relative risk (RR) 1.25, 95% credible interval (CI) 1.04–1.49; RR 1.08, CI 0.91–1.29 in the categories of intermediate and high deprivation, respectively, compared to low deprivation), but was not associated with respiratory cancer. Women living in the most deprived areas had a higher incidence of stomach (RR 1.77, CI 1.12–2.89), breast (RR 1.15, CI 0.90–1.45), and cervical (RR 1.13, CI 0.63–2.01) cancers and a lower incidence of respiratory cancer (RR 0.65, CI 0.38–1.11).

Conclusion

These first results in the French West Indies suggest specific patterns for some cancer sites that need to be further investigated.

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Pubertal growth and adult height in relation to breast cancer risk in African American women

Abstract

Adult height has been positively associated with breast cancer risk. The timing of pubertal growth – as measured by age at menarche and age at attained height – may also influence risk. We evaluated associations of adult height, age at attained height, and age at menarche with incidence of invasive breast cancer in 55,687 African American women in the prospective Black Women's Health Study. Over 20 years, 1,826 invasive breast cancers [1,015 estrogen receptor (ER) positive; 542 ER negative] accrued. We used multivariable Cox proportional hazards regression to estimate hazards ratios (HRs) and 95% confidence intervals (CIs) for associations with breast cancer overall and by ER status, mutually adjusted for the three factors of interest. Adult height was associated with increased risk of ER+ breast cancer (HR for ≥70 inches vs. ≤63 inches: 1.44; 95% CI: 1.09, 1.89) but not ER- (corresponding HR: 1.16; 95% CI: 0.78, 1.71) (P-heterogeneity=0.34). HRs for attained height before age 13 vs. age >17 were 1.30 (95% CI: 0.96, 1.76) for ER+ and 1.25 (95% CI: 0.80, 1.96) for ER- breast cancer. Results for age at menarche (≤11 years vs. ≥14 years) were similar for ER+ and ER- breast cancer (HR for breast cancer overall: 1.30; 95%CI: 1.12, 1.50). We confirmed height as a strong risk factor for ER+ breast cancer in African American women and identified early age at attained height as a risk factor for both ER+ and ER- breast cancer, albeit without statistical significance of the latter associations. While adult height and timing of pubertal growth are inter-related, our findings suggest that they may be independent risk factors for breast cancer. This article is protected by copyright. All rights reserved.

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