Association between weight gain during adjuvant chemotherapy for early-stage breast cancer and survival outcomes

Abstract

Obese and overweight women have an increased risk of breast cancer and worse outcomes at the time of diagnosis. Women tend to gain weight after breast cancer diagnosis and during chemotherapy for early-stage disease, which may in turn increase risk for worse outcomes. We examined if weight gained during adjuvant chemotherapy was associated with worse survival outcomes. We queried our database for data on patients who received adjuvant third-generation chemotherapy for early-stage breast cancer. Univariate and multivariate analyses by Cox regression were performed for survival outcomes across three categories according to BMI variation from start to end of chemotherapy: >0.5 kg/m² loss or gain and stable BMI (±0.5 kg/m²). We included 1998 patients in this study. Women over 50 years old and postmenopausal were more likely to lose weight during adjuvant chemotherapy, whereas women under 30 years old gained more weight (P < 0.001). At 1 year postchemotherapy, patients tended to return to their original weight (ρ = −0.3, P < 0.001). On multivariate analysis, BMI increase of >0.5 kg/m² compared to maintaining BMI was marginally associated with increased locoregional recurrence risk (HR: 2.53; 95% CI, 1.18–5.45; P = 0.017), adjusting for grade, stage, and radiation delivery. Weight variation during adjuvant chemotherapy for early-stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival.

Weight variation during adjuvant chemotherapy for early stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival.

http://ift.tt/2yD2eiw

Targeting MTA1/HIF-1α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

Abstract

The metastasis-associated protein 1(MTA1)/histone deacetylase (HDAC) unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA1, could block prostate tumor progression in vivo. We generated and utilized a luciferase reporter in a prostate-specific Pten-null mouse model (Pb-Cre⁺; Pten^f/f; Rosa26^Luc/+) to evaluate the anticancer efficacy of Pter/SAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associated proangiogenic factors HIF-1α, VEGF, and IL-1β leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/HIF-1α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF-1α tumor-promoting signaling in PCa. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targeted therapies in PCa.

Utilization of dietary bioactive molecules as chemo-sensitizers is an emerging approach in developing combination strategies that can potentially provide more efficacy and less toxicity for anticancer treatments. Our study offers preclinical proof for combinatorial strategy using natural product, pterostilbene, with histone deacetylase inhibitor, SAHA, as a MTA1-targeted interventional therapy to abrogate prostate cancer. Changes in MTA1-associated proangiogenic factors in serum may be used as molecular response biomarkers for such therapy.

http://ift.tt/2hAyXu6

Association between weight gain during adjuvant chemotherapy for early-stage breast cancer and survival outcomes

Abstract

Obese and overweight women have an increased risk of breast cancer and worse outcomes at the time of diagnosis. Women tend to gain weight after breast cancer diagnosis and during chemotherapy for early-stage disease, which may in turn increase risk for worse outcomes. We examined if weight gained during adjuvant chemotherapy was associated with worse survival outcomes. We queried our database for data on patients who received adjuvant third-generation chemotherapy for early-stage breast cancer. Univariate and multivariate analyses by Cox regression were performed for survival outcomes across three categories according to BMI variation from start to end of chemotherapy: >0.5 kg/m² loss or gain and stable BMI (±0.5 kg/m²). We included 1998 patients in this study. Women over 50 years old and postmenopausal were more likely to lose weight during adjuvant chemotherapy, whereas women under 30 years old gained more weight (P < 0.001). At 1 year postchemotherapy, patients tended to return to their original weight (ρ = −0.3, P < 0.001). On multivariate analysis, BMI increase of >0.5 kg/m² compared to maintaining BMI was marginally associated with increased locoregional recurrence risk (HR: 2.53; 95% CI, 1.18–5.45; P = 0.017), adjusting for grade, stage, and radiation delivery. Weight variation during adjuvant chemotherapy for early-stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival.

Weight variation during adjuvant chemotherapy for early stage breast cancer may occur as both weight gain and weight loss in a balanced manner. Furthermore, this variation seems to be transient in nature and does not appear to significantly influence recurrence rates and overall survival.

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Targeting MTA1/HIF-1α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression

Abstract

The metastasis-associated protein 1(MTA1)/histone deacetylase (HDAC) unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA1, could block prostate tumor progression in vivo. We generated and utilized a luciferase reporter in a prostate-specific Pten-null mouse model (Pb-Cre⁺; Pten^f/f; Rosa26^Luc/+) to evaluate the anticancer efficacy of Pter/SAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associated proangiogenic factors HIF-1α, VEGF, and IL-1β leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/HIF-1α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF-1α tumor-promoting signaling in PCa. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targeted therapies in PCa.

Utilization of dietary bioactive molecules as chemo-sensitizers is an emerging approach in developing combination strategies that can potentially provide more efficacy and less toxicity for anticancer treatments. Our study offers preclinical proof for combinatorial strategy using natural product, pterostilbene, with histone deacetylase inhibitor, SAHA, as a MTA1-targeted interventional therapy to abrogate prostate cancer. Changes in MTA1-associated proangiogenic factors in serum may be used as molecular response biomarkers for such therapy.

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Cold agglutinins in a patient undergoing normothermic cardiac operation with warm cardioplegia

Cold agglutinins are autoantibodies that agglutinate red blood cells at low temperatures, leading to haemagglutination and haemolysis. They are generally of no clinical significance. However, when people with cold agglutinins undergo cardiac operation with hypothermia and cold cardioplegia, they can experience complications. Thus, different perioperative management is required for such patients. We describe a 74-year-old man with cold agglutinins incidentally detected on the preoperative screening test. He had never experienced any complications or developed a haematological disease. Since cold agglutinins were incidentally detected on the preoperative test, a special strategy was used to manage the temperature of cardiopulmonary bypass (CPB) and cardioplegia. He successfully underwent normothermic cardiac operation with warm cardioplegia. A continuous retrograde hyperkalaemic infusion and intermittent antegrade infusion of warm cardioplegia with normothermic CPB is one of the best methods to avoid hypothermia and excessive activity and metabolism of the heart, and to provide a suitable operative field.

http://ift.tt/2gaYoWz

Use of a dynamic gait trainer for a child with thoracic level spinal cord injury

Paediatric spinal cord injury (SCI) can result in permanent mobility impairment with consequences for activity, participation and quality of life. This case documents the effect of an overground supported stepping intervention using a dynamic gait trainer. To our knowledge, there are no published studies on this intervention for children with SCI and similar interventions have only been reported in children at American Spinal Injury Association Impairment Scale (AIS) levels B and C.

A child with a T10 (thoracic level, vertebra 10), AIS level A injury, sustained at 2 years of age, continued to make gains in all areas including participation, activity, body structure and function over the following 4 years. Use of a dynamic gait trainer improved the participant's ability to be active and participate despite lack of further neuromuscular recovery. This novel approach with a commonly available device allowed the child to be active and participate in the absence of neural recovery.

http://ift.tt/2yfAI9N

Early sonographic detection of a succenturiate placenta after IVF in a 42-year-old woman with multiple comorbidities

We present a case of a 42-year-old woman with a pregnancy resulting from in vitro fertilisation and a medical history including two spontaneous abortions, hypercoagulable state and other comorbidities. At 13 4/7 weeks' gestation, during research ultrasonography, the patient was noted to have an anterior succenturiate placental lobe. Following an episode of vaginal bleeding at 21 6/7 weeks, she was diagnosed with a low-lying posterior placental lobe. Velamentous cord insertion, placenta previa and vasa previa were excluded at that time. After elective induction for advanced maternal age at 39 0/7 weeks, arrest of labour and chorioamnionitis resulted in a primary low transverse caesarean section and delivery of a healthy girl at 39 3/7 weeks. Gross examination of the placenta showed an irregular, singleton placenta with an attached succenturiate lobe and a marginally inserting umbilical cord. Both lobes were connected by two vessels.

http://ift.tt/2gaYk9h

Knotted urethral catheter: an unusual complication in adults

Knotting of feeding tubes or urinary catheters has been reported as a rare complication in paediatrics when draining the bladder. This is caused by inserting thin flexible tubes too far in, allowing it to coil. We present a case of a 70-year-old woman who was catheterised during a routine spinal surgery, and the catheter coiled and balloon failed to deflate requiring a cystostopic approach to puncture the balloon and remove it. Awareness of this complication in female catheterisation and education on length of catheter insertion is important to avoid this.

http://ift.tt/2yePZHZ

Metastatic primary seminal vesicle adenocarcinoma: management of a rare tumour with multiagent chemotherapy and hormonal therapy

Primary seminal vesicle adenocarcinoma is one of the rarest genitourinary cancers. The pathogenesis is unknown and clinical manifestations are protean. There is no defined treatment for this disease and various combinations of surgery, chemotherapy, radiation therapy and hormonal therapy have been used in the past. Here, we have reported a primary seminal vesicle adenocarcinoma with hepatic metastases, managed with multiagent chemotherapy (oxaliplatin and 5-fluorouracil based) and androgen ablation (with triptorelin). The key to management of such a case is early diagnosis and multimodal treatment. The reported survival rate continues to be poor even for a localised disease. A consolidated follow-up protocol ensures early diagnosis of recurrent or metastatic disease so that second-line therapy can be started.

http://ift.tt/2gb6G0j

Double PCL sign on sagittal MRI of the knee

Description

A 24-year-old male presented with left knee pain and swelling after a fall six weeks earlier playing football. Clinical examination revealed an antalgic gait and a moderate left knee effusion with tenderness along the medial joint line. Anterior drawer and Lachman tests were positive, suggesting an anterior cruciate ligament (ACL) injury. An MRI scan performed shortly after the injury revealed a large joint effusion and significant acute bone oedema involving the medial tibial condyle. While the posterior cruciate ligament (PCL) was intact, the ACL was elongated and suspicious for an intrasubstance tear. A bucket-handle tear of the medial meniscus was observed with the free fragment seen within the intercondylar notch. This gave rise to the double PCL sign on sagittal view. The patient underwent arthroscopic ACL reconstruction with a hamstring graft, and the medial meniscus was excised as it was unrepairable.

The 'double PCL' sign refers to the...

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Fulminant Bacillus cereus septicaemia with multiple organ ischaemic/haemorrhagic complications in a patient undergoing chemotherapy for acute myelogenous leukaemia

Bacillus cereus is a Gram-positive spore-forming rod widely found in the environment and is thought to be a frequent source of contamination. This micro-organism is reportedly a significant pathogenic agent among immunocompromised individuals. Furthermore, multiple cases of fulminant septicaemia have been reported among individuals receiving chemotherapy for acute myelogenous leukaemia. In some cases, B. cereus septicaemia was associated with multiple haemorrhages. We, herein, describe a patient with an extremely acute course of B. cereus septicaemia characterised by haemorrhage and infarction of multiple organs, which led to his death. Our findings suggest that delayed treatment of B. cereus in patients with haematologic malignancies undergoing chemotherapy may result in extremely poor outcomes; thus, immediate empirical treatment with vancomycin should be considered.

http://ift.tt/2gaY9L9

Metabolic Symbiosis in Cancer and Its Therapeutic Implication

Publication date: Available online 10 October 2017
Source:Seminars in Oncology
Author(s): Mark R. Lipstein, Ipsita Pal, Susan E. Bates, Changchun Deng




http://ift.tt/2xwwtaS

Metabolic Coupling and the Reverse Warburg Effect in Cancer, implications for novel biomarker and anticancer agent development

Publication date: Available online 10 October 2017
Source:Seminars in Oncology
Author(s): Lindsay Wilde, Megan Roche, Marina Domingo-Vidal, Katherina Tanson, Nancy Philp, Joseph Curry, Ubaldo Martinez-Outschoorn
Glucose is a key metabolite used by cancer cells to generate ATP, maintain redox state and create biomass. Glucose can be catabolized to lactate in the cytoplasm, which is termed glycolysis or alternatively can be catabolized to carbon dioxide and water in the mitochondria via oxidative phosphorylation (OXPHOS). Metabolic heterogeneity exists in a subset of human tumors, with some cells maintaining a glycolytic phenotype while others predominantly utilize OXPHOS. Cells within tumors interact metabolically with transfer of catabolites from supporting stromal cells to adjacent cancer cells. The Reverse Warburg Effect describes when glycolysis in the cancer-associated stroma metabolically supports adjacent cancer cells. This catabolite transfer, which induces stromal-cancer metabolic coupling, allows cancer cells to generate ATP, increase proliferation and reduce cell death. Catabolites implicated in metabolic coupling include the monocarboxylates lactate, pyruvate and ketone bodies. Monocarboxylate transporters (MCT) are critically necessary for release and uptake of these catabolites. MCT4 is involved in the release of monocarboxylates from cells, is regulated by catabolic transcription factors such as hypoxia inducible factor 1 alpha (HIF1A) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and is highly expressed in cancer-associated fibroblasts. Conversely, MCT1 is predominantly involved in the uptake of these catabolites and is highly expressed in a subgroup of cancer cells. MYC and TIGAR, which are genes involved in cellular proliferation and anabolism are inducers of MCT1. Profiling human tumors on the basis of an altered redox balance and intra-tumoral metabolic interactions may have important biomarker and therapeutic implications. Alterations in the redox state and mitochondrial function of cells can induce metabolic coupling. Hence, there is interest in redox and metabolic modulators as anticancer agents. Also, markers of metabolic coupling have been associated with poor outcomes in numerous human malignancies and may be useful prognostic and predictive biomarkers.



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Hodgkin Lymphoma: A Complex Metabolic Ecosystem with Glycolytic Reprogramming of the Tumor Microenvironment

Publication date: Available online 10 October 2017
Source:Seminars in Oncology
Author(s): Lekha Mikkilineni, Diana Whitaker-Menezes, Marina Domingo-Vidal, John Sprandio, Paola Avena, Paolo Cotzia, Alina Dulau-Florea, Jerald Gong, Guldeep Uppal, Tingting Zhan, Benjamin Leiby, Zhao Lin, Barbara Pro, Federica Sotgia, Michael P. Lisanti, Ubaldo Martinez-Outschoorn
BackgroundTwenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL since non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes.MethodsA case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin bleomycin vinblastine and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from 4 subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1) and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1 and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in >50% of cells.ResultsTOMM20, MCT1 and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared to tumor associated macrophages (TAMs) and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1 while TAMs have absent expression of TOMM20 and MCT1 in all but 2 cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but 1 case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment (TME). A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 [1.16-29.71] (two sided p< 0.05) compared to the low metabolic heterogeneity signature.ConclusionAggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease.



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Mitochondrial and glycolytic metabolic compartmentalization in Diffuse Large B Cell Lymphoma

Publication date: Available online 10 October 2017
Source:Seminars in Oncology
Author(s): Mahasweta Gooptu, Diana Whitaker-Menezes, John Sprandio, Marina Domingo-Vidal, Zhao Lin, Guldeep Uppal, Jerald Gong, Roberto Fratamico, Benjamin Leiby, Alina Dulau-Florea, Jaime Caro, Ubaldo Martinez-Outschoorn
Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non-neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor-associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should b studied to determine if it could represent a novel treatment target in DLBCL.



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How are Multifactorial Beliefs about the Role of Genetics and Behavior in Cancer Causation associated with Cancer Risk Cognitions and Emotions in the U.S. Population?

Abstract

Objective

People who believe that cancer has both genetic and behavioral risk factors have more accurate mental models of cancer causation and may be more likely to engage in cancer screening behaviors than people who do not hold such multifactorial causal beliefs. This research explored possible health cognitions and emotions that might produce such differences.

Methods

Using nationally representative cross-sectional data from the U.S. Health Information National Trends Survey (N=2,719), we examined whether endorsing a multifactorial model of cancer causation was associated with perceptions of risk and other cancer-related cognitions and affect. Data were analyzed using linear regression with jackknife variance estimation and procedures to account for the complex survey design and weightings.

Results

Bivariate and multivariable analyses indicated that people who endorsed multifactorial beliefs about cancer had higher absolute risk perceptions, lower pessimism about cancer prevention, and higher worry about harm from environmental toxins that could be ingested or that emanate from consumer products (ps<0.05). Bivariate analyses indicated that multifactorial beliefs were also associated with higher feelings of risk, but multivariable analyses suggested that this effect was accounted for by the negative affect associated with reporting a family history of cancer. Multifactorial beliefs were not associated with believing that everything causes cancer or that there are too many cancer recommendations to follow (ps>0.05).

Conclusion

Holding multifactorial causal beliefs about cancer are associated with a constellation of risk perceptions, health cognitions, and affect that may motivate cancer prevention and detection behavior.

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PD-1 blockade prevents the development and progression of carcinogen-induced oral premalignant lesions

Oral squamous cell carcinoma (OSCC) is preceded by progressive oral premalignant lesions (OPLs). Therefore, therapeutic strategies that prevent malignant progression of OPLs are expected to reduce the incidence of OSCC development. Immune checkpoint inhibitors that target the interaction of programmed death receptor 1 (PD-1) on T cells with the PD-1 ligand PD-L1 on cancer cells have been shown to extend the survival of patients with advanced OSCC. Here, we used the 4-Nitroquinoline-1-oxide (4-NQO) mouse model of oral carcinogenesis to test the hypothesis that PD-1 blockade may control the progression of OPLs. Mice were exposed to 4-NQO in their drinking water and then randomly assigned to two treatment groups that received either a blocking antibody for PD-1 or a control IgG. We found that anti-PD-1 treatment significantly reduced the number of oral lesions that developed in these mice, and prevented malignant progression. Low-grade dysplastic lesions responded to PD-1 blockade with a significant increase in the recruitment of CD8+ and CD4+ T cells and the accumulation of CTLA-4+ T cells in their microenvironment. Notably, PD-1 inhibition was accompanied by induction of interferon-, STAT1 activation and the production of the T cell effector granzyme B in infiltrating cells, and by the induction of apoptosis in the epithelial cells of the oral lesions, suggesting that T cell activation mediates the immunopreventive effects of anti-PD-1. These results support the potential clinical benefit of PD-1 immune checkpoint blockade to prevent OSCC development and progression and suggest that CTLA-4 inhibitors may enhance the preventive effects of anti-PD-1.

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Germline Testing Could Help More Patients [News in Brief]

Simultaneous tumor and germline sequencing increases discovery of actionable mutations, study finds.

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Langer's axillary arch: a frequent but rarely discussed anatomical variant in the radiologic literature

Abstract

The axillopectoral muscle is a rarely discussed variant of muscular anatomy of the axilla, with various clinical implications. We report a case of a 7-year-old girl with multiple genetic and developmental abnormalities who presented with asymmetrical right axillary bulging of unknown etiology. MRI demonstrated a small accessory axillary muscle, known as Langer's axillary arch and/or the axillopectoral muscle. Other than soft-tissue asymmetry, the patient experienced no additional related symptoms. However, this is an important variant to be aware of, as it can easily be discovered on imaging and may be a causative agent for various upper extremity symptoms that may resolve with appropriate recognition and surgical intervention.

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Corrigendum to “Avoidable cancer cases in the Nordic countries – The impact of overweight and obesity” [Eur J Cancer 79 (2017) 106–118]

Publication date: Available online 10 October 2017
Source:European Journal of Cancer
Author(s): Therese M.-L. Andersson, Elisabete Weiderpass, Gerda Engholm, Anne-Sofie Q. Lund, Elinborg Olafsdottir, Eero Pukkala, Magnus Stenbeck, Hans Storm




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Langer's axillary arch: a frequent but rarely discussed anatomical variant in the radiologic literature

Abstract

The axillopectoral muscle is a rarely discussed variant of muscular anatomy of the axilla, with various clinical implications. We report a case of a 7-year-old girl with multiple genetic and developmental abnormalities who presented with asymmetrical right axillary bulging of unknown etiology. MRI demonstrated a small accessory axillary muscle, known as Langer's axillary arch and/or the axillopectoral muscle. Other than soft-tissue asymmetry, the patient experienced no additional related symptoms. However, this is an important variant to be aware of, as it can easily be discovered on imaging and may be a causative agent for various upper extremity symptoms that may resolve with appropriate recognition and surgical intervention.

http://ift.tt/2y9g9wd

Tumour auto-contouring on 2d cine MRI for locally advanced lung cancer: A comparative study

Radiotherapy guidance based on magnetic resonance imaging (MRI) is currently becoming a clinical reality. Fast 2d cine MRI sequences are expected to increase the precision of radiation delivery by facilitating tumour delineation during treatment. This study compares four auto-contouring algorithms for the task of delineating the primary tumour in six locally advanced (LA) lung cancer patients.

http://ift.tt/2xyFnQk

Critical features and challenges associated with imaging in patients undergoing cancer immunotherapy

Publication date: Available online 10 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Cinzia Solinas, Michele Porcu, Zuzana Hlavata, Pushpamali De Silva, Marco Puzzoni, Karen Willard-Gallo, Mario Scartozzi, Luca Saba
Manipulating an individual's immune system through immune checkpoint blockade is revolutionizing the paradigms of cancer treatment. Peculiar patterns and kinetics of response have been observed with these new drugs, rendering the assessment of tumor burden particularly challenging in cancer immunotherapy. The mechanisms of action for immune checkpoint blockade, based upon engagement of the adaptive immune system, can generate unusual response patterns, including pseudoprogression, hyperprogression, atypical and delayed responses. In patients treated with immune checkpoint blockade and radiotherapy, a reduction in tumor burden at metastatic sites distant from the irradiation field (abscopal effect) have been observed, with synergistic systemic immune effects provoked by this combination. New toxicities have also been observed, due to excessive immune activity in several organs, including lung, colon, liver and endocrine glands. Efforts to standardize assessment of cancer immunotherapy responses include novel consensus guidelines derived by modifying World Health Organization (WHO) and Response Evaluation Criteria In Solid Tumors (RECIST) criteria. The aim of this review is to evaluate imaging techniques currently used routinely in the clinic and those being used as investigational tools in immunotherapy clinical trials.



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Critical features and challenges associated with imaging in patients undergoing cancer immunotherapy

Publication date: Available online 10 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Cinzia Solinas, Michele Porcu, Zuzana Hlavata, Pushpamali De Silva, Marco Puzzoni, Karen Willard-Gallo, Mario Scartozzi, Luca Saba
Manipulating an individual's immune system through immune checkpoint blockade is revolutionizing the paradigms of cancer treatment. Peculiar patterns and kinetics of response have been observed with these new drugs, rendering the assessment of tumor burden particularly challenging in cancer immunotherapy. The mechanisms of action for immune checkpoint blockade, based upon engagement of the adaptive immune system, can generate unusual response patterns, including pseudoprogression, hyperprogression, atypical and delayed responses. In patients treated with immune checkpoint blockade and radiotherapy, a reduction in tumor burden at metastatic sites distant from the irradiation field (abscopal effect) have been observed, with synergistic systemic immune effects provoked by this combination. New toxicities have also been observed, due to excessive immune activity in several organs, including lung, colon, liver and endocrine glands. Efforts to standardize assessment of cancer immunotherapy responses include novel consensus guidelines derived by modifying World Health Organization (WHO) and Response Evaluation Criteria In Solid Tumors (RECIST) criteria. The aim of this review is to evaluate imaging techniques currently used routinely in the clinic and those being used as investigational tools in immunotherapy clinical trials.



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Institutional Experience with Ostomies Created During Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion

Abstract

Background

Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) is a complex procedure that often requires ostomy creation to protect high-risk anastomoses. This study aimed to evaluate the authors' institutional experience with CRS-HIPEC-associated ostomies, determine predictors of ostomy creation and reversal, and assess their impact on survival.

Methods

The study analyzed clinicopathologic, perioperative, and oncologic data from a prospective database of 1435 CRS-HIPEC procedures for peritoneal metastases. The Kaplan–Meier method was used to estimate survival. Multivariate analyses identified associations with ostomy creation/reversal and survival.

Results

Ostomies were created in 34% of the patients, most commonly loop ileostomies (82%). Loop ileostomies were reversed in the majority of patients (83%), whereas non-loop ileostomies were infrequently reversed (< 10% reversal rate). In a multivariate logistic regression model, intermediate or high tumor grade, colectomy/proctectomy, longer operative time, and lower Charlson comorbidity index were associated with loop ileostomy creation, whereas incomplete macroscopic resection, colorectal histology, and major postoperative complications were associated with non-reversal of loop ileostomy. In a multivariate Cox proportional hazards model, intermediate or high tumor grade and non-reversal of loop ileostomy were associated with worse overall survival.

Conclusions

Loop ileostomies were almost always reversed, whereas non-loop ileostomies were almost always permanent. Hospital readmissions for loop ileostomy-related complications were common. Therefore, formal outpatient protocols for prevention and management should be implemented. Non-reversal of loop ileostomy was associated with very poor survival.

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Institutional Experience with Ostomies Created During Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion

Abstract

Background

Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) is a complex procedure that often requires ostomy creation to protect high-risk anastomoses. This study aimed to evaluate the authors' institutional experience with CRS-HIPEC-associated ostomies, determine predictors of ostomy creation and reversal, and assess their impact on survival.

Methods

The study analyzed clinicopathologic, perioperative, and oncologic data from a prospective database of 1435 CRS-HIPEC procedures for peritoneal metastases. The Kaplan–Meier method was used to estimate survival. Multivariate analyses identified associations with ostomy creation/reversal and survival.

Results

Ostomies were created in 34% of the patients, most commonly loop ileostomies (82%). Loop ileostomies were reversed in the majority of patients (83%), whereas non-loop ileostomies were infrequently reversed (< 10% reversal rate). In a multivariate logistic regression model, intermediate or high tumor grade, colectomy/proctectomy, longer operative time, and lower Charlson comorbidity index were associated with loop ileostomy creation, whereas incomplete macroscopic resection, colorectal histology, and major postoperative complications were associated with non-reversal of loop ileostomy. In a multivariate Cox proportional hazards model, intermediate or high tumor grade and non-reversal of loop ileostomy were associated with worse overall survival.

Conclusions

Loop ileostomies were almost always reversed, whereas non-loop ileostomies were almost always permanent. Hospital readmissions for loop ileostomy-related complications were common. Therefore, formal outpatient protocols for prevention and management should be implemented. Non-reversal of loop ileostomy was associated with very poor survival.

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Implementation of a School‐Based Educational Program to Increase Breast Cancer Awareness and Promote Intergenerational Transmission of Knowledge in a Rural Mexican Community

AbstractBackground.Rural women have limited access to breast cancer education, which partially contributes to late diagnosis and treatment. In this pilot study, we tested the feasibility of implementing a school‐based breast cancer educational program for adolescents in a rural Mexican community. We hypothesized that the adolescents' knowledge on breast cancer would increase as a result of the program, and that there would be intergenerational transmission of that knowledge to their older female relatives.Materials and Methods.Female adolescents from a rural middle school received the educational program. The program would be considered feasible and acceptable if more than 75% reported being satisfied with its contents. Changes in knowledge in the students and their relatives were evaluated using baseline and 4 months follow‐up questionnaires.Results.One hundred twenty‐six students were enrolled. The program was considered acceptable by 96% of the participants. The students' knowledge regarding breast cancer increased significantly from baseline to 4 months follow‐up (63% to 82%). One hundred ninety‐four female relatives completed the initial knowledge questionnaires. The relatives' knowledge regarding breast cancer showed a significant increase from baseline to 4 months follow‐up (55% to 61%).Conclusion.Implementing breast cancer educational programs for adolescents in rural communities is feasible and acceptable. The program increased the adolescents' knowledge on breast cancer, and promoted the intergenerational transmission of that knowledge to their female relatives. Intergenerational transmission of knowledge represents a potential method for providing population‐based health awareness education globally.Implications for Practice.In limited‐resource settings, education is a valuable tool for achieving early detection and downstaging of breast cancer. Unfortunately, rural women lack access to educational opportunities and information about breast cancer, which is a factor contributing to late diagnosis and treatment. In this study, we demonstrated that implementing a school‐based breast cancer educational program for female adolescents in a rural Mexican community was feasible, acceptable, and increased their knowledge about breast cancer. Furthermore, the program encouraged the transmission of information to the students' older relatives. Intergenerational transmission of knowledge represents a novel and potentially effective tool in cancer education and promotion.

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Ten Months: One Patient's Story of Stage IV Cancer

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Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET Cohort 2 Final Results

AbstractBackground.VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first‐line treatment regimen for patients with HER2‐positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co‐infusion of pertuzumab and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co‐infused, followed by vinorelbine.Patients and Methods.During cycle 1, patients with HER2‐positive locally advanced or MBC received loading doses of pertuzumab (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m2) on days two and nine. From cycle 2 onwards, patients received a co‐infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30–35 mg/m2) on days one and eight (or days two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression‐free survival (PFS) and safety.Results.Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0–73.6) in patients with measurable disease (91/107; 85.0%). Median PFS was 11.5 months (95% CI 10.3–15.8). The most common adverse events [AEs] were diarrhea (57.9%), neutropenia (57.0%), and nausea (41.1%). Grade ≥3 AEs occurred in 85 patients (79.4%) and serious AEs in 44 patients (41.1%). Eighteen patients (16.8%) had AEs suggestive of congestive heart failure.Conclusion.These results support the feasibility of pertuzumab and trastuzumab co‐infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017;22:1160–1168Implications for Practice.Combined treatment with pertuzumab, trastuzumab, and docetaxel is the standard of care for first‐line HER2‐positive metastatic breast cancer. However, some patients cannot, or choose not to, receive docetaxel. VELVET Cohort 2 results support the results from Cohort 1 that suggest that pertuzumab plus trastuzumab and vinorelbine is a suitable alternative for these patients. In addition to this, results from Cohort 2 support the feasibility of administering pertuzumab and trastuzumab together in a single infusion bag, which has the potential to offer greater patient convenience and reduce active health care professional time and medical resource utilization compared with administering them separately.

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A Predictive Score for Thrombosis Associated with Breast, Colorectal, Lung, or Ovarian Cancer: The Prospective COMPASS–Cancer‐Associated Thrombosis Study

AbstractBackground.The stratification of outpatients on chemotherapy for breast, colorectal, lung, and ovarian cancers at risk of venous thromboembolism (VTE) remains an unmet clinical need. The derivation of a risk assessment model (RAM) for VTE in these patients was the aim of the study "Prospective Comparison of Methods for thromboembolic risk assessment with clinical Perceptions and AwareneSS in real life patients–Cancer Associated Thrombosis" (COMPASS–CAT).Patients and Methods.The derivation cohort consisted of 1,023 outpatients. Patients on low molecular weight heparin (LMWH) thromboprophylaxis were excluded. Documented symptomatic VTE was the endpoint of the study.Results.Patients had breast (61%), colorectal (17%), lung (13%), or ovarian cancer (8.6%) at localized (30%) or advanced stage (70%). In 64% of patients, cancer was diagnosed within the last 6 months prior to inclusion. Most of them were on chemotherapy when assessed. Symptomatic VTE occurred in 8.5% of patients. The COMPASS–CAT RAM includes the following variables: (a) anthracycline or anti‐hormonal therapy, (b) time since cancer diagnosis, (c) central venous catheter, (d) stage of cancer, (e) presence of cardiovascular risk factors, (f) recent hospitalization for acute medical illness, (g) personal history of VTE, and (h) platelet count. At 6 months, patients stratified at low/intermediate and high‐risk groups had VTE rates of 1.7% and 13.3%, respectively. The area under the curve of receiver operating characteristics analysis was 0.85. The sensitivity and specificity of the RAM were 88% and 52%, respectively. The negative and positive predictive values of the RAM were 98% and 13%, respectively.Conclusion.The COMPASS–CAT RAM includes reliable and easily collected VTE risk predictors and, in contrast to the Khorana score, it is applicable after the initiation of anticancer treatment in patients with common solid tumors. Its robustness for stratification of patients at high and low/intermediate VTE risk needs to be externally validated.Implications for Practice.The Prospective Comparison of Methods for thromboembolic risk assessment with clinical Perceptions and AwareneSS in real life patients–Cancer Associated Thrombosis (COMPASS–CAT) study provides a new risk assessment model (RAM) for venous thromboembolism (VTE) applicable in outpatients with breast, colorectal, lung or ovarian cancer. The COMPASS–CAT RAM is robust, applicable during chemotherapy and determines the need for VTE prévention by including reliable and easily collected VTE predictors associated with cancer status, its treatment as well as with patients' characteristics and comorbidities. An independent external validation of the RAM is indicated before its use in clinical practice.

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Randomized Controlled Trial of a Home‐Based Walking Program to Reduce Moderate to Severe Aromatase Inhibitor‐Associated Arthralgia in Breast Cancer Survivors

AbstractBackground.In postmenopausal women diagnosed with breast cancer (BC), most BC tumors are hormone receptor positive and guidelines recommend adjuvant endocrine therapy that includes an aromatase inhibitor (AI). This study investigates the impact of a 6‐week, home‐based, self‐directed walking program on the commonly reported side effect of AI‐associated arthralgia (AIAA).Materials and Methods.In this phase II trial, consented BC patients were randomized to walking Intervention (n = 31) or Wait List Control (WLC; n = 31). Eligibility criteria included: stage 0–III BC, on AI for at least 4 weeks, ≥3 on a 5‐point scale inquiring about joint symptom intensity "at its worst," and exercising ≤150 minutes per week. Outcomes were self‐reported joint symptoms and psychosocial measures. Analyses comparing Intervention and WLC groups were conducted on an intention‐to‐treat basis to assess intervention impact at 6 weeks (postintervention) and at 6‐months follow‐up. Adjusted means were calculated to assess differences in two groups.Results.In our final sample (n = 62), mean age was 64 years, 74% were white, and 63% had a body mass index of 30 or higher. At postintervention, Intervention group participants reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living (ADL), and less perceived helplessness in managing joint symptoms. At 6‐months follow‐up (postwalking period in both Intervention and WLC), walking minutes per week had decreased significantly; however, improvements in stiffness and difficulty with ADLs were maintained.Conclusion.This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA.Implications for Practice.Breast cancer survivors whose adjuvant endocrine treatment includes an aromatase inhibitor (AI) often experience the side effect of AI‐associated arthralgia (AIAA). This study investigates the impact of a 6‐week, home‐based, self‐directed walking program in the management of AIAA. Compared with Wait List Control, women in the Intervention group reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living, and less perceived helplessness in managing joint symptoms. This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA.

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TERT Promoter Hypermethylation in Gastrointestinal Cancer: A Potential Stool Biomarker

AbstractBackground.There is a high demand for noninvasive screening tools for gastrointestinal cancer (GIC) detection, and GIC‐specific markers are required for such purposes. It is established that induction of the telomerase reverse transcriptase gene (TERT) coupled with telomerase activation is essential for cancer development/progression and aberrant TERT promoter methylation of specific 5′—C—phosphate—G—3′ (CpGs) has been linked to TERT induction in oncogenesis. Here we analyzed TERT promoter methylation in fecal samples from GIC patients and healthy adults and determined its value as a stool biomarker for GIC detection.Materials and Methods.Sixty‐nine GIC patients (34 colorectal carcinoma and 35 gastric cancer) and 62 healthy adults were recruited and fecal samples were collected. Paired tumors and adjacent non‐cancerous tissues from 34 patients and normal mucosa tissues from 12 healthy individuals were collected. TERT promoter methylation density was determined using pyrosequencing.Results.We identified two GIC‐specific methylation sites at −218 (CpG site 1) and −210 (CpG site 2) in the TERT promoter in tumor tissues. Methylated TERT promoter CpG sites 1 and 2 were also detectable in patient stool, while only background levels were observed in healthy individuals. The overall sensitivity reached 52.2% (95% confidence interval [CI]: 48.3–56.0) for fecal methylated TERT promoter assays at 90% specificity, which was comparable to other known stool methylation markers for GIC detection. The combined assays of fecal TERT promoter methylation and occult blood (OB) significantly improved sensitivity and specificity in colorectal cancer (area under curves for methylation alone: 0.798, 95% CI: 0.707–0.889 vs. methylation + OB: 0.920, 95% CI: 0.859–0.981; p = .028), but not in gastric cancer.Conclusion.This proof‐of‐concept study suggests the feasibility of stool TERT promoter methylation analyses as an additional tool in noninvasive GIC screening.Implications for Practice.Induction of telomerase reverse transcriptase (TERT) expression coupled with telomerase activation is essential for cancer development/progression, while aberrant TERT promoter methylation has been linked to TERT induction in oncogenesis. We identified two cancer‐specific methylation sites (CpG1 and 2) in the TERT promoter in tumors from GIC patients. Methylated TERT promoter CpG sites 1 and 2 were detectable in patient stool, while only background levels were observed in healthy individuals. The sensitivity and specificity was comparable to other known stool methylation markers for GIC detection. This proof‐of‐concept study suggests the feasibility of stool TERT promoter methylation analyses for noninvasive screening of GIC.

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Pulmonary Function Changes After Radiotherapy for Lung or Esophageal Cancer: A Systematic Review Focusing on Dose‐Volume Parameters

AbstractBackground.Despite technical developments in treatment delivery, radiation‐induced lung toxicity (RILT) remains a crucial problem in thoracic radiotherapy. Clinically based RILT scores have their limitations, and more objective measures such as pulmonary functions tests (PFTs) might help to improve treatment strategies.Purpose.To summarize the available evidence about the effect of dose to the lung in thoracic radiotherapy on forced expiratory volume in one second (FEV1) and diffusion capacity (DLCO) in patients with lung and esophageal cancer treated with curative intent.Material and methods.A systematic review following the PRISMA guidelines was performed, using MEDLINE and including clinical studies using (chemo)radiotherapy (CRT) or stereotactic ablative radiotherapy (SABR) for lung or CRT for esophageal cancer that reported both lung dose‐volume histogram (DVH) parameters and changes in PFT results. Search terms included lung and esophageal neoplasms, respiratory function tests, and radiotherapy.Results.Fifteen studies met the inclusion criteria. Seven out of 13 studies on lung cancer reported significant declines (defined as a p value < .05) in PFT results. Both esophageal studies reported significant DLCO declines. One SABR study found a correlation between low lung‐dose parameters and FEV1 decline. Relations between decline of FEV1 (three studies) or decline of DLCO (five studies), respectively, and DVH parameters were found in eight studies analyzing CRT. Furthermore, a heterogeneous range of clinical risk factors for pulmonary function changes were reported in the selected studies.Conclusions.There is evidence that pulmonary function declines after RT in a dose‐dependent manner, but solid data about lung DVH parameters predicting changes in PFT results are scarce. A major disadvantage was the wide variety of methods used, frequently lacking multivariable analyses. Studies using prospective high‐quality data, analyzed with appropriate statistical methods, are needed. The Oncologist 2017;22:1257–1264Implications for Practice.Radiation‐induced lung toxicity remains crucial in thoracic radiotherapy. To prevent this toxicity in the future and individualize patient treatment, objective measures of pulmonary toxicity are needed. Pulmonary function tests may provide such objective measures. This systematic review, included all available clinical studies using external beam radiotherapy for lung or esophageal cancer reporting pulmonary function combined with dose‐volume histogram parameters. There is preliminary evidence that pulmonary function declines post radiotherapy in a dose‐dependent manner. Data quality and analyses were generally limited. Analyses of high‐quality data are therefore urgently needed to improve individualization of advanced radiation therapy.

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Vincristine, Ifosfamide, and Doxorubicin for Initial Treatment of Ewing Sarcoma in Adults

AbstractBackground.There are no clinical trials specifically addressing chemotherapy for adults with Ewing sarcoma (ES). Five‐year event‐free survival (EFS) of adults on pediatric studies of ES (44%–47%) is worse than that of children treated with the same therapy (69%). The object of this study was to review the results of therapy with vincristine, ifosfamide, and doxorubicin (VID) in the multidisciplinary treatment of adults with ES at our institution.Materials and Methods.Charts for adults treated for ES from 1995 to 2011 were retrospectively reviewed. Clinician‐reported radiographic tumor response, type of local therapy, pathologic response, and survival data were collected.Results.Seventy‐one patients were identified who received VID as initial therapy. The median age was 25 (range: 16–64). Forty‐two patients (59%) presented with a localized disease and 29 patients (41%) presented with a distant metastasis. Of all patients treated with VID, 83.6% showed a radiological response. Patients who presented with a localized disease had a 5‐year overall survival (OS) of 68% (median not reached), compared with 10.3% (median: 1.9 years) in those who presented with distant metastases. Five‐year EFS was 67%. The nine patients with a pelvic primary tumor had inferior 5‐year OS (42%) to the 33 with primary tumors at other sites (75%). The 5‐year OS of those who had greater than or equal to 95% necrosis after neoadjuvant VID (n = 20; 5‐year OS: 84%) was superior to those who had less than 95% necrosis (n = 13; 5‐year OS: 53%).Conclusion.In adults with primary ES, VID combined with an adjuvant strategy based on post‐treatment percent necrosis has favorable outcomes compared with historical adult controls.Implications for Practice.Ewing sarcoma (ES) is a rare tumor in adults, and there are no dedicated clinical trials in the adult population. Most therapy is modeled after the published pediatric studies, although the small numbers of adult patients included on those studies did significantly worse than the children. We modeled our treatment on other adult sarcomas and reviewed the charts of 71 adult patients with ES treated with vincristine, ifosfamide, and doxorubicin (VID). In adults with primary ES, VID combined with an adjuvant strategy based on post‐treatment percent necrosis has favorable outcomes compared with historical adult controls.

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Patient‐Driven Second Opinions in Oncology: A Systematic Review

AbstractBackground.Although patient‐driven second opinions are increasingly sought in oncology, the desirability of this trend remains unknown. Therefore, this systematic review assesses evidence on the motivation for and frequency of requests for second opinions and examines how they evolve and their consequences for oncological practice.Materials and Methods.Relevant databases were sought using the terms "cancer," "second opinion," and "self‐initiated." Included were peer‐reviewed articles that reported on patient‐initiated second opinions within oncology. Selection, data extraction, and quality assessment were performed and discussed by two researchers.Results.Of the 25 included studies, the methodological designs were qualitative (n = 4), mixed (n = 1), or quantitative (n = 20). Study quality was rated high for 10 studies, moderate for eight, and low for seven studies. Reported rates of second opinion seeking ranged from 1%–88%. Higher education was most consistently related to seeking a second opinion. Patients' primary motivations were a perceived need for certainty or confirmation, a lack of trust, dissatisfaction with communication, and/or a need for more (personalized) information. Reported rates of diagnostic or therapeutic discrepancies between the first and second opinions ranged from 2%–51%.Discussion.Additional studies are required to further examine the medical, practical, and psychological consequences of second opinions for patients and oncologists. Future studies could compare the potential advantages and disadvantages of second opinion seeking, and might offer guidance to patients and physicians to better facilitate the second opinion process. Some practical recommendations are provided for oncologists to optimally discuss and conduct second opinions with their patients. The Oncologist 2017;22:1197–1211Implications for Practice.Although cancer patients increasingly seek a second opinion, the benefits of this process remain unclear. Results of this systematic review suggest that the available studies on this topic are highly variable in both methodology and quality. Moreover, reported rates for a second opinion (1%–88%) as well as for disagreement between the first and second opinion (2%–51%) range widely. The primary motivations of patients are a need for certainty, lack of trust, dissatisfaction with communication, and/or a need for more (personalized) information. Additional research should evaluate how unnecessary second opinions might be avoided. Practical suggestions are provided for oncologists to optimize second opinions.

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Randomized Phase II Trial of Parsatuzumab (Anti‐EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First‐Line Metastatic Colorectal Cancer

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Fixed Dosing of Monoclonal Antibodies in Oncology

AbstractMost monoclonal antibodies in oncology are administered in body–size‐based dosing schedules. This is believed to correct for variability in both drug distribution and elimination between patients. However, monoclonal antibodies typically distribute to the blood plasma and extracellular fluids only, which increase less than proportionally with the increase in body weight. Elimination takes place via proteolytic catabolism, a nonspecific immunoglobulin G elimination pathway, and intracellular degradation after binding to the target. The latter is the primary route of elimination and is related to target expression levels rather than body size. Taken together, the minor effects of body size on distribution and elimination of monoclonal antibodies and their usually wide therapeutic window do not support body–size‐based dosing. We evaluated effects of body weight on volume of distribution and clearance of monoclonal antibodies in oncology and show that a fixed dose for most of these drugs is justified based on pharmacokinetics. A survey of the savings after fixed dosing of monoclonal antibodies at our hospital showed that fixed dosing can reduce costs of health care, especially when pooling of preparations is not possible (which is often the case in smaller hospitals). In conclusion, based on pharmacokinetic parameters of monoclonal antibodies, there is a rationale for fixed dosing of these drugs in oncology. Therefore, we believe that fixed dosing is justified and can improve efficiency of the compounding. Moreover, drug spillage can be reduced and medication errors may become less likely.Implications for Practice.The currently available knowledge of elimination of monoclonal antibodies combined with the publicly available data from clinical trials and extensive population pharmacokinetic (PopPK) modeling justifies fixed dosing. Interpatient variation in exposure is comparable after body weight and fixed dosing and most monoclonal antibodies show relatively flat dose‐response relationships. For monoclonal antibodies, this results in wide therapeutic windows and no reduced clinical efficacy after fixed dosing. Therefore, we believe that fixed dosing at a well‐selected dose can increase medication safety and help in reduction of costs of health care without the loss of efficacy or safety margins.

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A Phase II Study with Lead‐In Safety Cohort of 5‐Fluorouracil, Oxaliplatin, and Lapatinib in Combination with Radiation Therapy as Neoadjuvant Treatment for Patients with Localized HER2‐Positive Esophagogastric Adenocarcinomas

AbstractLessons Learned.Neoadjuvant 5‐fluorouracil, oxaliplatin, and lapatinib in combination with radiation therapy is safe for neoadjuvant treatment for patients with localized human epidermal growth receptor 2‐positive esophagogastric adenocarcinoma.Evaluation of this drug combination in a larger patient pool would allow for more accurate analysis of its efficacy. Background.The optimal design of neoadjuvant chemoradiation for the treatment of localized esophagogastric cancers is the subject of much debate. In this nonrandomized trial, we evaluated neoadjuvant 5‐fluorouracil (5‐FU), oxaliplatin, and lapatinib in combination with radiation therapy as neoadjuvant treatment for patients with localized human epidermal growth receptor 2 (HER2)‐positive esophagogastric adenocarcinomas.Methods.Patients received neoadjuvant 5‐FU (225 mg/m2 continuous intravenous infusion, days 1–42), oxaliplatin (85 mg/m2 intravenously [IV], days 1, 15, and 29), and lapatinib (six patients, 1,000 mg p.o., days 1–42; six patients, 750 mg p.o., days 1–42) plus radiation (1.8 Gy/day Monday through Friday for 50.4 Gy total). Following restaging, eligible patients underwent definitive resection, and pathologic response to neoadjuvant therapy was assessed. Planned enrollment was 42 patients. The primary endpoint was the pathologic complete response (pCR) rate.Results.Twelve patients (median age 64 years; 67% male) received a median of 5.6 weeks of treatment (range: 1.1–8.4). The pCR rate was 8%; four of the 12 patients underwent tumor resection and one patient had a pCR, with pathologic partial response in the remaining three. The most common lapatinib‐related adverse events included (all grades) nausea (67%) and diarrhea (58%), although these were all grade 1 or 2. Enrollment was halted due to low accrual.Conclusion.The treatment regimen was determined to be safe. The study was terminated early due to low accrual.

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Ten Months: One Patient's Story of Stage IV Cancer

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Pregabalin for the Prevention of Oxaliplatin‐Induced Painful Neuropathy: A Randomized, Double‐Blind Trial

AbstractLessons Learned. Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin‐related neuropathic pain, compared with placebo.Background.Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin‐induced peripheral neuropathy (OXAIPN). Acute and chronic OXA‐related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti‐hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN.Methods.Pain‐free, chemotherapy‐naïve CRC patients receiving at least one cycle of modified‐FLOX [5‐FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1‐3‐5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow‐up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0–10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique‐4 (DN‐4), pain dimensions (short‐ form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile.Results.One hundred ninety‐nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79–1.26), and 0.85 (95% CI = 0.64–1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN‐4, NPSI, and NCS and side‐effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1–11.2]; pregabalin 6.8 [5.6–8.0]).Conclusion.The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.

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A Phase II Trial Evaluating the Safety of Rapid Infusion of Ofatumumab in Patients with Previously Treated Chronic Lymphocytic Leukemia

Lessons Learned. Ofatumumab infusion reactions can be diminished by escalating the dose rate in individual patients in sequential infusions.Background.Ofatumumab (OFA) is a fully humanized, anti‐CD20 antibody approved for use in chronic lymphocytic leukemia (CLL). The recommended administration requires long infusion times. We evaluated an accelerated infusion regimen of 2 hours.Methods.The first dose of OFA (300 mg) was given on week 1 day 1 starting at 3.6 mg/hour and doubling every 30 minutes until a rate of 240 mg/hour was reached. If tolerated, the second dose (1,000 mg) was given on week 1 day 3 starting at 50 mg/hour and doubling every 30 minutes until a rate of 800 mg/hour was reached. If tolerated, the third dose (2,000 mg) was given on week 2 day 1 at 800 mg/hour over the first 30 minutes and, if tolerated, at 1,068 mg/hour over the next 90 minutes (goal infusion time: 120 minutes). Subsequent OFA infusions were administered weekly in the same manner for 8 weeks, and then monthly for 4 months.Results.Thirty‐four patients were treated. Most infusion‐related reactions occurred during the first and second infusion. Eighty‐seven percent (87%) of patients finished the third infusion within 15 minutes of the planned 2 hours and only one had an infusion reaction.Conclusion.Using this stepped‐up dosing regimen, a rapid infusion of OFA is safe and well tolerated.

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Localized Adult Ewing Sarcoma: Favorable Outcomes with Alternating Vincristine, Doxorubicin, Cyclophosphamide, and Ifosfamide, Etoposide (VDC/IE)‐Based Multimodality Therapy

AbstractBackground.In children with localized Ewing sarcoma (ES), addition of ifosfamide and etoposide to cyclophosphamide, doxorubicin, and vincristine (VDC/IE) improved 5‐year overall survival (OS) to 70%–80%. Prior to delivery of VDC/IE in adults, 5‐year OS was <50%. We reviewed our institutional outcomes for adults with ES who received VDC/IE‐based treatment.Materials and Methods.Between 1997–2013, 67 adults with localized ES were treated with curative intent. Local recurrence‐free survival (LRFS), progression‐free survival (PFS), and OS were determined using Kaplan‐Meier method; comparisons were assessed with log‐rank. Proportional hazard models were used to determine predictive factors.Results.All patients received VDC/IE (median 14 cycles.) Local therapy was surgery for 33, radiation therapy for 17, or both for 17. Median follow‐up for living patients was 5.2 years. Six patients had disease progression on therapy. Site of first failure was local for three, local and distant for two, and distant for ten. Five‐year LRFS was 91%; 5‐year LRFS was 96% for nonpelvic disease and 64% for pelvic disease (p = .003). Five‐year PFS was 66%, and 5‐year OS was 79%. On multivariate analysis, pelvic site had a 3.3 times increased risk of progression (p = .01).Conclusion.Survival for adults with localized ES treated with VDC/IE‐based multimodality therapy appears to be better than historical data and similar to excellent outcomes in children. Pelvic site of disease remains a predictor of worse outcome. Given the paucity of literature for adult ES, these data help validate VDC/IE‐based therapy as an appropriate treatment approach for this rare disease in adults.Implications for Practice.Ewing sarcoma (ES) is rare in adults. Treatment approaches for adults have been extrapolated from the pediatric experience, and there is a sense that adults fare less well than children. We reviewed treatment outcomes in adults with localized ES treated with cyclophosphamide, doxorubicin, and vincristine in alternation with ifosfamide and etoposide (VDC/IE) as part of multimodality therapy. Survival outcomes appear to be better than historical data for adults and similar to the excellent outcomes for children. These data help validate VDC/IE‐based therapy as an appropriate treatment approach for this rare disease in adults.

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Phase II Trial of Sorafenib in Combination with Capecitabine in Patients with Hepatocellular Carcinoma: INST 08‐20

AbstractLessons Learned. There continues to be a lack of systemic options for advanced hepatocellular carcinoma (HCC); sorafenib and, very recently, regorafenib are the only approved options. There exists a potential to combine sorafenib with chemotherapeutic agents shown to be active in HCC, such as capecitabine, safely.Good tumor response was observed, with objective improvement in a few patients seldom seen by single agent sorafenib; however, because of the limited number of patients, meaningful conclusions on survival cannot be drawn.Background.Sorafenib is the currently approved first‐line treatment for hepatocellular carcinoma (HCC). Capecitabine has antitumor activity in hepatobiliary cancers. The combination of the two, if tolerated, could possibly improve antitumor response, and survival.Methods.Patients with advanced HCC ineligible for locoregional therapy, Eastern Cooperative Oncology Group performance status of ≤2, Child‐Pugh class A or B‐7 cirrhosis, hemoglobin ≥8.5 g/dL, platelets ≥50,000/μL, absolute neutrophil count (ANC) ≥1,500 cells/μL, and serum creatinine of ≤2.0 mg/dL were recruited. All subjects received a combination of sorafenib and capecitabine, on a 14‐day 7‐days on 7‐days off schedule. The primary end point was safety and secondary end points were overall survival (OS) and disease control rate.Results.A total of 15 out of 47 patients met inclusion criteria. Median age was 64 years (56–79) and 77% were male. With a median follow‐up of 12 months, median OS was 12.7 months (95% confidence interval [CI], 8.5–23.4). Disease control rate was 77% (complete response 8%, partial response 8%, and stable disease 61%). Common adverse events were as follows: (a) thrombocytopenia (64%); (b) anemia (14%); (c) hypophosphatemia (21%); (d) hypomagnesemia (14%); (e) hyperbilirubinemia (21%); (f) increased aspartate transaminase (AST) (14%); (g) hand‐foot syndrome (21%); and (h) deep vein thrombosis (21%).Conclusion.At tolerable doses, the combination of sorafenib and capecitabine seems an active and safe palliative treatment for HCC in class A and B‐7 patients with cirrhosis. The small sample size does not allow comparison with single‐agent sorafenib.

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Exceptional Response with Immunotherapy in a Patient with Anaplastic Thyroid Cancer

AbstractChemotherapy with or without radiation is the standard therapy for anaplastic thyroid cancer (ATC), although the response rate is not high and not durable. We describe a 62‐year‐old male who was diagnosed with ATC and initially treated with a thyroidectomy and lymph node dissection, followed by chemotherapy. Next generation sequencing was then performed to guide therapy and the tumor was found to have BRAF and programmed death‐ligand 1 (PD‐L1) positivity that was subsequently treated with vemurafenib and nivolumab. This led to substantial regression of tumor nodules. Genomic sequencing‐based approaches to identify therapeutic targets has potential for improving outcomes. Currently, the patient continues to be in complete radiographic and clinical remission 20 months after beginning treatment with nivolumab.Key Points. Programmed death‐1 (PD‐1)/PD‐L1 immunotherapy has shown evidence of durable responses in certain malignancies such as melanoma, lung cancer, and renal cell carcinoma.PD‐L1 positive tumors promote autoimmunity against the tumor; therefore, PD‐1/PD‐L1 blockade may be beneficial.Molecular profiling could possibly result in improved targeted therapy for certain malignancies.

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Efficacy and Safety of Pertuzumab and Trastuzumab Administered in a Single Infusion Bag, Followed by Vinorelbine: VELVET Cohort 2 Final Results

AbstractBackground.VELVET Cohort 1 demonstrated the applicability of pertuzumab, trastuzumab, and vinorelbine as an alternative first‐line treatment regimen for patients with HER2‐positive locally advanced or metastatic breast cancer (MBC) who cannot receive docetaxel. Co‐infusion of pertuzumab and trastuzumab may reduce clinic time and medical resource utilization. We report results from Cohort 2, in which pertuzumab and trastuzumab were co‐infused, followed by vinorelbine.Patients and Methods.During cycle 1, patients with HER2‐positive locally advanced or MBC received loading doses of pertuzumab (840 mg) and trastuzumab (8 mg/kg) on consecutive days, followed by vinorelbine (25 mg/m2) on days two and nine. From cycle 2 onwards, patients received a co‐infusion of pertuzumab (420 mg) and trastuzumab (6 mg/kg) on day one, followed by vinorelbine (30–35 mg/m2) on days one and eight (or days two and nine). The primary endpoint was objective response rate (ORR) in patients with measurable disease. Secondary endpoints included progression‐free survival (PFS) and safety.Results.Cohort 2 enrolled 107 patients. The ORR was 63.7% (95% confidence interval [CI] 53.0–73.6) in patients with measurable disease (91/107; 85.0%). Median PFS was 11.5 months (95% CI 10.3–15.8). The most common adverse events [AEs] were diarrhea (57.9%), neutropenia (57.0%), and nausea (41.1%). Grade ≥3 AEs occurred in 85 patients (79.4%) and serious AEs in 44 patients (41.1%). Eighteen patients (16.8%) had AEs suggestive of congestive heart failure.Conclusion.These results support the feasibility of pertuzumab and trastuzumab co‐infusion from a safety perspective and support Cohort 1 conclusions that vinorelbine offers an alternative chemotherapy companion for pertuzumab and trastuzumab. The Oncologist 2017;22:1160–1168Implications for Practice.Combined treatment with pertuzumab, trastuzumab, and docetaxel is the standard of care for first‐line HER2‐positive metastatic breast cancer. However, some patients cannot, or choose not to, receive docetaxel. VELVET Cohort 2 results support the results from Cohort 1 that suggest that pertuzumab plus trastuzumab and vinorelbine is a suitable alternative for these patients. In addition to this, results from Cohort 2 support the feasibility of administering pertuzumab and trastuzumab together in a single infusion bag, which has the potential to offer greater patient convenience and reduce active health care professional time and medical resource utilization compared with administering them separately.

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A Predictive Score for Thrombosis Associated with Breast, Colorectal, Lung, or Ovarian Cancer: The Prospective COMPASS–Cancer‐Associated Thrombosis Study

AbstractBackground.The stratification of outpatients on chemotherapy for breast, colorectal, lung, and ovarian cancers at risk of venous thromboembolism (VTE) remains an unmet clinical need. The derivation of a risk assessment model (RAM) for VTE in these patients was the aim of the study "Prospective Comparison of Methods for thromboembolic risk assessment with clinical Perceptions and AwareneSS in real life patients–Cancer Associated Thrombosis" (COMPASS–CAT).Patients and Methods.The derivation cohort consisted of 1,023 outpatients. Patients on low molecular weight heparin (LMWH) thromboprophylaxis were excluded. Documented symptomatic VTE was the endpoint of the study.Results.Patients had breast (61%), colorectal (17%), lung (13%), or ovarian cancer (8.6%) at localized (30%) or advanced stage (70%). In 64% of patients, cancer was diagnosed within the last 6 months prior to inclusion. Most of them were on chemotherapy when assessed. Symptomatic VTE occurred in 8.5% of patients. The COMPASS–CAT RAM includes the following variables: (a) anthracycline or anti‐hormonal therapy, (b) time since cancer diagnosis, (c) central venous catheter, (d) stage of cancer, (e) presence of cardiovascular risk factors, (f) recent hospitalization for acute medical illness, (g) personal history of VTE, and (h) platelet count. At 6 months, patients stratified at low/intermediate and high‐risk groups had VTE rates of 1.7% and 13.3%, respectively. The area under the curve of receiver operating characteristics analysis was 0.85. The sensitivity and specificity of the RAM were 88% and 52%, respectively. The negative and positive predictive values of the RAM were 98% and 13%, respectively.Conclusion.The COMPASS–CAT RAM includes reliable and easily collected VTE risk predictors and, in contrast to the Khorana score, it is applicable after the initiation of anticancer treatment in patients with common solid tumors. Its robustness for stratification of patients at high and low/intermediate VTE risk needs to be externally validated.Implications for Practice.The Prospective Comparison of Methods for thromboembolic risk assessment with clinical Perceptions and AwareneSS in real life patients–Cancer Associated Thrombosis (COMPASS–CAT) study provides a new risk assessment model (RAM) for venous thromboembolism (VTE) applicable in outpatients with breast, colorectal, lung or ovarian cancer. The COMPASS–CAT RAM is robust, applicable during chemotherapy and determines the need for VTE prévention by including reliable and easily collected VTE predictors associated with cancer status, its treatment as well as with patients' characteristics and comorbidities. An independent external validation of the RAM is indicated before its use in clinical practice.

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Clinical Application of Targeted Deep Sequencing in Solid‐Cancer Patients and Utility for Biomarker‐Selected Clinical Trials

AbstractMolecular profiling of actionable mutations in refractory cancer patients has the potential to enable "precision medicine," wherein individualized therapies are guided based on genomic profiling. The molecular‐screening program was intended to route participants to different candidate drugs in trials based on clinical‐sequencing reports. In this screening program, we used a custom target‐enrichment panel consisting of cancer‐related genes to interrogate single‐nucleotide variants, insertions and deletions, copy number variants, and a subset of gene fusions. From August 2014 through April 2015, 654 patients consented to participate in the program at Samsung Medical Center. Of these patients, 588 passed the quality control process for the 381‐gene cancer‐panel test, and 418 patients were included in the final analysis as being eligible for any anticancer treatment (127 gastric cancer, 122 colorectal cancer, 62 pancreatic/biliary tract cancer, 67 sarcoma/other cancer, and 40 genitourinary cancer patients). Of the 418 patients, 55 (12%) harbored a biomarker that guided them to a biomarker‐selected clinical trial, and 184 (44%) patients harbored at least one genomic alteration that was potentially targetable. This study demonstrated that the panel‐based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker‐selected clinical trials. Given the expanding list of biomarker‐selected trials, the guidance percentage to matched trials is anticipated to increase.Implications for Practice.This study demonstrated that the panel‐based sequencing program resulted in an increased rate of trial enrollment of metastatic cancer patients into biomarker‐selected clinical trials. Given the expanding list of biomarker‐selected trials, the guidance percentage to matched trials is anticipated to increase.

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Randomized Controlled Trial of a Home‐Based Walking Program to Reduce Moderate to Severe Aromatase Inhibitor‐Associated Arthralgia in Breast Cancer Survivors

AbstractBackground.In postmenopausal women diagnosed with breast cancer (BC), most BC tumors are hormone receptor positive and guidelines recommend adjuvant endocrine therapy that includes an aromatase inhibitor (AI). This study investigates the impact of a 6‐week, home‐based, self‐directed walking program on the commonly reported side effect of AI‐associated arthralgia (AIAA).Materials and Methods.In this phase II trial, consented BC patients were randomized to walking Intervention (n = 31) or Wait List Control (WLC; n = 31). Eligibility criteria included: stage 0–III BC, on AI for at least 4 weeks, ≥3 on a 5‐point scale inquiring about joint symptom intensity "at its worst," and exercising ≤150 minutes per week. Outcomes were self‐reported joint symptoms and psychosocial measures. Analyses comparing Intervention and WLC groups were conducted on an intention‐to‐treat basis to assess intervention impact at 6 weeks (postintervention) and at 6‐months follow‐up. Adjusted means were calculated to assess differences in two groups.Results.In our final sample (n = 62), mean age was 64 years, 74% were white, and 63% had a body mass index of 30 or higher. At postintervention, Intervention group participants reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living (ADL), and less perceived helplessness in managing joint symptoms. At 6‐months follow‐up (postwalking period in both Intervention and WLC), walking minutes per week had decreased significantly; however, improvements in stiffness and difficulty with ADLs were maintained.Conclusion.This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA.Implications for Practice.Breast cancer survivors whose adjuvant endocrine treatment includes an aromatase inhibitor (AI) often experience the side effect of AI‐associated arthralgia (AIAA). This study investigates the impact of a 6‐week, home‐based, self‐directed walking program in the management of AIAA. Compared with Wait List Control, women in the Intervention group reported significantly increased walking minutes per week, reduced stiffness, less difficulty with activities of daily living, and less perceived helplessness in managing joint symptoms. This study adds to the growing evidence base suggesting exercise as a safe alternative or adjunct to medications for the management of AIAA.

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TERT Promoter Hypermethylation in Gastrointestinal Cancer: A Potential Stool Biomarker

AbstractBackground.There is a high demand for noninvasive screening tools for gastrointestinal cancer (GIC) detection, and GIC‐specific markers are required for such purposes. It is established that induction of the telomerase reverse transcriptase gene (TERT) coupled with telomerase activation is essential for cancer development/progression and aberrant TERT promoter methylation of specific 5′—C—phosphate—G—3′ (CpGs) has been linked to TERT induction in oncogenesis. Here we analyzed TERT promoter methylation in fecal samples from GIC patients and healthy adults and determined its value as a stool biomarker for GIC detection.Materials and Methods.Sixty‐nine GIC patients (34 colorectal carcinoma and 35 gastric cancer) and 62 healthy adults were recruited and fecal samples were collected. Paired tumors and adjacent non‐cancerous tissues from 34 patients and normal mucosa tissues from 12 healthy individuals were collected. TERT promoter methylation density was determined using pyrosequencing.Results.We identified two GIC‐specific methylation sites at −218 (CpG site 1) and −210 (CpG site 2) in the TERT promoter in tumor tissues. Methylated TERT promoter CpG sites 1 and 2 were also detectable in patient stool, while only background levels were observed in healthy individuals. The overall sensitivity reached 52.2% (95% confidence interval [CI]: 48.3–56.0) for fecal methylated TERT promoter assays at 90% specificity, which was comparable to other known stool methylation markers for GIC detection. The combined assays of fecal TERT promoter methylation and occult blood (OB) significantly improved sensitivity and specificity in colorectal cancer (area under curves for methylation alone: 0.798, 95% CI: 0.707–0.889 vs. methylation + OB: 0.920, 95% CI: 0.859–0.981; p = .028), but not in gastric cancer.Conclusion.This proof‐of‐concept study suggests the feasibility of stool TERT promoter methylation analyses as an additional tool in noninvasive GIC screening.Implications for Practice.Induction of telomerase reverse transcriptase (TERT) expression coupled with telomerase activation is essential for cancer development/progression, while aberrant TERT promoter methylation has been linked to TERT induction in oncogenesis. We identified two cancer‐specific methylation sites (CpG1 and 2) in the TERT promoter in tumors from GIC patients. Methylated TERT promoter CpG sites 1 and 2 were detectable in patient stool, while only background levels were observed in healthy individuals. The sensitivity and specificity was comparable to other known stool methylation markers for GIC detection. This proof‐of‐concept study suggests the feasibility of stool TERT promoter methylation analyses for noninvasive screening of GIC.

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Pulmonary Function Changes After Radiotherapy for Lung or Esophageal Cancer: A Systematic Review Focusing on Dose‐Volume Parameters

AbstractBackground.Despite technical developments in treatment delivery, radiation‐induced lung toxicity (RILT) remains a crucial problem in thoracic radiotherapy. Clinically based RILT scores have their limitations, and more objective measures such as pulmonary functions tests (PFTs) might help to improve treatment strategies.Purpose.To summarize the available evidence about the effect of dose to the lung in thoracic radiotherapy on forced expiratory volume in one second (FEV1) and diffusion capacity (DLCO) in patients with lung and esophageal cancer treated with curative intent.Material and methods.A systematic review following the PRISMA guidelines was performed, using MEDLINE and including clinical studies using (chemo)radiotherapy (CRT) or stereotactic ablative radiotherapy (SABR) for lung or CRT for esophageal cancer that reported both lung dose‐volume histogram (DVH) parameters and changes in PFT results. Search terms included lung and esophageal neoplasms, respiratory function tests, and radiotherapy.Results.Fifteen studies met the inclusion criteria. Seven out of 13 studies on lung cancer reported significant declines (defined as a p value < .05) in PFT results. Both esophageal studies reported significant DLCO declines. One SABR study found a correlation between low lung‐dose parameters and FEV1 decline. Relations between decline of FEV1 (three studies) or decline of DLCO (five studies), respectively, and DVH parameters were found in eight studies analyzing CRT. Furthermore, a heterogeneous range of clinical risk factors for pulmonary function changes were reported in the selected studies.Conclusions.There is evidence that pulmonary function declines after RT in a dose‐dependent manner, but solid data about lung DVH parameters predicting changes in PFT results are scarce. A major disadvantage was the wide variety of methods used, frequently lacking multivariable analyses. Studies using prospective high‐quality data, analyzed with appropriate statistical methods, are needed. The Oncologist 2017;22:1257–1264Implications for Practice.Radiation‐induced lung toxicity remains crucial in thoracic radiotherapy. To prevent this toxicity in the future and individualize patient treatment, objective measures of pulmonary toxicity are needed. Pulmonary function tests may provide such objective measures. This systematic review, included all available clinical studies using external beam radiotherapy for lung or esophageal cancer reporting pulmonary function combined with dose‐volume histogram parameters. There is preliminary evidence that pulmonary function declines post radiotherapy in a dose‐dependent manner. Data quality and analyses were generally limited. Analyses of high‐quality data are therefore urgently needed to improve individualization of advanced radiation therapy.

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Association of Pre‐Chemotherapy Peripheral Blood Pro‐Inflammatory and Coagulation Factors with Physical Function in Women with Breast Cancer

AbstractBackground.Pro‐inflammatory and coagulation factors serve as biomarkers of aging and functional reserve. The purpose of this study was to determine if pro‐inflammatory (interleukin‐6 [IL‐6], C‐reactive protein [CRP]), and coagulation (D‐dimer) factors were associated with pre‐chemotherapy functional status in women with stage I–III breast cancer.Patients and Methods.Prior to chemotherapy initiation in patients with stage I–III breast cancer, the following was captured: IL‐6, CRP, D‐dimer blood levels, and physical function measures including activities of daily living (ADL, subscale of Medical Outcomes Study Physical Health); instrumental activities of daily living (IADL, subscale of the Older Americans Resources and Services Program); Timed Up and Go (TUG); physician‐rated Karnofsky Performance Status (KPS); and self‐rated KPS. The association of these biomarkers with physical function measures was evaluated.Results.One hundred sixty patients (mean age 58.3 years, range 30–81 years) with stage I–III breast cancer (stages I [n = 34; 21.5%], II [n = 88; 55.7%], III [n = 36; 22.8%]) were enrolled. The group with poorest physical function (defined by ADL <70, IADL <14, and TUG ≥10 seconds) had higher levels of IL‐6 (p = .05), D‐dimer (p = .0004), and CRP (p = .05). There was no significant association between these biomarkers and KPS. Patients with at least two biomarkers in the highest quartile were more likely to have poorer physical function (odds ration [OR] 18.75, p < .001). In multivariate analysis adjusting for age, stage, number of comorbidities, and body mass index, the association remained (OR 14.6, p = .002).Conclusion.Pre‐chemotherapy biomarkers of aging are associated with poorer physical function among patients with breast cancer across the aging spectrum. The Oncologist 2017;22:1189–1196Implications for Practice.Commonly used physical function assessment tools may not reflect the diverse nature of physical function and risk for chemotherapy toxicity, particularly in older adults. No laboratory test reflects functional reserve. Pro‐inflammatory and coagulation factors, such as IL‐6, CRP, and D‐dimer, can serve as biomarkers of aging and physical function; however, few studies have evaluated their utility in patients with cancer. This study was designed to understand the association between pre‐chemotherapy biomarkers and physical function in women with early stage breast cancer undergoing adjuvant chemotherapy. Results indicate that elevated pre‐chemotherapy levels in two of the three peripheral biomarkers are associated with the poorest physical function among patients with breast cancer across the aging spectrum.

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Vincristine, Ifosfamide, and Doxorubicin for Initial Treatment of Ewing Sarcoma in Adults

AbstractBackground.There are no clinical trials specifically addressing chemotherapy for adults with Ewing sarcoma (ES). Five‐year event‐free survival (EFS) of adults on pediatric studies of ES (44%–47%) is worse than that of children treated with the same therapy (69%). The object of this study was to review the results of therapy with vincristine, ifosfamide, and doxorubicin (VID) in the multidisciplinary treatment of adults with ES at our institution.Materials and Methods.Charts for adults treated for ES from 1995 to 2011 were retrospectively reviewed. Clinician‐reported radiographic tumor response, type of local therapy, pathologic response, and survival data were collected.Results.Seventy‐one patients were identified who received VID as initial therapy. The median age was 25 (range: 16–64). Forty‐two patients (59%) presented with a localized disease and 29 patients (41%) presented with a distant metastasis. Of all patients treated with VID, 83.6% showed a radiological response. Patients who presented with a localized disease had a 5‐year overall survival (OS) of 68% (median not reached), compared with 10.3% (median: 1.9 years) in those who presented with distant metastases. Five‐year EFS was 67%. The nine patients with a pelvic primary tumor had inferior 5‐year OS (42%) to the 33 with primary tumors at other sites (75%). The 5‐year OS of those who had greater than or equal to 95% necrosis after neoadjuvant VID (n = 20; 5‐year OS: 84%) was superior to those who had less than 95% necrosis (n = 13; 5‐year OS: 53%).Conclusion.In adults with primary ES, VID combined with an adjuvant strategy based on post‐treatment percent necrosis has favorable outcomes compared with historical adult controls.Implications for Practice.Ewing sarcoma (ES) is a rare tumor in adults, and there are no dedicated clinical trials in the adult population. Most therapy is modeled after the published pediatric studies, although the small numbers of adult patients included on those studies did significantly worse than the children. We modeled our treatment on other adult sarcomas and reviewed the charts of 71 adult patients with ES treated with vincristine, ifosfamide, and doxorubicin (VID). In adults with primary ES, VID combined with an adjuvant strategy based on post‐treatment percent necrosis has favorable outcomes compared with historical adult controls.

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Patient‐Driven Second Opinions in Oncology: A Systematic Review

AbstractBackground.Although patient‐driven second opinions are increasingly sought in oncology, the desirability of this trend remains unknown. Therefore, this systematic review assesses evidence on the motivation for and frequency of requests for second opinions and examines how they evolve and their consequences for oncological practice.Materials and Methods.Relevant databases were sought using the terms "cancer," "second opinion," and "self‐initiated." Included were peer‐reviewed articles that reported on patient‐initiated second opinions within oncology. Selection, data extraction, and quality assessment were performed and discussed by two researchers.Results.Of the 25 included studies, the methodological designs were qualitative (n = 4), mixed (n = 1), or quantitative (n = 20). Study quality was rated high for 10 studies, moderate for eight, and low for seven studies. Reported rates of second opinion seeking ranged from 1%–88%. Higher education was most consistently related to seeking a second opinion. Patients' primary motivations were a perceived need for certainty or confirmation, a lack of trust, dissatisfaction with communication, and/or a need for more (personalized) information. Reported rates of diagnostic or therapeutic discrepancies between the first and second opinions ranged from 2%–51%.Discussion.Additional studies are required to further examine the medical, practical, and psychological consequences of second opinions for patients and oncologists. Future studies could compare the potential advantages and disadvantages of second opinion seeking, and might offer guidance to patients and physicians to better facilitate the second opinion process. Some practical recommendations are provided for oncologists to optimally discuss and conduct second opinions with their patients. The Oncologist 2017;22:1197–1211Implications for Practice.Although cancer patients increasingly seek a second opinion, the benefits of this process remain unclear. Results of this systematic review suggest that the available studies on this topic are highly variable in both methodology and quality. Moreover, reported rates for a second opinion (1%–88%) as well as for disagreement between the first and second opinion (2%–51%) range widely. The primary motivations of patients are a need for certainty, lack of trust, dissatisfaction with communication, and/or a need for more (personalized) information. Additional research should evaluate how unnecessary second opinions might be avoided. Practical suggestions are provided for oncologists to optimize second opinions.

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Randomized Phase II Trial of Parsatuzumab (Anti‐EGFL7) or Placebo in Combination with FOLFOX and Bevacizumab for First‐Line Metastatic Colorectal Cancer

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