Bilateral Renal Metastasis of Hürthle Cell Thyroid Cancer with Discordant Uptake Between I-131 Sodium Iodide and F-18 FDG

Abstract

Renal metastasis of thyroid cancer is extremely rare. We report the case of a 62-year-old woman with Hürthle cell thyroid cancer (HCTC) with lungs, bones, and bilateral kidneys metastases. The renal metastatic lesions were clearly demonstrated by ¹³¹I whole body scan (WBS) with SPECT/CT. However, they exhibited false-negative results in ¹⁸F-FDG PET/CT, kidney ultrasonography, and contrast-enhanced CT scan. The findings imply that tumors have low glucose metabolism and are able to accumulate radioiodine, which is not commonly found in the relatively aggressive nature of HCTC. The patient received two sessions of 200 mCi ¹³¹I therapy within 6 months duration. There was complete treatment response as evaluated by the second post-therapeutic ¹³¹I SPECT/CT and serum thyroglobulin. To our knowledge, renal metastasis from HCTC with positive ¹³¹I but negative ¹⁸F-FDG uptake has not been reported in the literature. This case suggests that ¹³¹I SPECT/CT is useful for lesion localization and prediction of ¹³¹I therapy response.

http://ift.tt/2hcFGtd

Bilateral Renal Metastasis of Hürthle Cell Thyroid Cancer with Discordant Uptake Between I-131 Sodium Iodide and F-18 FDG

Abstract

Renal metastasis of thyroid cancer is extremely rare. We report the case of a 62-year-old woman with Hürthle cell thyroid cancer (HCTC) with lungs, bones, and bilateral kidneys metastases. The renal metastatic lesions were clearly demonstrated by ¹³¹I whole body scan (WBS) with SPECT/CT. However, they exhibited false-negative results in ¹⁸F-FDG PET/CT, kidney ultrasonography, and contrast-enhanced CT scan. The findings imply that tumors have low glucose metabolism and are able to accumulate radioiodine, which is not commonly found in the relatively aggressive nature of HCTC. The patient received two sessions of 200 mCi ¹³¹I therapy within 6 months duration. There was complete treatment response as evaluated by the second post-therapeutic ¹³¹I SPECT/CT and serum thyroglobulin. To our knowledge, renal metastasis from HCTC with positive ¹³¹I but negative ¹⁸F-FDG uptake has not been reported in the literature. This case suggests that ¹³¹I SPECT/CT is useful for lesion localization and prediction of ¹³¹I therapy response.

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Gastrointestinal stromal tumors (GISTs): SEAP–SEOM consensus on pathologic and molecular diagnosis

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (<10 mm–35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed.

http://ift.tt/2h6DeGR

Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma

Abstract

Background

Vascular endothelial growth factor (VEGF), in addition to being pro-angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV).

Methods

Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment.

Results

The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid-derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed.

Conclusions

Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy.

http://ift.tt/2hmKmQq

LJM716 in Japanese patients with head and neck squamous cell carcinoma or HER2-overexpressing breast or gastric cancer

Abstract

Purpose

Human epidermal growth factor receptor 3 (HER3) has been identified as an important component of many receptor tyrosine kinase-driven cancers. LJM716 is a human IgG monoclonal antibody that binds HER3, trapping it in an inactive conformation. In this study, a phase I dose escalation was performed with a primary objective to establish the maximum tolerated dose and/or the recommended dose of LJM716 in Japanese patients with selected advanced solid tumors. Secondary objectives included the evaluation of the safety and tolerability, preliminary antitumor activity, and pharmacokinetics of LJM716 in Japanese patients.

Methods

LJM716 was administered intravenously at doses of 10, 20, or 40 mg/kg once weekly, in 28-day cycles, to 12 patients with HER2-amplified breast cancer or gastric cancer, or with esophageal squamous cell carcinoma or squamous cell carcinoma of the head and neck, regardless of HER2 status.

Results

The maximum tolerated dose was not reached, and the recommended dose was established at 40 mg/kg. No dose-limiting toxicities were observed in the first cycle. The most frequently reported adverse events were diarrhea, fatigue, stomatitis, pyrexia, and paronychia. One unconfirmed partial response was observed in a patient with breast cancer, and 50% of the patients achieved stable disease as the best overall response. Exposure increased with ascending dose, and half-life was estimated to be 11–14 days. No anti-LJM716 antibodies were detected.

Conclusions

LJM716 was well tolerated in Japanese patients, and a degree of tumor shrinkage was observed.

Clinical trial information

ClinicalTrials.gov NCT01911936.

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Synergistic disruption of ERα/HER2 crosstalk by endoxifen and lapatinib in breast cancer cells

Abstract

Background

Despite decades of clinical success, tamoxifen therapy is complicated by inter-individual variability due to CYP450 polymorphism and resistance attributed to ERα/HER2 crosstalk. Direct administration of endoxifen shows promise in circumventing obligatory CYP450 bioactivation while maintaining efficacy. Separately, disruption of the crosstalk using probe antagonists against ERα (tamoxifen) and HER2 (e.g., lapatinib) has been explored clinically. However, the efficacy of this combination may be confounded by lapatinib, a potent inactivator of CYP3A4/5 which could negate the bioactivation of tamoxifen to the active metabolite endoxifen. Additionally, in a manner analogous to tamoxifen, endoxifen is similarly not immune to the development of ERα/HER2 crosstalk that could result in resistance. Simultaneous antagonism of ERα and HER2 using endoxifen and lapatinib could overcome these problems.

Methods

Metabolism studies were performed in human liver microsomes to determine the extent of inhibition of tamoxifen bioactivation by lapatinib. Synergism of endoxifen and lapatinib was assessed using the combination index design in a panel of cell models exhibiting either a priori ERα/HER2 crosstalk (BT474) or acquired ERα/HER2 crosstalk (TAM-R and MCF-7/HER2).

Results

Lapatinib inhibited tamoxifen bioactivation by up to 1.8-fold. Synergistic activity was uncovered for lapatinib and endoxifen against BT474, TAM-R and MCF-7/HER2 models of ERα/HER2 crosstalk. Western blot confirmed that endoxifen and lapatinib disrupted this crosstalk.

Conclusion

This forward-looking study extends the success of tamoxifen by exploring the effectiveness of combining the next-generation tamoxifen derivative, endoxifen with an anti-HER2 agent to combat ERα/HER2 crosstalk, and at the same time provides a solution to the predicted pharmacokinetic antagonism between lapatinib and tamoxifen.

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Gastrointestinal stromal tumors (GISTs): SEAP–SEOM consensus on pathologic and molecular diagnosis

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (<10 mm–35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed.

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Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma

Abstract

Background

Vascular endothelial growth factor (VEGF), in addition to being pro-angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV).

Methods

Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment.

Results

The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid-derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed.

Conclusions

Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy.

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Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma

Abstract

Background

Vascular endothelial growth factor (VEGF), in addition to being pro-angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV).

Methods

Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment.

Results

The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid-derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed.

Conclusions

Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy.

http://ift.tt/2hmKmQq

Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma

Abstract

Background

Vascular endothelial growth factor (VEGF), in addition to being pro-angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV).

Methods

Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment.

Results

The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid-derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed.

Conclusions

Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy.

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Unusual Histology in Hodgkin’s Lymphoma: Report of an Interesting Case

Abstract

Hodgkin's lymphoma has a significant presence in the Indian subcontinent. Microscopically, the hallmark of Hodgkin's lymphoma (HL) is the Hodgkin and Reed-Sternberg (HRS) cell, which is usually surrounded by a cellular infiltrate of non-malignant inflammatory cells that constitute the majority of the tumor tissue. Cells which are known to be histologic mimics of HRS cells include immunoblasts, plasmablasts and rarely dendritic cells. We report a case of a 70-year-old male who presented with fever and lymphadenopathy. In the present case, the large cells with prominent nucleoli stained positively for both CD15 and CD30 and hence the possibility of angioimmunoblastic lymphadenopathy which was considered on the H&E-stained sections was excluded. In addition, noteworthy microscopic features in this case were angiogenesis and the presence of mast cells, both associated with a poor prognosis. The clinical impression was that of disseminated tuberculosis, but on histopathology, the final opinion was 'Hodgkin's lymphoma not classifiable with an unusual histology'. The aim of reporting this case is to highlight the unusual presentation in the form of prominent angiogenesis and mast cell infiltration in a case of HL, which is indicative of a poor prognosis.

http://ift.tt/2gl8VwY

Association between adjuvant chemotherapy and risk of acute kidney injury in elderly women diagnosed with early-stage breast cancer

Abstract

Purpose

We studied elderly Medicare enrollees newly diagnosed with early-stage breast cancer to examine the association between adjuvant chemotherapy and acute kidney injury (AKI).

Methods

Using the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we conducted a retrospective cohort study including women diagnosed with stages I–III breast cancer at ages 66–89 years between 1992 and 2007. We performed one-to-one matching on time-dependent propensity score on the day of adjuvant chemotherapy initiation within 6 months after the first cancer-directed surgery based on the estimated probability of chemotherapy initiation at each day for each patient, using a Cox proportional hazards model. We estimated the cumulative incidence of AKI using Kaplan–Meier methods. We used Cox proportional hazards models to evaluate the association between chemotherapy and the risk of AKI, and compared the risk among major chemotherapy types.

Results

The study included 28,048 women. The 6-month cumulative incidence of AKI was 0.80% for chemotherapy-treated patients, compared with 0.30% for untreated patients (P < 0.001). Adjuvant chemotherapy was associated with a nearly threefold increased risk of AKI [hazard ratio (HR) 2.73; 95% CI 1.8–4.1]. Compared with anthracycline-based chemotherapy, the HRs (95% CIs) were 1.66 (0.94–2.91), 0.88 (0.53–1.47), and 1.15 (0.57–2.32) for taxane-based, CMF, and other chemotherapy, respectively.

Conclusion

Our findings showed that adjuvant chemotherapy was associated with increased risk of AKI in elderly women diagnosed with early-stage breast cancer. The risk seemed to vary by regimen type, but the differences were not statistically significant.

http://ift.tt/2heZaOh

Synergistic disruption of ERα/HER2 crosstalk by endoxifen and lapatinib in breast cancer cells

Abstract

Background

Despite decades of clinical success, tamoxifen therapy is complicated by inter-individual variability due to CYP450 polymorphism and resistance attributed to ERα/HER2 crosstalk. Direct administration of endoxifen shows promise in circumventing obligatory CYP450 bioactivation while maintaining efficacy. Separately, disruption of the crosstalk using probe antagonists against ERα (tamoxifen) and HER2 (e.g., lapatinib) has been explored clinically. However, the efficacy of this combination may be confounded by lapatinib, a potent inactivator of CYP3A4/5 which could negate the bioactivation of tamoxifen to the active metabolite endoxifen. Additionally, in a manner analogous to tamoxifen, endoxifen is similarly not immune to the development of ERα/HER2 crosstalk that could result in resistance. Simultaneous antagonism of ERα and HER2 using endoxifen and lapatinib could overcome these problems.

Methods

Metabolism studies were performed in human liver microsomes to determine the extent of inhibition of tamoxifen bioactivation by lapatinib. Synergism of endoxifen and lapatinib was assessed using the combination index design in a panel of cell models exhibiting either a priori ERα/HER2 crosstalk (BT474) or acquired ERα/HER2 crosstalk (TAM-R and MCF-7/HER2).

Results

Lapatinib inhibited tamoxifen bioactivation by up to 1.8-fold. Synergistic activity was uncovered for lapatinib and endoxifen against BT474, TAM-R and MCF-7/HER2 models of ERα/HER2 crosstalk. Western blot confirmed that endoxifen and lapatinib disrupted this crosstalk.

Conclusion

This forward-looking study extends the success of tamoxifen by exploring the effectiveness of combining the next-generation tamoxifen derivative, endoxifen with an anti-HER2 agent to combat ERα/HER2 crosstalk, and at the same time provides a solution to the predicted pharmacokinetic antagonism between lapatinib and tamoxifen.

http://ift.tt/2gsCR90

Immune modulation associated with vascular endothelial growth factor (VEGF) blockade in patients with glioblastoma

Abstract

Background

Vascular endothelial growth factor (VEGF), in addition to being pro-angiogenic, is an immunomodulatory cytokine systemically and in the tumor microenvironment. We previously reported the immunomodulatory effects of radiation and temozolomide (TMZ) in newly diagnosed glioblastoma. This study aimed to assess changes in peripheral blood mononuclear cell (PBMC) populations, plasma cytokines, and growth factor concentrations following treatment with radiation, TMZ, and bevacizumab (BEV).

Methods

Eleven patients with newly diagnosed glioblastoma were treated with radiation, TMZ, and BEV, following surgery. We measured immune-related PBMC subsets using multi-parameter flow cytometry and plasma cytokine and growth factor concentrations using electrochemiluminescence-based multiplex analysis at baseline and after 6 weeks of treatment.

Results

The absolute number of peripheral blood regulatory T cells (Tregs) decreased significantly following treatment. The lower number of peripheral Tregs was associated with a CD4+ lymphopenia, and thus, the ratio of Tregs to PBMCs was unchanged. The addition of bevacizumab to standard radiation and temozolomide led to the decrease in the number of circulating Tregs when compared with our prior study. There was a significant decrease in CD8+ cytotoxic and CD4+ recent thymic emigrant T cells, but no change in the number of myeloid-derived suppressor cells. Significant increases in plasma VEGF and placental growth factor (PlGF) concentrations were observed.

Conclusions

Treatment with radiation, TMZ, and BEV decreased the number but not the proportion of peripheral Tregs and increased the concentration of circulating VEGF. This shift in the peripheral immune cell profile may modulate the tumor environment and have implications for combining immunotherapy with anti-angiogenic therapy.

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Unusual Histology in Hodgkin’s Lymphoma: Report of an Interesting Case

Abstract

Hodgkin's lymphoma has a significant presence in the Indian subcontinent. Microscopically, the hallmark of Hodgkin's lymphoma (HL) is the Hodgkin and Reed-Sternberg (HRS) cell, which is usually surrounded by a cellular infiltrate of non-malignant inflammatory cells that constitute the majority of the tumor tissue. Cells which are known to be histologic mimics of HRS cells include immunoblasts, plasmablasts and rarely dendritic cells. We report a case of a 70-year-old male who presented with fever and lymphadenopathy. In the present case, the large cells with prominent nucleoli stained positively for both CD15 and CD30 and hence the possibility of angioimmunoblastic lymphadenopathy which was considered on the H&E-stained sections was excluded. In addition, noteworthy microscopic features in this case were angiogenesis and the presence of mast cells, both associated with a poor prognosis. The clinical impression was that of disseminated tuberculosis, but on histopathology, the final opinion was 'Hodgkin's lymphoma not classifiable with an unusual histology'. The aim of reporting this case is to highlight the unusual presentation in the form of prominent angiogenesis and mast cell infiltration in a case of HL, which is indicative of a poor prognosis.

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Synergistic disruption of ERα/HER2 crosstalk by endoxifen and lapatinib in breast cancer cells

Abstract

Background

Despite decades of clinical success, tamoxifen therapy is complicated by inter-individual variability due to CYP450 polymorphism and resistance attributed to ERα/HER2 crosstalk. Direct administration of endoxifen shows promise in circumventing obligatory CYP450 bioactivation while maintaining efficacy. Separately, disruption of the crosstalk using probe antagonists against ERα (tamoxifen) and HER2 (e.g., lapatinib) has been explored clinically. However, the efficacy of this combination may be confounded by lapatinib, a potent inactivator of CYP3A4/5 which could negate the bioactivation of tamoxifen to the active metabolite endoxifen. Additionally, in a manner analogous to tamoxifen, endoxifen is similarly not immune to the development of ERα/HER2 crosstalk that could result in resistance. Simultaneous antagonism of ERα and HER2 using endoxifen and lapatinib could overcome these problems.

Methods

Metabolism studies were performed in human liver microsomes to determine the extent of inhibition of tamoxifen bioactivation by lapatinib. Synergism of endoxifen and lapatinib was assessed using the combination index design in a panel of cell models exhibiting either a priori ERα/HER2 crosstalk (BT474) or acquired ERα/HER2 crosstalk (TAM-R and MCF-7/HER2).

Results

Lapatinib inhibited tamoxifen bioactivation by up to 1.8-fold. Synergistic activity was uncovered for lapatinib and endoxifen against BT474, TAM-R and MCF-7/HER2 models of ERα/HER2 crosstalk. Western blot confirmed that endoxifen and lapatinib disrupted this crosstalk.

Conclusion

This forward-looking study extends the success of tamoxifen by exploring the effectiveness of combining the next-generation tamoxifen derivative, endoxifen with an anti-HER2 agent to combat ERα/HER2 crosstalk, and at the same time provides a solution to the predicted pharmacokinetic antagonism between lapatinib and tamoxifen.

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Cancers, Vol. 8, Pages 111: The Enrichment of Survivin in Exosomes from Breast Cancer Cells Treated with Paclitaxel Promotes Cell Survival and Chemoresistance

The generation and release of membrane-enclosed packets from cancer cells, called extracellular vesicles (EVs), play important roles in propagating transformed phenotypes, including promoting cell survival. EVs mediate their effects by transferring their contents, which include specific proteins and nucleic acids, to target cells. However, how the cargo and function of EVs change in response to different stimuli remains unclear. Here, we discovered that treating highly aggressive MDAMB231 breast cancer cells with paclitaxel (PTX), a chemotherapy that stabilizes microtubules, causes them to generate a specific class of EV, namely exosomes, that are highly enriched with the cell survival protein and cancer marker, Survivin. Treating MDAMB231 cells with a variety of other chemotherapeutic agents, and inhibitors that block cell growth and survival, did not have the same effect as PTX, with the exception of nocodazole, another inhibitor of microtubule dynamics. Exosomes isolated from PTX-treated MDAMB231 cells strongly promoted the survival of serum-starved and PTX-treated fibroblasts and SKBR3 breast cancer cells, an effect that was ablated when Survivin was knocked-down from these vesicles using siRNA. These findings underscore how the enrichment of a specific cargo in exosomes promotes cell survival, as well as can potentially serve as a marker of PTX resistance.

http://ift.tt/2hbuHQH

Cancers, Vol. 8, Pages 110: Biology, Therapy and Implications of Tumor Exosomes in the Progression of Melanoma

Cancer is the second leading cause of death in the United States, and about 6% of the estimated cancer diagnoses this year will be melanoma cases. Melanomas are derived from transformation of the pigment producing cells of the skin, melanocytes. Early stage melanoma is usually curable by surgical resection, but late stage or subsequent secondary metastatic tumors are treated with some success with chemotherapies, radiation and/or immunotherapies. Most cancer patients die from metastatic disease, which is especially the case in melanoma. A better understanding of tumor metastasis will provide insights and guide rational therapeutic designs. Recently, the importance of melanoma-derived exosomes in the progression of that cancer has become more apparent, namely, their role in various stages of metastasis, including the induction of migration, invasion, primary niche manipulation, immune modulation and pre-metastatic niche formation. This review focuses on the critical roles that melanoma exosomes play in the progression of this deadly disease.

http://ift.tt/2h4Dc2s

Cancers, Vol. 8, Pages 111: The Enrichment of Survivin in Exosomes from Breast Cancer Cells Treated with Paclitaxel Promotes Cell Survival and Chemoresistance

The generation and release of membrane-enclosed packets from cancer cells, called extracellular vesicles (EVs), play important roles in propagating transformed phenotypes, including promoting cell survival. EVs mediate their effects by transferring their contents, which include specific proteins and nucleic acids, to target cells. However, how the cargo and function of EVs change in response to different stimuli remains unclear. Here, we discovered that treating highly aggressive MDAMB231 breast cancer cells with paclitaxel (PTX), a chemotherapy that stabilizes microtubules, causes them to generate a specific class of EV, namely exosomes, that are highly enriched with the cell survival protein and cancer marker, Survivin. Treating MDAMB231 cells with a variety of other chemotherapeutic agents, and inhibitors that block cell growth and survival, did not have the same effect as PTX, with the exception of nocodazole, another inhibitor of microtubule dynamics. Exosomes isolated from PTX-treated MDAMB231 cells strongly promoted the survival of serum-starved and PTX-treated fibroblasts and SKBR3 breast cancer cells, an effect that was ablated when Survivin was knocked-down from these vesicles using siRNA. These findings underscore how the enrichment of a specific cargo in exosomes promotes cell survival, as well as can potentially serve as a marker of PTX resistance.

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Cancers, Vol. 8, Pages 110: Biology, Therapy and Implications of Tumor Exosomes in the Progression of Melanoma

Cancer is the second leading cause of death in the United States, and about 6% of the estimated cancer diagnoses this year will be melanoma cases. Melanomas are derived from transformation of the pigment producing cells of the skin, melanocytes. Early stage melanoma is usually curable by surgical resection, but late stage or subsequent secondary metastatic tumors are treated with some success with chemotherapies, radiation and/or immunotherapies. Most cancer patients die from metastatic disease, which is especially the case in melanoma. A better understanding of tumor metastasis will provide insights and guide rational therapeutic designs. Recently, the importance of melanoma-derived exosomes in the progression of that cancer has become more apparent, namely, their role in various stages of metastasis, including the induction of migration, invasion, primary niche manipulation, immune modulation and pre-metastatic niche formation. This review focuses on the critical roles that melanoma exosomes play in the progression of this deadly disease.

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Posterior scleritis presenting as conjunctivitis in a child

A 14-year-old male child presented with redness and decreased vision in the right eye for 7 days. He was being treated for viral conjunctivitis for right eye at a local hospital. His visual acuity was 6/24 OD and 6/9 OS. Slit-lamp examination revealed diffuse conjunctival congestion in the right eye. Dilated fundus examination revealed mild disc hyperaemia and retinal striae in both the eyes. A peripapillary serous detachment of macula in the right eye was seen on optical coherence tomography. B scan ultrasonography revealed increased scleral thickening and characteristic 'T' sign in both the eyes. Investigations revealed no other relevant systemic association. A diagnosis of bilateral posterior scleritis was made. The patient was started on topical steroids and oral non-steroidal anti-inflammatory drugs. Within 2 weeks of therapy the visual acuity improved to 6/6, the serous detachment resolved and retinal striae reduced in both the eyes.

http://ift.tt/2gsobXj

Antisynthetase syndrome (ASS) presenting as acute respiratory distress syndrome (ARDS) in a patient without myositis features

A woman aged 61 years presented to the emergency room with a 1-week history of dyspnoea on exertion and dry cough. X-ray of the chest showed diffuse interstitial opacities and was started on antibiotics and furosemide, and despite these measures, patient's respiratory status worsened, prompting endotracheal intubation. CT of the chest showed diffuse bilateral ground glass opacities and underwent bronchoscope with trans-bronchial biopsy that showed chronic bronchitis. Pt was empirically started on intravenous steroids due to concerns for interstitial lung disease (ILD). Autoimmune work up was sent and underwent video-assisted thoracoscopic surgery-guided biopsy of the lung that showed non-specific interstitial pattern with fibrosis. The patient was diagnosed as having antisynthetase syndrome with pulmonary involvement (ILD) as the cause of her acute respiratory failure. Azathioprine was started as steroid-sparing agent and was weaned off the ventilator to a tracheostomy collar and discharged to long-term rehabilitation centre.

http://ift.tt/2gsnQnB

Forgetting to remember: hypoglycaemic encephalopathy

A 37-year-old woman with a history of poorly controlled type 1 diabetes presented acutely with a decreased Glasgow Coma Scale and a diagnosis of hypoglycaemic brain injury. Her MRI highlighted bilateral hippocampi diffusion restriction and T2 hyperintensity. Clinically, she had a marked cognitive deficit, particularly of short-term, anterograde amnesia. She was managed conservatively and with intensive rehabilitation.

http://ift.tt/2hbqNY8

Congenital dacryocystocele

DescriptionCase description

A neonate aged 7 days brought to the eye emergency service with the history of swelling in the lower medial aspect of the left eye since birth (figure 1). The systemically baby was stable without respiratory symptoms. There was an ill-defined reddish cystic swelling with central faint bluish discolouration, rest of the eyelid and ocular examination was normal. Nasal cavity examination was normal; ultrasonography showed well-defined cystic swelling without internal debris, and MRI of the head and orbit revealed well-defined cystic swelling in the lacrimal sac area with collection inside (figure 2). A diagnosis of congenital dacryocystocele was made and advised gentle lacrimal sac massage along with topical moxifloxacin 0.5% eye drops four times. At the end of 2 weeks, there was complete resolution of the swelling without any complications (figure 3). At present, after 3 months, the patient is in...

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Combining an antiviral with rituximab in EBV-related haemophagocytic lymphohistiocytosis led to rapid viral clearance; and a comprehensive review

Epstein-Barr virus (EBV)-related haemophagocytic lymphohistiocytosis (EBVr-HLH) has a better prognosis when the virus is rapidly cleared, but the best antiviral approach is controversial. We present a patient to whom the therapeutic standard rituximab was co-administered with valacyclovir and an HLH-specific treatment with favourable viral and clinical responses. We conducted an extensive literature review and contacted several world reference centres and experts to inquire about their approaches and experience. We conclude that antivirals are infrequently used for EBVr-HLH, despite their laboratory-proven and likely clinical beneficial effect on some EBV-related diseases. However, the role of antivirals remains obscure. Concerns about their lack of efficacy are based on observational data and reports of the cellular tropism of EBV. Therefore, the adjunct use of antivirals may be considered when myelotoxicity is not the primary concern, and related outcomes should be systematically recorded to produce higher quality evidence.

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Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers

Abstract

Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed 8 cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia.

Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3, and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of: 1: CRC and high risk adenoma and 2: CRC. Logistic regression was performed. Final reduced models were constructed selecting the 4 biomarkers with the highest likelihood scores.

Subjects (N=4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer (CC) and 193 rectal cancer (RC). Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1342 had non-neoplastic bowell disease, and 1978 subjects had "clean" colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUC's were 0.76 and, 0.84, respectively. The postive predictive value (PPV) at 90% sensitivity was 25% for endpoint 1 and the negative predictive value (NPV) was 93%. For endpoint 2 the PPV was 18% and the NPV was 97%.

Combinations of serological protein biomarkers provided a significant identification of subjects with high-risk of presence of colorectal neoplasia.

The present set of biomarkers could become important adjunct in early detection of CRC. This article is protected by copyright. All rights reserved.

http://ift.tt/2htaCEG

Detection of colorectal neoplasia: Combination of eight blood-based, cancer-associated protein biomarkers

Abstract

Serological biomarkers may be an option for early detection of colorectal cancer (CRC). The present study assessed 8 cancer-associated protein biomarkers in plasma from subjects undergoing first time ever colonoscopy due to symptoms attributable to colorectal neoplasia.

Plasma AFP, CA19-9, CEA, hs-CRP, CyFra21-1, Ferritin, Galectin-3, and TIMP-1 were determined in EDTA-plasma using the Abbott ARCHITECT® automated immunoassay platform. Primary endpoints were detection of: 1: CRC and high risk adenoma and 2: CRC. Logistic regression was performed. Final reduced models were constructed selecting the 4 biomarkers with the highest likelihood scores.

Subjects (N=4,698) were consecutively included during 2010-2012. Colonoscopy detected 512 CRC patients, 319 colonic cancer (CC) and 193 rectal cancer (RC). Extra colonic malignancies were detected in 177 patients, 689 had adenomas of which 399 were high-risk, 1342 had non-neoplastic bowell disease, and 1978 subjects had "clean" colorectum. Univariable analysis demonstrated that all biomarkers were statistically significant. Multivariate logistic regression demonstrated that the blood-based biomarkers in combination significantly predicted the endpoints. The reduced model resulted in selection of CEA, hs-CRP, CyFra21-1 and Ferritin for the two endpoints; AUC's were 0.76 and, 0.84, respectively. The postive predictive value (PPV) at 90% sensitivity was 25% for endpoint 1 and the negative predictive value (NPV) was 93%. For endpoint 2 the PPV was 18% and the NPV was 97%.

Combinations of serological protein biomarkers provided a significant identification of subjects with high-risk of presence of colorectal neoplasia.

The present set of biomarkers could become important adjunct in early detection of CRC. This article is protected by copyright. All rights reserved.

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Cycles of silence: First Nations women overcoming social and historical barriers in supportive cancer care

Abstract

Background

First Nations people with cancer in Canada confront several critical inequities in physical and psychosocial domains. First Nations women are at a particular disadvantage as they are disproportionately affected by social determinants of health, but how they navigate these challenges within their communities is poorly understood.

Objective

Our study explores survivorship experiences of First Nations women with cancer and their caregivers. Drawing from a larger data set on survivorship, we identify several major barriers to cancer communication and support in First Nations communities.

Methods

Our team conducted a participatory, arts-based study using several data collection methods (interviews, sharing sessions, photovoice and other creative activities) with 43 participants (24 cancer survivors and 19 caregivers) from four First Nations communities in Canada.

Results

Two major themes have emerged out of our data analyses: 1) suffering without support leads to cycles of silence, and 2) community-based supports can disrupt these cycles. We identified several social, historical and institutional barriers to speaking about cancer and finding/providing support; however, communities met the challenge of silence through voluntary and unsolicited provision of support.

Conclusions

Widespread silence around cancer reflects both the limited access First Nations people have to formal, supportive programs and services, as well as the creative ways they provide emotional, social, and financial support within their informal networks. Beyond the support of their communities, they also required institutional provision of care that is culturally safe, addressing the colonial impacts on cancer communication and the disproportionate burdens of disease in First Nations communities.

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Sharing information about cancer with one's family is associated with improved quality of life

Abstract

Objective

The aim of this study was to investigate the association between cancer patients' ability to share information about their illness with their social network and attachment style dimensions, alexithymia and quality of life. We hypothesised that ability to share information about one's cancer with family, friends and medical teams would be positively associated with quality of life and secure attachment and negatively associated with alexithymia.

Methods

Forty-five cancer patients were recruited from the Psycho-oncology unit of the San Camillo-Forlanini Hospital in Rome. We collected anamnestic data and self-report data on social sharing ability, quality of life, alexithymia and attachment.

Results

Sharing with family (B = 4.66; SE = 1.82; β = .52; SE = 0.20; t(41) = 2.6; p = .0143) was the only predictor of global health status and attachment security was the only predictor of mean social sharing (B = 0.25; SE = 0.06; β = .63; SE = 0.14; t(41) = 4.4; p < .0001).

Conclusions

Encouraging patients to share information about their experience of cancer may help to improve their quality of life. Attachment security seems to promote social sharing. Psychological assessments of cancer patients should cover both ability to share information about one's cancer with family and attachment security.

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Antioxidant Supplementation Is Not Associated with Long-term Quality of Life in Stage-II Colorectal Cancer Survivors: A Follow-up of the Study of Colorectal Cancer Survivors Cohort.

Antioxidant Supplementation Is Not Associated with Long-term Quality of Life in Stage-II Colorectal Cancer Survivors: A Follow-up of the Study of Colorectal Cancer Survivors Cohort.

Nutr Cancer. 2016 Dec 08;:1-8

Authors: Tsinovoi CL, Xun P, He K

Abstract
Cancer survivors are motivated to change lifestyle following diagnosis, but studies investigating the outcomes are scarce. The purpose of this study was to examine the associations between antioxidant supplementation and quality of life (QoL) in stage-II colorectal cancer survivors. Four-hundred-fifty-three survivors were enrolled from the North Carolina Cancer Registry from 2009 to 2011. Interview data on demography, treatment, health behaviors, and QoL were collected at diagnosis, and at 12 and 24 mo post-diagnosis. Antioxidant supplementation was self-reported as use of selenium, zinc, beta-carotene, vitamin A, vitamin E, or vitamin C at baseline. Two-hundred-sixty-one subjects completed the 24-mo interview. After adjusting for multiple confounders, there was no association between antioxidant use and the Functional Assessment of Cancer Treatment-Colorectal [β = 1.41; 95% confidence interval (CI): -2.48, 5.30] or the medical outcomes 12-item short form (physical composite score: β = 0.84; 95% CI: -1.39, 3.07; mental composite score: β = -0.61; 95% CI: -2.65, 1.43). This study revealed no benefit of antioxidant use among survivors, possibly explained by a limited sample size of antioxidant users. More prospective studies are necessary to assess the benefits of antioxidants.

PMID: 27929676 [PubMed - as supplied by publisher]

http://ift.tt/2heeYAC

Vitamin D and Calcium for Colorectal Adenoma Chemoprevention.

Vitamin D and Calcium for Colorectal Adenoma Chemoprevention.

Nutr Cancer. 2016 Dec 08;:1

Authors: Kupfer SS, Li YC, Bissonnette M

PMID: 27929663 [PubMed - as supplied by publisher]

http://ift.tt/2gk7LBW

Healthcare Costs Among Patients with Heart Failure: A Comparison of Costs between Matched Decedent and Survivor Cohorts

Abstract

Introduction

Prior research suggests increased costs during the final months of life, yet little is known about healthcare cost differences between patients with heart failure (HF) who die or survive.

Methods

A retrospective claims study from a large US health plan [commercial and Medicare Advantage with Part D (MAPD)] was conducted. Patients were ≥18 years old with two non-inpatient or one inpatient claim(s) with HF diagnosis code(s). The earliest HF claim date during 1 January 2010–31 December 2011 was the index date. Cohort assignment was based on evidence of death within 1 year (decedents) or survival for >1 year (survivors) post-index. Per-patient-per-month (PPPM) and 1-year (variable decedent follow-up) costs (all-cause and HF-related) were calculated up to 1 year post-index. Cohorts were matched on demographic and clinical characteristics. Independent samples t tests and Pearson's chi-square tests were used to examine cohort differences.

Results

Among patients with HF, 8344 survivors were 1:1 matched to decedents [mean age 75 years, 50% female, 88% MAPD; mean time to decedents' death: 150 (SD 105) days]. Compared to survivors, more decedents had no pharmacy claims for HF-related outpatient pharmacotherapy within 60 days post-index (42.1% vs. 27.1%; p < 0.001). Decedents also incurred higher all-cause medical costs (PPPM: $21,400 vs. $2663; 1 year: $60,048 vs. $32,394; both p < 0.001) and higher HF-related medical costs (PPPM: $16,477 vs. $1358; 1 year: $39,052 vs. $16,519; both p < 0.001). Hospitalizations accounted for more than half of all-cause PPPM medical costs (54.6% for survivors, 84.3% for decedents).

Conclusion

Patients with HF who died within 1 year after an index HF encounter incurred markedly higher costs within 1 year (despite the much shorter post-index period) and PPPM costs than those who survived, with the majority of costs attributable to hospitalizations for both patient cohorts. There may be opportunities for improving outcomes in HF, considering higher use of pharmacotherapy and lower costs were seen among survivors.

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Decision-Making in Clinical Practice: Oral Anticoagulant Therapy in Patients with Non-valvular Atrial Fibrillation and a Single Additional Stroke Risk Factor

Abstract

Approximately 1 in 3–4 patients presenting with an ischemic stroke will also have atrial fibrillation (AF), and AF-related strokes can be effectively prevented using oral anticoagulant therapy (OAC), either with well-controlled vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs). In addition, OAC use (both VKAs and NOACs) is associated with a 26% reduction in all-cause mortality (VKAs) or an additional 10% mortality reduction with NOACs relative to VKAs. The decision to use OAC in individual AF patient is based on the estimated balance of the benefit from ischemic stroke reduction against the risk of major OAC-related bleeding [essentially intracranial hemorrhage (ICH)]. Better appreciation of the importance of VKAs' anticoagulation quality [a target time in therapeutic range (TTR) of ≥70%] and the availability of NOACs (which offer better safety compared to VKAs) have decreased the estimated threshold for OAC treatment in AF patients towards lower stroke risk levels. Still, contemporary registry-based data show that OAC is often underused in AF patients at increased risk of stroke. The uncertainty whether to use OAC may be particularly pronounced in AF patients with a single additional stroke risk factor, who are often (mis)perceived as having a "borderline" or insufficient stroke risk to trigger the use of OAC. However, observational data from real-world AF cohorts show that the annual stroke rates in such patients are higher than in patients with no additional stroke risk factors, and OAC use has been associated with reduction in stroke, systemic embolism, or death in comparison to no therapy or aspirin, with no increase in the risk of bleeding relative to aspirin. In this review article, we summarize the basic principles of stroke risk stratification in AF patients and discuss contemporary real-world evidence on OAC use and outcomes of OAC treatment in AF patients with a single additional stroke risk factor in various real-world AF cohorts.

http://ift.tt/2gH7W6o

Antioxidant Supplementation Is Not Associated with Long-term Quality of Life in Stage-II Colorectal Cancer Survivors: A Follow-up of the Study of Colorectal Cancer Survivors Cohort.

Antioxidant Supplementation Is Not Associated with Long-term Quality of Life in Stage-II Colorectal Cancer Survivors: A Follow-up of the Study of Colorectal Cancer Survivors Cohort.

Nutr Cancer. 2016 Dec 08;:1-8

Authors: Tsinovoi CL, Xun P, He K

Abstract
Cancer survivors are motivated to change lifestyle following diagnosis, but studies investigating the outcomes are scarce. The purpose of this study was to examine the associations between antioxidant supplementation and quality of life (QoL) in stage-II colorectal cancer survivors. Four-hundred-fifty-three survivors were enrolled from the North Carolina Cancer Registry from 2009 to 2011. Interview data on demography, treatment, health behaviors, and QoL were collected at diagnosis, and at 12 and 24 mo post-diagnosis. Antioxidant supplementation was self-reported as use of selenium, zinc, beta-carotene, vitamin A, vitamin E, or vitamin C at baseline. Two-hundred-sixty-one subjects completed the 24-mo interview. After adjusting for multiple confounders, there was no association between antioxidant use and the Functional Assessment of Cancer Treatment-Colorectal [β = 1.41; 95% confidence interval (CI): -2.48, 5.30] or the medical outcomes 12-item short form (physical composite score: β = 0.84; 95% CI: -1.39, 3.07; mental composite score: β = -0.61; 95% CI: -2.65, 1.43). This study revealed no benefit of antioxidant use among survivors, possibly explained by a limited sample size of antioxidant users. More prospective studies are necessary to assess the benefits of antioxidants.

PMID: 27929676 [PubMed - as supplied by publisher]

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Vitamin D and Calcium for Colorectal Adenoma Chemoprevention.

Vitamin D and Calcium for Colorectal Adenoma Chemoprevention.

Nutr Cancer. 2016 Dec 08;:1

Authors: Kupfer SS, Li YC, Bissonnette M

PMID: 27929663 [PubMed - as supplied by publisher]

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Healthcare Costs Among Patients with Heart Failure: A Comparison of Costs between Matched Decedent and Survivor Cohorts

Abstract

Introduction

Prior research suggests increased costs during the final months of life, yet little is known about healthcare cost differences between patients with heart failure (HF) who die or survive.

Methods

A retrospective claims study from a large US health plan [commercial and Medicare Advantage with Part D (MAPD)] was conducted. Patients were ≥18 years old with two non-inpatient or one inpatient claim(s) with HF diagnosis code(s). The earliest HF claim date during 1 January 2010–31 December 2011 was the index date. Cohort assignment was based on evidence of death within 1 year (decedents) or survival for >1 year (survivors) post-index. Per-patient-per-month (PPPM) and 1-year (variable decedent follow-up) costs (all-cause and HF-related) were calculated up to 1 year post-index. Cohorts were matched on demographic and clinical characteristics. Independent samples t tests and Pearson's chi-square tests were used to examine cohort differences.

Results

Among patients with HF, 8344 survivors were 1:1 matched to decedents [mean age 75 years, 50% female, 88% MAPD; mean time to decedents' death: 150 (SD 105) days]. Compared to survivors, more decedents had no pharmacy claims for HF-related outpatient pharmacotherapy within 60 days post-index (42.1% vs. 27.1%; p < 0.001). Decedents also incurred higher all-cause medical costs (PPPM: $21,400 vs. $2663; 1 year: $60,048 vs. $32,394; both p < 0.001) and higher HF-related medical costs (PPPM: $16,477 vs. $1358; 1 year: $39,052 vs. $16,519; both p < 0.001). Hospitalizations accounted for more than half of all-cause PPPM medical costs (54.6% for survivors, 84.3% for decedents).

Conclusion

Patients with HF who died within 1 year after an index HF encounter incurred markedly higher costs within 1 year (despite the much shorter post-index period) and PPPM costs than those who survived, with the majority of costs attributable to hospitalizations for both patient cohorts. There may be opportunities for improving outcomes in HF, considering higher use of pharmacotherapy and lower costs were seen among survivors.

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Decision-Making in Clinical Practice: Oral Anticoagulant Therapy in Patients with Non-valvular Atrial Fibrillation and a Single Additional Stroke Risk Factor

Abstract

Approximately 1 in 3–4 patients presenting with an ischemic stroke will also have atrial fibrillation (AF), and AF-related strokes can be effectively prevented using oral anticoagulant therapy (OAC), either with well-controlled vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs). In addition, OAC use (both VKAs and NOACs) is associated with a 26% reduction in all-cause mortality (VKAs) or an additional 10% mortality reduction with NOACs relative to VKAs. The decision to use OAC in individual AF patient is based on the estimated balance of the benefit from ischemic stroke reduction against the risk of major OAC-related bleeding [essentially intracranial hemorrhage (ICH)]. Better appreciation of the importance of VKAs' anticoagulation quality [a target time in therapeutic range (TTR) of ≥70%] and the availability of NOACs (which offer better safety compared to VKAs) have decreased the estimated threshold for OAC treatment in AF patients towards lower stroke risk levels. Still, contemporary registry-based data show that OAC is often underused in AF patients at increased risk of stroke. The uncertainty whether to use OAC may be particularly pronounced in AF patients with a single additional stroke risk factor, who are often (mis)perceived as having a "borderline" or insufficient stroke risk to trigger the use of OAC. However, observational data from real-world AF cohorts show that the annual stroke rates in such patients are higher than in patients with no additional stroke risk factors, and OAC use has been associated with reduction in stroke, systemic embolism, or death in comparison to no therapy or aspirin, with no increase in the risk of bleeding relative to aspirin. In this review article, we summarize the basic principles of stroke risk stratification in AF patients and discuss contemporary real-world evidence on OAC use and outcomes of OAC treatment in AF patients with a single additional stroke risk factor in various real-world AF cohorts.

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Endometrial cancer risk prediction including serum-based biomarkers: Results from the EPIC cohort

Abstract

Endometrial cancer risk prediction models including lifestyle, anthropometric, and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines, and cytokines were evaluated in a step-wise backward selection process; biomarkers were retained at p<0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, and triglycerides were selected into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination. This article is protected by copyright. All rights reserved.

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Sentinel node metastasis mitotic rate (SN-MMR) as a prognostic indicator of rapidly progressing disease in patients with sentinel node-positive melanomas

Abstract

Risk stratification of sentinel lymph node biopsy (SNB)-positive patients with malignant melanoma differs among current classification systems. To improve classification of patients with rapidly progressive disease who may profit from adjuvant therapy with novel immune or targeted treatment modalities, a single-center retrospective analysis was performed including all melanoma patients diagnosed with a positive SN at a university-based skin cancer center over a 10-year period (2002-2012) (96 of 419 patients). Sentinel node metastasis mitotic rate (SN-MMR) and further histologic parameters were determined by blinded histological re-evaluation and correlated with clinical follow-up (overall [OS], melanoma-specific [MSS], and disease-free survival [DFS]). Median follow-up was 53 months.

In univariate analyses, SN tumor penetrative depth (TPD), maximum tumor diameter (MTD), number of positive SN, SN-MMR and the S-, Rotterdam, RDC, Hannover I and II classification systems correlated with OS, MSS and DFS. Multivariate Cox regression analyses showed that a binary classification system based only on the SN-MMR (<1 vs ≥1 mitoses/mm²) was the strongest independent prognostic indicator for all endpoints analyzed. Kaplan-Meier analyses confirmed binary SN-MMR to be superior to stratify patients into high and low risk groups (45.45% vs 87.92% 5-yr MSS).

The general prognostic validity of the published SN classification systems was confirmed. The novel SN-MMR classification system may improve discrimination of patients with slowly and rapidly progressive disease. We therefore propose its implementation into clinical practice as the SN-MMR can be easily and reliably determined in routine pathology reports. Its prognostic value for the selection of patients amenable to adjuvant therapies should be studied in clinical trials. This article is protected by copyright. All rights reserved.

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Patient-derived Xenografts of Gastrointestinal Cancers Are Susceptible to Rapid and Delayed B-Lymphoproliferation

Abstract

Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B-lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts. This article is protected by copyright. All rights reserved.

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The Survival Impact of Delayed Surgery and Adjuvant Chemotherapy on Stage II/III Rectal Cancer with Pathological Complete Response after Neoadjuvant Chemoradiation

ABSTRACT

Neoadjuvant concurrent chemoradiation (CCRT) is standard treatment for clinical stage II/III rectal cancers. However, whether patients with pathological complete response (pT0N0, pCR) should receive adjuvant chemotherapy and whether delayed surgery will influence the pCR rate remains controversial. A nationwide population study was conducted using the Taiwan Cancer Registry Database from January 2007 to December 2013. Kaplan-Meier survival analysis was performed. Cox proportional hazards models were used to estimate multivariate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). Of the 1914 patients who received neoadjuvant CCRT, 259 (13.6%) achieved pCR and had better survival (adjusted HR: 0.37, 95% CI: 0.24-0.58; p<0.001). The cumulative rate of pCR rose up to 83.4% in the 9^th week and slowly reached a plateau after the 11^th week. Among the patients with pCR, those who received adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (adjusted HR: 0.72, 95 CI: 0.27-1.93; p=0.52). By subgroup analysis, those younger than 70 years old and received adjuvant chemotherapy had better survival benefit than those without adjuvant chemotherapy (adjusted HR: 0.19, 95% CI: 0.04-0.97; p=0.046). Delayed surgery by 9-12 weeks after the end of neoadjuvant CCRT can maximize the pCR rate, which is correlated with better survival. Adjuvant chemotherapy may be considered in patients with pCR and aged <70 years old, but further prospectively randomized controlled trials are warranted to validate these findings. This article is protected by copyright. All rights reserved.

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Endometrial cancer risk prediction including serum-based biomarkers: Results from the EPIC cohort

Abstract

Endometrial cancer risk prediction models including lifestyle, anthropometric, and reproductive factors have limited discrimination. Adding biomarker data to these models may improve predictive capacity; to our knowledge, this has not been investigated for endometrial cancer. Using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we investigated the improvement in discrimination gained by adding serum biomarker concentrations to risk estimates derived from an existing risk prediction model based on epidemiologic factors. Serum concentrations of sex steroid hormones, metabolic markers, growth factors, adipokines, and cytokines were evaluated in a step-wise backward selection process; biomarkers were retained at p<0.157 indicating improvement in the Akaike information criterion (AIC). Improvement in discrimination was assessed using the C-statistic for all biomarkers alone, and change in C-statistic from addition of biomarkers to preexisting absolute risk estimates. We used internal validation with bootstrapping (1000-fold) to adjust for over-fitting. Adiponectin, estrone, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, and triglycerides were selected into the model. After accounting for over-fitting, discrimination was improved by 2.0 percentage points when all evaluated biomarkers were included and 1.7 percentage points in the model including the selected biomarkers. Models including etiologic markers on independent pathways and genetic markers may further improve discrimination. This article is protected by copyright. All rights reserved.

http://ift.tt/2haZQn6

Sentinel node metastasis mitotic rate (SN-MMR) as a prognostic indicator of rapidly progressing disease in patients with sentinel node-positive melanomas

Abstract

Risk stratification of sentinel lymph node biopsy (SNB)-positive patients with malignant melanoma differs among current classification systems. To improve classification of patients with rapidly progressive disease who may profit from adjuvant therapy with novel immune or targeted treatment modalities, a single-center retrospective analysis was performed including all melanoma patients diagnosed with a positive SN at a university-based skin cancer center over a 10-year period (2002-2012) (96 of 419 patients). Sentinel node metastasis mitotic rate (SN-MMR) and further histologic parameters were determined by blinded histological re-evaluation and correlated with clinical follow-up (overall [OS], melanoma-specific [MSS], and disease-free survival [DFS]). Median follow-up was 53 months.

In univariate analyses, SN tumor penetrative depth (TPD), maximum tumor diameter (MTD), number of positive SN, SN-MMR and the S-, Rotterdam, RDC, Hannover I and II classification systems correlated with OS, MSS and DFS. Multivariate Cox regression analyses showed that a binary classification system based only on the SN-MMR (<1 vs ≥1 mitoses/mm²) was the strongest independent prognostic indicator for all endpoints analyzed. Kaplan-Meier analyses confirmed binary SN-MMR to be superior to stratify patients into high and low risk groups (45.45% vs 87.92% 5-yr MSS).

The general prognostic validity of the published SN classification systems was confirmed. The novel SN-MMR classification system may improve discrimination of patients with slowly and rapidly progressive disease. We therefore propose its implementation into clinical practice as the SN-MMR can be easily and reliably determined in routine pathology reports. Its prognostic value for the selection of patients amenable to adjuvant therapies should be studied in clinical trials. This article is protected by copyright. All rights reserved.

http://ift.tt/2h4IvyI

Patient-derived Xenografts of Gastrointestinal Cancers Are Susceptible to Rapid and Delayed B-Lymphoproliferation

Abstract

Patient-derived cancer xenografts (PDX) are widely used to identify and evaluate novel therapeutic targets, and to test therapeutic approaches in preclinical mouse avatar trials. Despite their widespread use, potential caveats of PDX models remain considerably underappreciated. Here, we demonstrate that EBV-associated B-lymphoproliferations frequently develop following xenotransplantation of human colorectal and pancreatic carcinomas in highly immunodeficient NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ (NSG) mice (18/47 and 4/37 mice, respectively), and in derived cell cultures in vitro. Strikingly, even PDX with carcinoma histology can host scarce EBV-infected B-lymphocytes that can fully overgrow carcinoma cells during serial passaging in vitro and in vivo. As serial xenografting is crucial to expand primary tumor tissue for biobanks and cohorts for preclinical mouse avatar trials, the emerging dominance of B-lymphoproliferations in serial PDX represents a serious confounding factor in these models. Consequently, repeated phenotypic assessments of serial PDX are mandatory at each expansion step to verify "bona fide" carcinoma xenografts. This article is protected by copyright. All rights reserved.

http://ift.tt/2grXIZT

The Survival Impact of Delayed Surgery and Adjuvant Chemotherapy on Stage II/III Rectal Cancer with Pathological Complete Response after Neoadjuvant Chemoradiation

ABSTRACT

Neoadjuvant concurrent chemoradiation (CCRT) is standard treatment for clinical stage II/III rectal cancers. However, whether patients with pathological complete response (pT0N0, pCR) should receive adjuvant chemotherapy and whether delayed surgery will influence the pCR rate remains controversial. A nationwide population study was conducted using the Taiwan Cancer Registry Database from January 2007 to December 2013. Kaplan-Meier survival analysis was performed. Cox proportional hazards models were used to estimate multivariate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI). Of the 1914 patients who received neoadjuvant CCRT, 259 (13.6%) achieved pCR and had better survival (adjusted HR: 0.37, 95% CI: 0.24-0.58; p<0.001). The cumulative rate of pCR rose up to 83.4% in the 9^th week and slowly reached a plateau after the 11^th week. Among the patients with pCR, those who received adjuvant chemotherapy had no survival benefits compared to those without adjuvant chemotherapy (adjusted HR: 0.72, 95 CI: 0.27-1.93; p=0.52). By subgroup analysis, those younger than 70 years old and received adjuvant chemotherapy had better survival benefit than those without adjuvant chemotherapy (adjusted HR: 0.19, 95% CI: 0.04-0.97; p=0.046). Delayed surgery by 9-12 weeks after the end of neoadjuvant CCRT can maximize the pCR rate, which is correlated with better survival. Adjuvant chemotherapy may be considered in patients with pCR and aged <70 years old, but further prospectively randomized controlled trials are warranted to validate these findings. This article is protected by copyright. All rights reserved.

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New candidate genes for lack of sensitivity to therapy in pediatric leukemias.

New candidate genes for lack of sensitivity to therapy in pediatric leukemias.

Curr Cancer Drug Targets. 2016 Dec 08;

Authors: Bereza W, Szczepanek J, Laskowska J, Tretyn A

Abstract
In recent years, significant development of molecular genetics has contributed to the better understanding of leukemogenesis and classification of the different leukemia subtypes. Patients diagnosed with acute leukemia usually undergo chemotherapy, which involves the induction of remission, consolidation of remission and maintenance therapy. Patients are still vulnerable to relapse due to differences in the sensitivity of leukemia cells to the chemotherapeutic agent, because of the active drugs removal from the cells, improving the repair of DNA damage or abnormalities in the apoptotic pathway. Cell adhesion and miRNA expression level also affect the drug resistance. New candidate genes and genes correlated with the disease have been sought to increase the survival of patients with leukemia. Candidate gene is usually a loci located in a certain chromosomal region suspected of involvement to the disease course or its expression product regulates disease progression. There are classic and digital method of finding candidate genes. These techniques are inexpensive, quick and easy to carry out. Unfortunately, due to insufficient knowledge of the disease etiology and low accuracy, researchers cannot detect all genes, involved in leukemogenesis and cell resistance. Currently, scientists have many tools used for selecting genes, such as expression microarrays, comparative genomic hybridization and next-generation sequencing. Among the validation techniques for candidate genes, the mostly used ones are fluorescent in situ hybridization and real-time PCR. In our review we present 18 candidate genes of resistance to therapy in childhood leukemia.

PMID: 27928969 [PubMed - as supplied by publisher]

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Society of Surgical Oncology Breast Disease Working Group Statement on Prophylactic (Risk-Reducing) Mastectomy

Abstract

Over the past several years, there has been an increasing rate of bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM) surgeries. Since publication of the 2007 SSO position statement on the use of risk-reducing mastectomy, there have been significant advances in the understanding of breast cancer biology and treatment. The purpose of this manuscript is to review the current literature as a resource to facilitate a shared and informed decision-making process regarding the use of risk-reducing mastectomy.

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YM155 induces apoptosis in p53-deficient T-acute lymphoblastic leukemia cells independent of survivin inhibition.

T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from the malignant transformation of T-cell progenitors. Despite the significant progress in current treatment, challenges remain the lifelong morbidity after current chemotherapy regimens and postrelapse survival. In addition, patients with T-ALL have inferior outcomes compared with those with B-cell precursor; consequently, novel therapeutic approaches are still necessary to improve the outcome in this cohort. YM155 is an imidazolium derivative originally discovered as a suppressant of survivin expression. It has been reported that YM155 has potent antiproliferative activity on a variety of human cancer cell lines; however, its effects in T-ALL cells have been underexplored. The aim of the present study was to examine the effects of YM155 on p53-deficient T-ALL cell lines, JURKAT and CCRF-CEM. Resazurin dye was used to evaluate cell viability. Colony formation was observed in MethoCult methylcellulose medium. Apoptotic cells were detected by flow cytometry (annexin V labeling and TUNEL assay). Cell cycle analysis was carried out by DNA quantification in flow cytometry. DNA damage was assessed using a comet assay and the survivin expression profile was evaluated by real-time PCR and immunoblotting. YM155 treatment decreased cell viability and clonogenicity capacity of T-ALL cells, increased the apoptosis index and DNA damage, and altered the cell cycle dynamic, independent of survivin inhibition. Taken together, the data reinforce that YM155 may be useful as a therapeutic possibility to combat leukemia. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

from Cancer via ola Kala on Inoreader http://ift.tt/2ha3sG7
via IFTTT

Society of Surgical Oncology Breast Disease Working Group Statement on Prophylactic (Risk-Reducing) Mastectomy

Abstract

Over the past several years, there has been an increasing rate of bilateral prophylactic mastectomy (BPM) and contralateral prophylactic mastectomy (CPM) surgeries. Since publication of the 2007 SSO position statement on the use of risk-reducing mastectomy, there have been significant advances in the understanding of breast cancer biology and treatment. The purpose of this manuscript is to review the current literature as a resource to facilitate a shared and informed decision-making process regarding the use of risk-reducing mastectomy.

http://ift.tt/2ha4Poe

YM155 induces apoptosis in p53-deficient T-acute lymphoblastic leukemia cells independent of survivin inhibition.

T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from the malignant transformation of T-cell progenitors. Despite the significant progress in current treatment, challenges remain the lifelong morbidity after current chemotherapy regimens and postrelapse survival. In addition, patients with T-ALL have inferior outcomes compared with those with B-cell precursor; consequently, novel therapeutic approaches are still necessary to improve the outcome in this cohort. YM155 is an imidazolium derivative originally discovered as a suppressant of survivin expression. It has been reported that YM155 has potent antiproliferative activity on a variety of human cancer cell lines; however, its effects in T-ALL cells have been underexplored. The aim of the present study was to examine the effects of YM155 on p53-deficient T-ALL cell lines, JURKAT and CCRF-CEM. Resazurin dye was used to evaluate cell viability. Colony formation was observed in MethoCult methylcellulose medium. Apoptotic cells were detected by flow cytometry (annexin V labeling and TUNEL assay). Cell cycle analysis was carried out by DNA quantification in flow cytometry. DNA damage was assessed using a comet assay and the survivin expression profile was evaluated by real-time PCR and immunoblotting. YM155 treatment decreased cell viability and clonogenicity capacity of T-ALL cells, increased the apoptosis index and DNA damage, and altered the cell cycle dynamic, independent of survivin inhibition. Taken together, the data reinforce that YM155 may be useful as a therapeutic possibility to combat leukemia. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2ha3sG7