Statin use after esophageal cancer diagnosis and survival: A population based cohort study

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Chris R. Cardwell, Andrew D. Spence, Carmel M. Hughes, Liam J. Murray
BackgroundA recent epidemiological study of esophageal cancer patients concluded statin use post-diagnosis was associated with large (38%) and significant reductions in cancer-specific mortality. We investigated statin use and cancer-specific mortality in a large population-based cohort of esophageal cancer patients.MethodsNewly diagnosed [2009–2012] esophageal cancer patients were identified from the Scottish Cancer Registry and linked with the Prescribing Information System and Scotland Death Records (to January 2015). Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by post-diagnostic statin use (using a 6 month lag to reduce reverse causation) and to adjust these HRs for potential confounders.Results1921 esophageal cancer patients were included in the main analysis, of whom 651 (34%) used statins after diagnosis. There was little evidence of a reduction in esophageal cancer-specific mortality in statin users compared with non-users after diagnosis (adjusted HR=0.93, 95% CI, 0.81, 1.07) and no dose response associations were seen. However, statin users compared with non-users in the year before diagnosis had a weak reduction in esophageal cancer-specific mortality (adjusted HR=0.88, 95% CI, 0.79, 0.99).ConclusionsIn this large population-based esophageal cancer cohort, there was little evidence of a reduction in esophageal cancer-specific mortality with statin use after diagnosis.



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Statin use after esophageal cancer diagnosis and survival: A population based cohort study

Publication date: June 2017
Source:Cancer Epidemiology, Volume 48
Author(s): Chris R. Cardwell, Andrew D. Spence, Carmel M. Hughes, Liam J. Murray
BackgroundA recent epidemiological study of esophageal cancer patients concluded statin use post-diagnosis was associated with large (38%) and significant reductions in cancer-specific mortality. We investigated statin use and cancer-specific mortality in a large population-based cohort of esophageal cancer patients.MethodsNewly diagnosed [2009–2012] esophageal cancer patients were identified from the Scottish Cancer Registry and linked with the Prescribing Information System and Scotland Death Records (to January 2015). Time-dependent Cox regression models were used to calculate hazard ratios (HR) for cancer-specific mortality and 95% confidence intervals (CIs) by post-diagnostic statin use (using a 6 month lag to reduce reverse causation) and to adjust these HRs for potential confounders.Results1921 esophageal cancer patients were included in the main analysis, of whom 651 (34%) used statins after diagnosis. There was little evidence of a reduction in esophageal cancer-specific mortality in statin users compared with non-users after diagnosis (adjusted HR=0.93, 95% CI, 0.81, 1.07) and no dose response associations were seen. However, statin users compared with non-users in the year before diagnosis had a weak reduction in esophageal cancer-specific mortality (adjusted HR=0.88, 95% CI, 0.79, 0.99).ConclusionsIn this large population-based esophageal cancer cohort, there was little evidence of a reduction in esophageal cancer-specific mortality with statin use after diagnosis.



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Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GIST) have emerged as a compelling clinical and biological model for the rational development of therapeutic strategies targeting critical oncogenic events over the past two decades. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial driver for GIST tumor initiation, transformation, and cancer cell proliferation. Three tyrosine kinase inhibitors (TKIs) with KIT inhibitory activity – imatinib, sunitinib, and regorafenib – are approved to treat advanced GIST and have successfully exploited this addiction to KIT oncogenic signaling, demonstrating remarkable activity in a disease that historically had no successful systemic therapy options. However, GIST refractory to approved TKIs remain an unmet clinical need, as virtually all patients with metastatic GIST eventually progress on any given therapy. The main and best-established mechanism of resistance is the polyclonal expansion of multiple subpopulations harboring different secondary KIT mutations. The present review aims at summarizing current and forthcoming treatment directions in advanced imatinib-resistant GIST supported by a strong biological rationale.

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Novel Insights into the Treatment of Imatinib-Resistant Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GIST) have emerged as a compelling clinical and biological model for the rational development of therapeutic strategies targeting critical oncogenic events over the past two decades. Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial driver for GIST tumor initiation, transformation, and cancer cell proliferation. Three tyrosine kinase inhibitors (TKIs) with KIT inhibitory activity – imatinib, sunitinib, and regorafenib – are approved to treat advanced GIST and have successfully exploited this addiction to KIT oncogenic signaling, demonstrating remarkable activity in a disease that historically had no successful systemic therapy options. However, GIST refractory to approved TKIs remain an unmet clinical need, as virtually all patients with metastatic GIST eventually progress on any given therapy. The main and best-established mechanism of resistance is the polyclonal expansion of multiple subpopulations harboring different secondary KIT mutations. The present review aims at summarizing current and forthcoming treatment directions in advanced imatinib-resistant GIST supported by a strong biological rationale.

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Young adult cancer survivors and work: a systematic review

Abstract

Context

Sixty-three percent of cancer survivors continue to work, or return to work after treatment. Among this population, work ability and challenges encountered in the workplace by young adult cancer survivors have not been well established.

Purpose

The purposes of the study are to describe what is currently known about work-related issues for young adult cancer survivors diagnosed between ages 15 and 39, to identify gaps in the research literature, and to suggest interventions or improvements in work processes and occupational settings.

Methods

A narrative review of articles using PubMed, CINAHL, and PsychInfo was conducted without date limitations. Search phrases included young adult cancer survivors, long-term cancer survivors, young adults affected by cancer, further combined with key terms employment, work, and occupationally active. Inclusion criteria for publications were young adult cancer survivors initially diagnosed between the ages of 15 and 39, data about work or employment was presented, and articles written in English.

Results

Twenty-three publications met the inclusion criteria. Work-related issues included the potential for reduced work productivity from cancer-changed physical and cognitive functional ability that affected income, and resulted in distress. Coping style, support systems, and changing perspectives about work and life in general were also influential on career decisions among young adult cancer survivors.

Conclusions

More research is needed to study interventions to better manage health changes in young adult cancer survivors within the context of the workplace. Since financial hardship has been shown to be especially high among young cancer survivors, employment is essential to ensure payment of cancer-associated costs and continued medical care.

Implications for Cancer Survivors

While young adult cancer survivors may initially grapple with cancer-related physical and psychosocial changes that impact work productivity or influence choice of occupation, employment appears to enhance overall quality of life.

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Young adult cancer survivors and work: a systematic review

Abstract

Context

Sixty-three percent of cancer survivors continue to work, or return to work after treatment. Among this population, work ability and challenges encountered in the workplace by young adult cancer survivors have not been well established.

Purpose

The purposes of the study are to describe what is currently known about work-related issues for young adult cancer survivors diagnosed between ages 15 and 39, to identify gaps in the research literature, and to suggest interventions or improvements in work processes and occupational settings.

Methods

A narrative review of articles using PubMed, CINAHL, and PsychInfo was conducted without date limitations. Search phrases included young adult cancer survivors, long-term cancer survivors, young adults affected by cancer, further combined with key terms employment, work, and occupationally active. Inclusion criteria for publications were young adult cancer survivors initially diagnosed between the ages of 15 and 39, data about work or employment was presented, and articles written in English.

Results

Twenty-three publications met the inclusion criteria. Work-related issues included the potential for reduced work productivity from cancer-changed physical and cognitive functional ability that affected income, and resulted in distress. Coping style, support systems, and changing perspectives about work and life in general were also influential on career decisions among young adult cancer survivors.

Conclusions

More research is needed to study interventions to better manage health changes in young adult cancer survivors within the context of the workplace. Since financial hardship has been shown to be especially high among young cancer survivors, employment is essential to ensure payment of cancer-associated costs and continued medical care.

Implications for Cancer Survivors

While young adult cancer survivors may initially grapple with cancer-related physical and psychosocial changes that impact work productivity or influence choice of occupation, employment appears to enhance overall quality of life.

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Review of radiological classifications of pancreatic cancer with peripancreatic vessel invasion: are new grading criteria required?

Abstract

Pancreatic cancer is mainly diagnosed at an advanced stage when adjacent vessel invasion is present; however, radical resection is potentially curative for selected patients with adjacent vessel invasion. Therefore, accurately judging the resectability of patients with adjacent vessel invasion represents a crucially important step in diagnosis and treatment. Currently, decisions regarding resectability are based on imaging studies, commonly contrast computed tomography (CT). Several radiological classifications have been published for vascular infiltration in pancreatic cancer. However, radiologists always formulate these CT grading systems according to their own experience, resulting in different judgment methods and parameters. And it is controversial in evaluating performance and clinical application. Besides, the conventional CT grading systems mainly focus on the evaluation of vessel invasion so as to less on the outcome of patient evaluation. In this review, we summarize the mainstream CT grading systems for vascular invasion in pancreatic cancer, with the aim of improving the clinical value of CT grading systems for predicting resectability and survival.

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Review of radiological classifications of pancreatic cancer with peripancreatic vessel invasion: are new grading criteria required?

Abstract

Pancreatic cancer is mainly diagnosed at an advanced stage when adjacent vessel invasion is present; however, radical resection is potentially curative for selected patients with adjacent vessel invasion. Therefore, accurately judging the resectability of patients with adjacent vessel invasion represents a crucially important step in diagnosis and treatment. Currently, decisions regarding resectability are based on imaging studies, commonly contrast computed tomography (CT). Several radiological classifications have been published for vascular infiltration in pancreatic cancer. However, radiologists always formulate these CT grading systems according to their own experience, resulting in different judgment methods and parameters. And it is controversial in evaluating performance and clinical application. Besides, the conventional CT grading systems mainly focus on the evaluation of vessel invasion so as to less on the outcome of patient evaluation. In this review, we summarize the mainstream CT grading systems for vascular invasion in pancreatic cancer, with the aim of improving the clinical value of CT grading systems for predicting resectability and survival.

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Role of microscopic spread beyond gross disease as an adverse prognostic factor in oral squamous cell carcinoma

Publication date: Available online 6 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Aseem Mishra, Sourav Datta, Akshat Malik, Apurva Garg, Deepa Nair, Sudhir Nair, Manish Mair, Munita Bal, Jaiprakash Agarwal, Pankaj Chaturvedi
IntroductionDespite meticulous surgery and proper adjuvant treatment, outcome of oral squamous cell carcinoma remains unpredictable. This shows that there may be other factors which should be considered while prognosticating these patients. Many a times there is spread of disease beyond the gross margin which can alter the margin status. We hypothesized that microscopic spread beyond gross disease may portend a poor prognosis.MethodThis is a retrospective study of prospectively collected data of 1025 treatment naïve oral squamous cell carcinoma patients. All patients underwent surgery from January 2012 to October 2013, this was followed by appropriate adjuvant treatment. Demographic and histopathological details were noted from the electronic medical records.ResultsMicroscopic spread beyond gross disease (MSGD) is associated with higher incidence of nodal positivity (p<0.046), perineural invasion (p<0.001), thicker tumors (p<0.024) and poor differentiation (p<0.060). The overall survival in patients with MSGD was 32.45 months versus 37.5 months in patients without MSGD (p<0.002).ConclusionTumors with MSGD tend to have a higher incidence of nodal metastasis, PNI and thicker tumors. Presence of MSGD was associated with lower overall survival as compared to those without.



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Long-term follow-up after near-infrared fluorescence-guided resection of colorectal liver metastases: a retrospective multicenter analysis

Publication date: Available online 6 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Henricus J.M. Handgraaf, Leonora S.F. Boogerd, Diederik J. Höppener, Andrea Peloso, Babs G. Sibinga Mulder, Charlotte E.S. Hoogstins, Henk H. Hartgrink, Cornelis J.H. van de Velde, J. Sven D. Mieog, Rutger-Jan Swijnenburg, Hein Putter, Marcello Maestri, Andries E. Braat, John V. Frangioni, Alexander L. Vahrmeijer
BackgroundSeveral studies demonstrated that intraoperative near-infrared fluorescence (NIRF) imaging using indocyanine green (ICG) identifies (sub)capsular colorectal liver metastases (CRLM) missed by other techniques. It is unclear if this results in any survival benefit. This study evaluates long-term follow-up after NIRF-guided resection of CRLM using ICG.MethodsFirst, patients undergoing resection of CRLM with or without NIRF imaging were analyzed retrospectively. Perioperative details, liver-specific recurrence-free interval and overall survival were compared. Second, the prognosis of patients in whom additional metastases were identified solely by NIRF was studied.ResultsEighty-six patients underwent resection with NIRF imaging and 87 without. In significantly more patients of the NIRF imaging cohort additional metastases were identified during surgery (25% vs. 13%, p=0.04). Tumors identified solely by NIRF imaging were significantly smaller compared to additional metastases identified also by inspection, palpation or intraoperative ultrasound (3.2 ± 1.8 mm vs. 7.4 ± 2.6 mm, p<0.001). Liver-specific recurrence-free survival at 4 years was 47% with NIRF imaging and 39% without (hazard ratio at multivariate analysis 0.73, 95%CI 0.42-1.28, p=0.28). Overall survival at 4 years was 62% and 59%, respectively (p=0.79). No liver recurrences occurred within 3 years follow-up in 52% of patients in whom additional metastases were resected based on only NIRF imaging.ConclusionsThis study suggests that NIRF imaging identifies significantly more and smaller tumors during resection of CRLM, preventing recurrences in a subset of patients. Given its safety profile and low expense, routine use can be considered until tumor targeting fluorescent tracers are clinically available.



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Prognostic implications of occult nodal tumour cells in stage I and II colon cancer

Publication date: Available online 5 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): Didi.A.M. Sloothaak, Ragna. L.A. van der Linden, Cornelis J.H. van de Velde, Willem A. Bemelman, Daan.J. Lips, J.C. van der Linden, Heleen Doornewaard, Pieter.J. Tanis, Koop Bosscha, Edwin S. van der Zaag, Christianne J. Buskens
INTRODUCTIONOccult nodal tumour cells should be categorised as micrometastasis (MMs) and isolated tumour cells (ITCs). A recent meta-analysis demonstrated that MMs, but not ITCs, are prognostic for disease recurrence in patients with stage I/II colon cancer.AIMS & METHODS: The objective of this retrospective multicenter study was to correlate MMs and ITCs to characteristics of the primary tumour, and to determine their prognostic value in patients with stage I/II colon cancer.RESULTS192 patient were included in the study with a median follow up of 46 month (IQR 33-81 months). MMs were found in eight patients (4.2%), ITCs in 37 (19.3%) and occult tumour cells were absent in 147 patients (76.6%). Between these groups, tumour differentiation and venous or lymphatic invasion was equally distributed. Advanced stage (pT3/pT4) was found in 66.0% of patients without occult tumour cells (97/147), 72.9% of patients with ITCs (27/37), and 100% in patients with MMs (8/8), although this was a non-significant trend. Patients with MMs showed a significantly reduced 3 year-disease free survival compared to patients with ITCs or patients without occult tumour cells (75,0% versus 88,0% and 94,8%, respectively, p=0.005). When adjusted for T-stage, MMs independently predicted recurrence of cancer (OR 7.6 95%CI 1.5-37.4, p=0.012)CONCLUSIONIn this study, the incidence of MMs and ITCs in patients with stage I/II colon cancer was 4.2% and 19.3%, respectively. MMs were associated with an reduced 3 year disease free survival rate, but ITCs were not.

Teaser

This study analysed the occurrence of nodal micrometastasis (MMs) and isolated tumour cells (ITCs) in relation to characteristics of the primary tumour and oncological outcome in 192 patients with stage I/II colon cancer. Nodal micrometastasis were associated with pT-stage and disease recurrence, but ITCs were not.


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The management of soft tissue tumours of the abdominal wall

Publication date: Available online 6 May 2017
Source:European Journal of Surgical Oncology (EJSO)
Author(s): H.G. Smith, D. Tzanis, C. Messiou, C. Benson, J.A. van der Hage, M. Fiore, S. Bonvalot, A.J. Hayes
Background: Soft tissue tumours of the abdominal wall account for approximately 10% of all soft tissue tumours. Tumours at this site comprise a heterogeneous group of pathologies with distinct clinical behaviours and responses to treatment. The management of these tumours has largely been extrapolated from studies of soft tissue tumours at other sites. This review aims to summarise the existing data relating to abdominal wall tumours and suggest principles for managing soft tissue tumours at this site.MethodsRelevant articles were retrieved from a comprehensive literature search using the PubMed database. Key words included abdominal wall, soft tissue tumours, surgery, radiotherapy and chemotherapy. No restrictions on publication date were used.ResultsThe most common pathologies presenting in the abdominal wall are desmoid tumours, soft-tissue sarcoma and dermatofibrosarcoma protuberans (DFSP). Desmoid tumours should be managed with an initial period of observation, with surgery reserved for progressive lesions. Surgery should be the primary treatment for soft-tissue sarcomas and DFSP, with radiotherapy reserved for large-high grade tumours and preferentially given pre-operatively.ConclusionsAbdominal wall tumours are rare and should be managed in centres with experience in the management of soft tissue tumours. Management should be tailored to the biological behaviour of specific pathologies.



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Safety and efficacy of radium-223 dichloride in Japanese patients with castration-resistant prostate cancer and bone metastases

Abstract

Background

Radiation therapy with radium-223 dichloride improves overall survival, reduces symptomatic skeletal events in Caucasian patients with castration-resistant prostate cancer (CRPC) and bone metastases, and is well tolerated. We report here the results of the first efficacy and safety study of radium-223 dichloride in a Japanese population.

Methods

In this open-label, uncontrolled, non-randomized, phase I trial, radium-223 dichloride was given to Japanese patients with CRPC and ≥2 bone metastases in 4-week cycles. The patients were divided into three cohorts, with cohort 1 and the expansion cohort receiving injections of radium-223 dichloride [55 kBq/kg body weight (BW)] every 4 weeks (Q4W) for up to six injections, and cohort 2 receiving an initial single radium-223 dichloride injection of 110 kBq/kg BW followed by up to five injections of 55 kBq/kg BW Q4W. Safety was determined via adverse event (AE) reporting, and biochemical bone markers were assessed for treatment efficacy.

Results

In total 19 patients received at least one dose of radium-223 dichloride and 18 patients experienced at least one treatment-emergent AE (TEAE) of which the most common were anemia, thrombocytopenia, and lymphocytopenia. Serious AEs were reported in three patients but none were drug-related. In the patients of cohort 1 + expansion cohort (55 kBq/kg BW Q4W treatment; n = 16), prostate-specific antigen levels remained stable or slightly increased while the bone alkaline phosphatase (ALP) level significantly decreased. The response rates of bone ALP (≥30 and ≥50% reductions) were 81.8 and 36.4% at week 12, and 81.3 and 50.0% at the end of treatment.

Conclusions

Radium-223 dichloride was well tolerated in these Japanese patients and, at a dose of 55 kBq/kg BW, efficacy on biomarkers was as expected. The outcomes in Japanese patients were consistent with those reported in other non-Japanese populations.

Trial registration

ClinicalTrials.gov record NCT01565746.

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Safety and efficacy of radium-223 dichloride in Japanese patients with castration-resistant prostate cancer and bone metastases

Abstract

Background

Radiation therapy with radium-223 dichloride improves overall survival, reduces symptomatic skeletal events in Caucasian patients with castration-resistant prostate cancer (CRPC) and bone metastases, and is well tolerated. We report here the results of the first efficacy and safety study of radium-223 dichloride in a Japanese population.

Methods

In this open-label, uncontrolled, non-randomized, phase I trial, radium-223 dichloride was given to Japanese patients with CRPC and ≥2 bone metastases in 4-week cycles. The patients were divided into three cohorts, with cohort 1 and the expansion cohort receiving injections of radium-223 dichloride [55 kBq/kg body weight (BW)] every 4 weeks (Q4W) for up to six injections, and cohort 2 receiving an initial single radium-223 dichloride injection of 110 kBq/kg BW followed by up to five injections of 55 kBq/kg BW Q4W. Safety was determined via adverse event (AE) reporting, and biochemical bone markers were assessed for treatment efficacy.

Results

In total 19 patients received at least one dose of radium-223 dichloride and 18 patients experienced at least one treatment-emergent AE (TEAE) of which the most common were anemia, thrombocytopenia, and lymphocytopenia. Serious AEs were reported in three patients but none were drug-related. In the patients of cohort 1 + expansion cohort (55 kBq/kg BW Q4W treatment; n = 16), prostate-specific antigen levels remained stable or slightly increased while the bone alkaline phosphatase (ALP) level significantly decreased. The response rates of bone ALP (≥30 and ≥50% reductions) were 81.8 and 36.4% at week 12, and 81.3 and 50.0% at the end of treatment.

Conclusions

Radium-223 dichloride was well tolerated in these Japanese patients and, at a dose of 55 kBq/kg BW, efficacy on biomarkers was as expected. The outcomes in Japanese patients were consistent with those reported in other non-Japanese populations.

Trial registration

ClinicalTrials.gov record NCT01565746.

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Clinicopathological and Molecular Study of Triple-Negative Breast Cancer in Algerian Patients

Abstract

Triple-negative breast cancer (TNBC) is associated with aggressive tumor behavior, poor prognosis and BRCA1 mutations. There are limited data regarding TNBC among Algerian women. In this study, we sought to determine clinical and tumor characteristics associated with TNBC. We also screened for the prevalence of BRCA1 mutations in unselected cohort of TNBC patients. Clinical and tumor characteristics data of 877 breast cancer patients diagnosed between 2011 and 2015, were collected from cancer registry of public hospital of Rouiba. Patients were divided in two groups: those with TNBC and those with other breast cancer subtypes. Differences between the two groups with regard to clinical and tumor characteristics were compared using Fisher's exact test. BRCA1 mutations analysis was performed in unselected cohort of 103 women with TNBC, including all exons where a mutation was previously found in Algerian population (exons 2, 3, 5, 11). The median age at diagnosis for TNBC and non-TNBC patients was 47.4 years and 49.4 years, respectively. The proportion of TNBC was 19.95%. Our data showed significant differences in menopausal status, TNM stage, histological type, tumor histological grade, Ki67 expression and family history of breast cancer between TNBC and non-TNBC patients. Four distinct deleterious mutations in BRCA1 gene were detected in eight young TNBC patients. TNBC is associated with young age, poor histopathological characteristics and family history of breast cancer. BRCA1 mutations have been detected in young TNBC patients. TNBC phenotype should be added as criterion to screen for BRCA1 mutations in Algerian women.

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Melanoma antigens and related immunological markers

Publication date: Available online 6 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Jacob Pitcovski, Ehud Shahar, Elina Aizenshtein, Raphael Gorodetsky
Melanoma is a highly lethal cancer deriving from transformed dermal melanocytes. Early diagnosed primary melanoma may be curable, but the cure-rate of more advanced stages is limited, with high mortality rate. With the progression of the tumor, the melanocytes overexpress intracellular or cell-surface molecules, including ectopic normal and tumor-specific proteins. Some of these induce a specific immune response by T and B lymphocytes. Antibodies raised against melanoma antigens were proposed for differential disease diagnosis, staging, prognosis and evaluation of treatment efficiency. Nevertheless, treatments based on stimulation of specific anti-melanoma immune responses have had only limited success. It seems that efficient immunotherapy should become more feasible pending on finding new adequate antigens to target. New insights into immune regulation of the tumor microenvironment and its progression may help the development of more successful treatments. We present here up-to-date information on known major melanoma-associated antigens, which could serve as tools for diagnosis as well as for clinical immunotherapy. This approach with promising results for treating some other selected malignancies is still experimental with a very limited success in melanoma. The development of new immune modulators of the tumor microenvironment and neo-antigens may be additional promising directions and may open new opportunities for the immunotherapy of melanoma.



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Melanoma antigens and related immunological markers

Publication date: Available online 6 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Jacob Pitcovski, Ehud Shahar, Elina Aizenshtein, Raphael Gorodetsky
Melanoma is a highly lethal cancer deriving from transformed dermal melanocytes. Early diagnosed primary melanoma may be curable, but the cure-rate of more advanced stages is limited, with high mortality rate. With the progression of the tumor, the melanocytes overexpress intracellular or cell-surface molecules, including ectopic normal and tumor-specific proteins. Some of these induce a specific immune response by T and B lymphocytes. Antibodies raised against melanoma antigens were proposed for differential disease diagnosis, staging, prognosis and evaluation of treatment efficiency. Nevertheless, treatments based on stimulation of specific anti-melanoma immune responses have had only limited success. It seems that efficient immunotherapy should become more feasible pending on finding new adequate antigens to target. New insights into immune regulation of the tumor microenvironment and its progression may help the development of more successful treatments. We present here up-to-date information on known major melanoma-associated antigens, which could serve as tools for diagnosis as well as for clinical immunotherapy. This approach with promising results for treating some other selected malignancies is still experimental with a very limited success in melanoma. The development of new immune modulators of the tumor microenvironment and neo-antigens may be additional promising directions and may open new opportunities for the immunotherapy of melanoma.



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A Review of Autologous Stem Cell Transplantation in Lymphoma

Abstract

Purpose of Review

Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20–30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients.

Recent Findings

There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL.

Summary

Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.

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A Review of Autologous Stem Cell Transplantation in Lymphoma

Abstract

Purpose of Review

Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20–30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients.

Recent Findings

There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL.

Summary

Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.

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Diaphragmatic Surgery and Related Complications In Primary Cytoreduction for Advanced Ovarian, Tubal, and Peritoneal Carcinoma

Abstract

Background

To evaluate the procedures and complications of diaphragm peritonectomy (DP) and diaphragm full-thickness resection (DFTR) during primary cytoreduction for advanced stage epithelial ovarian cancer.

Methods

All the patients with epithelial ovarian carcinoma who underwent diaphragm procedures at our institution between January 2009 and August 2015 were identified. Clinicopathological data were retrospectively collected from the patients' medical records. Postoperative morbidities were assessed according to the Memorial Sloan-Kettering Cancer Center (MSKCC) grading system.

Results

A total of 150 patients were included in the study. The majority of the patients had ovarian cancer (96%), stage IIIC disease (76%) and serous histology (89.3%). DP and DFTR were performed in 124 (82.7%) and 26 (17.3%) patients, respectively. A total of 142 upper abdominal procedures in addition to the diaphragmatic surgery were performed in 77 (51.3%) patients. No macroscopic residual disease was observed in 35.3% of the patients, while 84% of the total patient cohort had residual disease ≤1 cm. The overall incidence of at least one major morbidity (MSKCC grades 3–5) was 18.0%, whereas pleural effusions (33.3%), pneumonia (15.3%) and pneumothorax (7.3%) were the most commonly reported morbidities. The rate of postoperative pleural drainage was 14.6% in total, while half the patients in the DFTR group received drainage intraoperatively (11.5%) and postoperatively (38.5%). The incidence of postoperative pleural effusion was associated with stage IV disease (hazard ratio [HR], 17.2; 95% confidence interval [CI]: 4.5–66.7; P < 0.001), DFTR (HR, 4.9; 95% CI: 1.2–19.9; P = 0.028) and a long surgery time (HR, 15.4; 95% CI: 4.3–55.5; P < 0.001).

Conclusions

Execution of DP and DFTR as part of an extensive upper abdominal procedure resulted in an acceptable morbidity rate. Pleural effusion, pneumonia and pneumothorax were the most common pulmonary morbidities. The pleural drainage rate was not high enough to justify prophylactic chest tube placement for all the patients. However, patients who underwent DFTR merited special consideration for intraoperative prophylactic drainage.

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Diaphragmatic Surgery and Related Complications In Primary Cytoreduction for Advanced Ovarian, Tubal, and Peritoneal Carcinoma

Abstract

Background

To evaluate the procedures and complications of diaphragm peritonectomy (DP) and diaphragm full-thickness resection (DFTR) during primary cytoreduction for advanced stage epithelial ovarian cancer.

Methods

All the patients with epithelial ovarian carcinoma who underwent diaphragm procedures at our institution between January 2009 and August 2015 were identified. Clinicopathological data were retrospectively collected from the patients' medical records. Postoperative morbidities were assessed according to the Memorial Sloan-Kettering Cancer Center (MSKCC) grading system.

Results

A total of 150 patients were included in the study. The majority of the patients had ovarian cancer (96%), stage IIIC disease (76%) and serous histology (89.3%). DP and DFTR were performed in 124 (82.7%) and 26 (17.3%) patients, respectively. A total of 142 upper abdominal procedures in addition to the diaphragmatic surgery were performed in 77 (51.3%) patients. No macroscopic residual disease was observed in 35.3% of the patients, while 84% of the total patient cohort had residual disease ≤1 cm. The overall incidence of at least one major morbidity (MSKCC grades 3–5) was 18.0%, whereas pleural effusions (33.3%), pneumonia (15.3%) and pneumothorax (7.3%) were the most commonly reported morbidities. The rate of postoperative pleural drainage was 14.6% in total, while half the patients in the DFTR group received drainage intraoperatively (11.5%) and postoperatively (38.5%). The incidence of postoperative pleural effusion was associated with stage IV disease (hazard ratio [HR], 17.2; 95% confidence interval [CI]: 4.5–66.7; P < 0.001), DFTR (HR, 4.9; 95% CI: 1.2–19.9; P = 0.028) and a long surgery time (HR, 15.4; 95% CI: 4.3–55.5; P < 0.001).

Conclusions

Execution of DP and DFTR as part of an extensive upper abdominal procedure resulted in an acceptable morbidity rate. Pleural effusion, pneumonia and pneumothorax were the most common pulmonary morbidities. The pleural drainage rate was not high enough to justify prophylactic chest tube placement for all the patients. However, patients who underwent DFTR merited special consideration for intraoperative prophylactic drainage.

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Meningocele manque

Description

A 53-year-old man presented with right-sided sciatic-like pain. He was otherwise asymptomatic with no weakness, sphincter disturbances or gait problems. On examination, upper motor neuron signs were elicited in both lower limbs and an MRI of the whole spine was requested.

MRI showed dorsal tethering of the spinal cord secondary to a fibrous band, associated with two midline lipomas (figure 1). The affected cord segment was triangular in cross section (figure 2), and a syrinx was also observed at the affected level. Radiological appearances were compatible with meningocele manqué (MM).

Figure 1

Sagittal T2-weighted (A) and T1-weighted (B) MRI of the cervical spine shows a thin band of tissue tethering the dorsal cord to the dura at T1–2 level (arrow) with resultant formation of a syrinx. At T2–3 level, there is a focal lesion at the dorsal aspect of the thoracic cord...

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A curious cause of pseudo-haematuria: a neglected vaginal pessary

Description

Vaginal pessaries represent a valid therapeutic option for the management of female pelvic organ prolapse in elderly women with significant comorbidities. Although leading to good functional and quality of life outcomes, when neglected, they can cause significant and severe complications.1

An 87-year-old woman semidependent and uncooperative due to progressive Alzheimer's dementia, who has lived in a nursing home for the last 5 years, presented to our outpatient clinic for 'intermittent hematuria'. She carried a pelvic ultrasound documenting a 'polypoid formation with 23 mm on the posterior bladder wall suggesting a bladder tumour'.

The blood loss had been detected intermittently in the diaper that she uses for hygienic purposes.

There were no analytical abnormalities except for leucoerythrocyturia with positive Escherichia coli urine culture. The hypothesis of a urothelial lesion led to the scheduling of a cystoscopy under anaesthesia and an abdominopelvic CT scan.

The abdominopelvic CT scan documented...

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You are what you eat: ophthalmological manifestations of severe B12 deficiency

Severe B₁₂ vitamin deficiency due to diminished dietary intake is a known cause of severe pancytopenia with bleeding diathesis. The authors report a case with sudden-onset bilateral vision loss, severe pancytopenia and multiple organ failure secondary to B₁₂ vitamin deficiency in a patient with a strict vegetarian diet. On funduscopic examination the patient had multiple bilateral exuberant haemorrhages in all retinal layers. Five months after presentation, he had a complete visual recovery without ophthalmological intervention.

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Unilateral infective sacroiliitis in a boy presenting with a limp

A 9-year-old boy admitted to a district general hospital with a 1-week history of fever and a 2-day history of right hip pain. Initial workup revealed raised inflammatory markers and unremarkable imaging studies. After clinical review, there was minimal improvement of the patient's condition 5 days after presentation; therefore, an MRI of the pelvis/hips was carried out, which supported a clinical diagnosis of right-sided infective sacroiliitis. Infective sacroiliitis is rare and only represents 1%–2% of septic arthritis in children. The condition still remains a diagnostic challenge first due to poor localisation of symptoms with referred pain to the hip, thigh and lower back and second due to a lack of awareness by non-specialist clinicians. Early diagnosis is a key to avoid sequelae such as an abscess, degenerative changes of the sacroiliac joint and can be achieved by a thorough clinical examination, monitoring inflammatory markers and MRI.

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Management of a cutaneous squamous cell carcinoma overlying an AV fistula

Cutaneous squamous cell carcinoma (cSCC) currently affects over 700 000 patients per year in the USA alone, and its incidence continues to rise in recent years. A known risk factor for cSCC is chronic inflammation; a cSCC that develops at a site of chronic inflammation is known as Marjolin's ulcer. We present the case of a 76-year-old man with end-stage renal disease requiring chronic haemodialysis who developed an invasive cSCC at the cannulation site of an underlying arteriovenous (AV) fistula. In this instance, treatment with standard surgical excision or Mohs surgery would pose unique risks associated with injury to an otherwise functional AV fistula. Thus, the lesion was treated with electron beam radiation therapy, which offers a similar efficacy to surgery while minimising risk to the fistula. This resulted in a successful oncological outcome with no complications.

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Myeloneuropathy due to multiple giant plexiform neurofibromas - an unusual presentation of neurofibromatosis type 1

Description

A man aged 33 years presented with a 10-year progressive history of difficulty in walking with poor gripping of flip-flops on feet. It was further associated with foot drop and weakened handgrip. There was a recent history of multiple falls and difficulty in climbing stairs or standing from a squatting position. Family history was suggestive of neurofibromatosis type 1 (NF-1) in grandfather, father, paternal aunt and cousin. Physical examination revealed multiple café-au-lait spots, axillary freckling, Lisch nodules with cutaneous and subcutaneous neurofibromas. On neurological examination, there was spastic quadriparesis with foot drop, distal sensory loss and absent ankle reflexes, which were suggestive of myeloneuropathy. MRI of the cervical spine and whole spine showed characteristic dumbbell-shaped neurofibromas, extending along the Intraspinal and extraspinal areas at multiple cord levels and also along various nerves of the upper and lower limb involving plexuses and roots (figure 1 and

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Radiological, pathological and gross correlation of an isolated renal cell carcinoma metastasis to the stomach

Description

A 59-year-old asymptomatic woman presented for follow-up CT thorax, abdomen and pelvis (CT-TAP). Fifteen months previously she underwent a left radical nephrectomy for a T1bN0MO, 5.5 cm Fuhrman grade 4 clear cell renal cell carcinoma (CCRCC) (figure 1).

Figure 1

Portal venous phase coronal image CT-TAP. The 6.8 cm expansile, heterogenous lesion is centred in the renal cortex of the mid/upper pole of the left kidney (yellow circle). It appears well encapsulated (red arrows) and abuts the renal sinus with no clear invasion. The low attenuation may be due to necrosis or cystic components. CT-TAP, CT thorax, abdomen and pelvis.

The CT-TAP revealed a new 3.6 cm peripherally enhancing, centrally necrotic, intramural lesion in the fundus of the stomach (figure 2). It was decided to biopsy the lesion via oesophago-gastro duodenoscopy (OGD). It was not apparent on direct visualisation of the stomach mucosa, thus...

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Fever without a source: evolution of a diagnosis from Kawasaki disease to acute myelogenous leukaemia

A previously healthy 11-month-old male patient presented with fever, abdominal pain and irritability. As part of an extensive evaluation for the cause of his fevers, an echocardiogram was performed and showed mildly dilated coronary arteries, leading to a diagnosis of incomplete Kawasaki disease (KD). He was treated with intravenous immunoglobulin (IVIG), defervesced and was discharged home. Two weeks later, he presented with anaemia initially attributed to haemolytic anaemia secondary to IVIG and received a red blood cell transfusion. However, his anaemia recurred 2 weeks later with leucocytosis, prompting a bone marrow aspirate 4 weeks after his diagnosis of KD. This demonstrated acute myelogenous leukaemia most consistent with acute megakaryocytic leukaemia. This case highlights the potentially subtle presentation of acute leukaemia and the need to keep an open mind and reconsider the initial diagnosis as new information comes to light in the care of an ill child.

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Frequency and pathogenesis of central liver nodules in Alagille syndrome patients: Reply to Libbrecht and Cassiman

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Frequency and pathogenesis of central liver nodules in Alagille syndrome patients: Reply to Libbrecht and Cassiman

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Endoscopic Mucosal Resection of Granular Cell Tumors in the Esophagus: a Study of Four Cases and Brief Literature Review

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Endoscopic Mucosal Resection of Granular Cell Tumors in the Esophagus: a Study of Four Cases and Brief Literature Review

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Percent mammographic density prediction: development of a model in the nurses’ health studies

Abstract

Purpose

To develop a model to predict percent mammographic density (MD) using questionnaire data and mammograms from controls in the Nurses' Health Studies' nested breast cancer case–control studies. Further, we assessed the association between both measured and predicted percent MD and breast cancer risk.

Methods

Using data from 2,955 controls, we assessed several variables as potential predictors. We randomly divided our dataset into a training dataset (two-thirds of the dataset) and a testing dataset (one-third of the dataset). We used stepwise linear regression to identify the subset of variables that were most predictive. Next, we examined the correlation between measured and predicted percent MD in the testing dataset and computed the r ² in the total dataset. We used logistic regression to examine the association between measured and predicted percent MD and breast cancer risk.

Results

In the training dataset, several variables were selected for inclusion, including age, body mass index, and parity, among others. In the testing dataset, the Spearman correlation coefficient between predicted and measured percent MD was 0.61. As the prediction model performed well in the testing dataset, we developed the final model in the total dataset. The final prediction model explained 41% of the variability in percent MD. Both measured and predicted percent MD were similarly associated with breast cancer risk adjusting for age, menopausal status, and hormone use (OR per five unit increase = 1.09 for both).

Conclusion

These results suggest that predicted percent MD may be useful for research studies in which mammograms are unavailable.

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Percent mammographic density prediction: development of a model in the nurses’ health studies

Abstract

Purpose

To develop a model to predict percent mammographic density (MD) using questionnaire data and mammograms from controls in the Nurses' Health Studies' nested breast cancer case–control studies. Further, we assessed the association between both measured and predicted percent MD and breast cancer risk.

Methods

Using data from 2,955 controls, we assessed several variables as potential predictors. We randomly divided our dataset into a training dataset (two-thirds of the dataset) and a testing dataset (one-third of the dataset). We used stepwise linear regression to identify the subset of variables that were most predictive. Next, we examined the correlation between measured and predicted percent MD in the testing dataset and computed the r ² in the total dataset. We used logistic regression to examine the association between measured and predicted percent MD and breast cancer risk.

Results

In the training dataset, several variables were selected for inclusion, including age, body mass index, and parity, among others. In the testing dataset, the Spearman correlation coefficient between predicted and measured percent MD was 0.61. As the prediction model performed well in the testing dataset, we developed the final model in the total dataset. The final prediction model explained 41% of the variability in percent MD. Both measured and predicted percent MD were similarly associated with breast cancer risk adjusting for age, menopausal status, and hormone use (OR per five unit increase = 1.09 for both).

Conclusion

These results suggest that predicted percent MD may be useful for research studies in which mammograms are unavailable.

http://ift.tt/2pkJCf3

A patient with a history of breast cancer and multiple bone lesions: a case report

Long-term severe hyperparathyroidism leads to thinning of cortical bone and cystic bone defects referred to as osteitis fibrosa cystica. Cysts filled with hemosiderin deposits may appear colored as "brown tumors....

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The voice quality after laser surgery versus radiotherapy of T1a glottic carcinoma: systematic review and meta-analysis

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A comprehensive dosimetric study on switching from a Type-B to a Type-C dose algorithm for modern lung SBRT

Type-C dose algorithms provide more accurate dosimetry for lung SBRT treatment planning. However, because current dosimetric protocols were developed based on conventional algorithms, its applicability for the...

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A comprehensive dosimetric study on switching from a Type-B to a Type-C dose algorithm for modern lung SBRT

Type-C dose algorithms provide more accurate dosimetry for lung SBRT treatment planning. However, because current dosimetric protocols were developed based on conventional algorithms, its applicability for the...

http://ift.tt/2qNrFGb

Cancers, Vol. 9, Pages 45: Metformin in Lung Cancer: Review of in Vitro and in Vivo Animal Studies

Cancer cells display enhanced growth rates and a resistance to apoptosis. The ability of cancer cells to evade homeostasis and proliferate uncontrollably while avoiding programmed cell death/apoptosis is acquired through mutations to key signaling molecules, which regulate pathways involved in cell proliferation and survival and these mutations allow them to develop resistance to many chemotherapeutic agents, highlighting the need for development of new potent anti-cancer agents. Metformin has long been used as a treatment for type 2 diabetes and has recently attracted attention as a potential agent to be used in the treatment of cancer. The present review summarizes the existing in vitro and in vivo animal studies focusing on the anti-lung cancer effects of metformin and its effects on key proliferative and anti-apoptotic signaling pathways.

http://ift.tt/2pMhWCr

Cancers, Vol. 9, Pages 45: Metformin in Lung Cancer: Review of in Vitro and in Vivo Animal Studies

Cancer cells display enhanced growth rates and a resistance to apoptosis. The ability of cancer cells to evade homeostasis and proliferate uncontrollably while avoiding programmed cell death/apoptosis is acquired through mutations to key signaling molecules, which regulate pathways involved in cell proliferation and survival and these mutations allow them to develop resistance to many chemotherapeutic agents, highlighting the need for development of new potent anti-cancer agents. Metformin has long been used as a treatment for type 2 diabetes and has recently attracted attention as a potential agent to be used in the treatment of cancer. The present review summarizes the existing in vitro and in vivo animal studies focusing on the anti-lung cancer effects of metformin and its effects on key proliferative and anti-apoptotic signaling pathways.

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RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies

Abstract

Targeting deficient mechanisms of cellular DNA repair still represents the basis for the treatment of the majority of solid tumors, and increased DNA repair capacity is a hallmark mechanism of resistance not only to DNA-damaging treatments such as cytotoxic drugs and radiotherapy, but also to small molecule targeted drugs such as inhibitors of poly-ADP ribose polymerase (PARP). Hence, there is substantial medical need for potent and convenient biomarkers of individual response to DNA-targeted treatment in personalized cancer care. RAD51 is a highly conserved protein that catalyzes DNA repair via homologous recombination, a major DNA repair pathway which directly modulates cellular sensitivity to DNA-damaging treatments. The clinical and biological significance of RAD51 protein expression is still under investigation. Pre-clinical studies consistently show the important role of nuclear RAD51 immunoreactivity in chemo- and radioresistance. Validating data from clinical trials however is limited at present, and some clinical studies show controversial results. This review gives a comprehensive overview on the current knowledge about the prognostic and predictive value of RAD51 protein expression and genetic variability in patients with solid malignancies. This article is protected by copyright. All rights reserved.

http://ift.tt/2qNB1Sr

Why is colon cancer survival improving by time? A nationwide survival analysis spanning 35 years

Abstract

There is limited information present to explain temporal improvements in colon cancer survival. This nationwide study investigates the temporal changes in survival over a 35-year period (1970-2004) in Iceland and uses incidence, mortality, surgery rate, stage distribution, lymph node yield, tumor location and histological type to find explanations for these changes. Patients diagnosed with colon cancer in Iceland 1970-2004 were identified (n=1962). All histopathology was reassessed. Proportions, age-standardized incidence and mortality, relative, cancer-specific and overall survival and conditional survival were calculated. When comparing first and last diagnostic periods (1970-1978 and 1997-2004), 5-year relative survival improved by 12% for men and 9% for women. At the same time surgery rate increased by 12% and the proportion of stage I increased by 9%. Stage-stratified, improved 5-year relative survival was mainly observed in stage II and III and coincided with higher lymph node yields, proportional reduction of stage II cancers and proportional increase of stage III cancers, indicating stage migration between these stages. Improvement in 1-year survival was mainly observed in stage III and IV. Five-year survival improvement for patients living beyond 1 year was minimum to none. There were no changes in histology that coincided with neither increased incidence nor possibly influencing improved survival. Concluding, as a novel finding, 1-year mortality, which previously has been identified as an important variable in explaining international survival differences, is in this study identified as also being important in explaining temporal improvements in colon cancer survival in Iceland. This article is protected by copyright. All rights reserved.

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Serology of Streptococcus gallolyticus subspecies gallolyticus and its association with colorectal cancer and precursors

Abstract

Streptococcus gallolyticus subspecies gallolyticus (SGG) is potentially associated with colorectal cancer (CRC) and its precursors. A previous case-control study measured antibody responses to SGG pilus proteins Gallo2178 and Gallo2179 and identified significant associations with a small fraction of CRC cases. We aimed at replicating and expanding these findings in an independent study including additional SGG antigens and explored the association with precancerous lesions.

We applied multiplex serology to measure antibodies to eleven SGG proteins in serum samples of a screening colonoscopy trial (BliTz study) including participants diagnosed with either non-advanced adenoma (NAA, n=30), advanced adenoma (AA, n=100), CRC (n=50) or controls (n=228). In addition, we analysed CRC samples (n=318) from patients recruited in a clinical setting (DACHSplus study).

The association of antibody responses to SGG pilus proteins Gallo2178 and Gallo2179 with CRC was replicated with 4% positive DACHSplus cases compared to 0% positive BliTz controls. Positivity to two or more proteins of a newly defined panel of six SGG markers was significantly associated with CRC in the DACHSplus study (OR: 1.81, 95% CI: 1.07-3.06). Odds for CRC, AA and NAA in the BliTz study were also increased with antibody responses to SGG, and the association was significant for NAA (OR: 2.98, 95% CI: 1.18-7.57).

Antibody responses to SGG are associated with CRC and its precursors. The newly identified SGG 6-marker panel and associations found with precancerous lesions should be further explored. This article is protected by copyright. All rights reserved.

http://ift.tt/2qNDdsZ

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

Abstract

NK-92 cells, and their derivative, designated aNK, were obtained from a patient with non-Hodgkin lymphoma. Prior clinical studies employing adoptively transferred irradiated aNK cells have provided evidence of clinical benefit and an acceptable safety. aNK cells have now been engineered to express IL-2 and the high affinity (ha) CD16 allele (designated haNK). Avelumab is a human IgG1 anti‒PD-L1 monoclonal antibody, which has shown evidence of clinical activity in a range of human tumors. Prior in vitro studies have shown that avelumab has the ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells when combined with NK cells. In the studies reported here, the ability of avelumab to enhance the lysis of a range of human carcinoma cells by irradiated haNK cells via the ADCC mechanism is demonstrated; this ADCC is shown to be inhibited by anti-CD16 blocking antibody and by concanamycin A, indicating the use of the granzyme/perforin pathway in tumor cell lysis. Studies also show that while NK cells have the ability to lyse aNK or haNK cells, the addition of NK cells to irradiated haNK cells does not inhibit haNK-mediated lysis of human tumor cells, with or without the addition of avelumab. Avelumab-mediated lysis of tumor cells by irradiated haNK cells is also shown to be similar to that of NK cells bearing the V/V Fc receptor high affinity allele. These studies thus provide the rationale for the clinical evaluation of the combined use of avelumab with that of irradiated adoptively transferred haNK cells. This article is protected by copyright. All rights reserved.

http://ift.tt/2pQBDcv

Why is colon cancer survival improving by time? A nationwide survival analysis spanning 35 years

Abstract

There is limited information present to explain temporal improvements in colon cancer survival. This nationwide study investigates the temporal changes in survival over a 35-year period (1970-2004) in Iceland and uses incidence, mortality, surgery rate, stage distribution, lymph node yield, tumor location and histological type to find explanations for these changes. Patients diagnosed with colon cancer in Iceland 1970-2004 were identified (n=1962). All histopathology was reassessed. Proportions, age-standardized incidence and mortality, relative, cancer-specific and overall survival and conditional survival were calculated. When comparing first and last diagnostic periods (1970-1978 and 1997-2004), 5-year relative survival improved by 12% for men and 9% for women. At the same time surgery rate increased by 12% and the proportion of stage I increased by 9%. Stage-stratified, improved 5-year relative survival was mainly observed in stage II and III and coincided with higher lymph node yields, proportional reduction of stage II cancers and proportional increase of stage III cancers, indicating stage migration between these stages. Improvement in 1-year survival was mainly observed in stage III and IV. Five-year survival improvement for patients living beyond 1 year was minimum to none. There were no changes in histology that coincided with neither increased incidence nor possibly influencing improved survival. Concluding, as a novel finding, 1-year mortality, which previously has been identified as an important variable in explaining international survival differences, is in this study identified as also being important in explaining temporal improvements in colon cancer survival in Iceland. This article is protected by copyright. All rights reserved.

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Serology of Streptococcus gallolyticus subspecies gallolyticus and its association with colorectal cancer and precursors

Abstract

Streptococcus gallolyticus subspecies gallolyticus (SGG) is potentially associated with colorectal cancer (CRC) and its precursors. A previous case-control study measured antibody responses to SGG pilus proteins Gallo2178 and Gallo2179 and identified significant associations with a small fraction of CRC cases. We aimed at replicating and expanding these findings in an independent study including additional SGG antigens and explored the association with precancerous lesions.

We applied multiplex serology to measure antibodies to eleven SGG proteins in serum samples of a screening colonoscopy trial (BliTz study) including participants diagnosed with either non-advanced adenoma (NAA, n=30), advanced adenoma (AA, n=100), CRC (n=50) or controls (n=228). In addition, we analysed CRC samples (n=318) from patients recruited in a clinical setting (DACHSplus study).

The association of antibody responses to SGG pilus proteins Gallo2178 and Gallo2179 with CRC was replicated with 4% positive DACHSplus cases compared to 0% positive BliTz controls. Positivity to two or more proteins of a newly defined panel of six SGG markers was significantly associated with CRC in the DACHSplus study (OR: 1.81, 95% CI: 1.07-3.06). Odds for CRC, AA and NAA in the BliTz study were also increased with antibody responses to SGG, and the association was significant for NAA (OR: 2.98, 95% CI: 1.18-7.57).

Antibody responses to SGG are associated with CRC and its precursors. The newly identified SGG 6-marker panel and associations found with precancerous lesions should be further explored. This article is protected by copyright. All rights reserved.

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via IFTTT

ADCC employing an NK cell line (haNK) expressing the high affinity CD16 allele with avelumab, an anti-PD-L1 antibody

Abstract

NK-92 cells, and their derivative, designated aNK, were obtained from a patient with non-Hodgkin lymphoma. Prior clinical studies employing adoptively transferred irradiated aNK cells have provided evidence of clinical benefit and an acceptable safety. aNK cells have now been engineered to express IL-2 and the high affinity (ha) CD16 allele (designated haNK). Avelumab is a human IgG1 anti‒PD-L1 monoclonal antibody, which has shown evidence of clinical activity in a range of human tumors. Prior in vitro studies have shown that avelumab has the ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) of human tumor cells when combined with NK cells. In the studies reported here, the ability of avelumab to enhance the lysis of a range of human carcinoma cells by irradiated haNK cells via the ADCC mechanism is demonstrated; this ADCC is shown to be inhibited by anti-CD16 blocking antibody and by concanamycin A, indicating the use of the granzyme/perforin pathway in tumor cell lysis. Studies also show that while NK cells have the ability to lyse aNK or haNK cells, the addition of NK cells to irradiated haNK cells does not inhibit haNK-mediated lysis of human tumor cells, with or without the addition of avelumab. Avelumab-mediated lysis of tumor cells by irradiated haNK cells is also shown to be similar to that of NK cells bearing the V/V Fc receptor high affinity allele. These studies thus provide the rationale for the clinical evaluation of the combined use of avelumab with that of irradiated adoptively transferred haNK cells. This article is protected by copyright. All rights reserved.

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RAD51 as a potential surrogate marker for DNA repair capacity in solid malignancies

Abstract

Targeting deficient mechanisms of cellular DNA repair still represents the basis for the treatment of the majority of solid tumors, and increased DNA repair capacity is a hallmark mechanism of resistance not only to DNA-damaging treatments such as cytotoxic drugs and radiotherapy, but also to small molecule targeted drugs such as inhibitors of poly-ADP ribose polymerase (PARP). Hence, there is substantial medical need for potent and convenient biomarkers of individual response to DNA-targeted treatment in personalized cancer care. RAD51 is a highly conserved protein that catalyzes DNA repair via homologous recombination, a major DNA repair pathway which directly modulates cellular sensitivity to DNA-damaging treatments. The clinical and biological significance of RAD51 protein expression is still under investigation. Pre-clinical studies consistently show the important role of nuclear RAD51 immunoreactivity in chemo- and radioresistance. Validating data from clinical trials however is limited at present, and some clinical studies show controversial results. This review gives a comprehensive overview on the current knowledge about the prognostic and predictive value of RAD51 protein expression and genetic variability in patients with solid malignancies. This article is protected by copyright. All rights reserved.

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