Treatment and survival disparities by ethnicity in New Zealand women with stage I–III breast cancer tumour subtypes

Abstract

Purpose

This study aims to look at the distribution of different subtypes of stage I–III breast cancer in Māori and Pacific versus non-Māori/Pacific women, and to examine cancer outcomes by ethnicity within these different subtypes.

Method

This study included 9,015 women diagnosed with stage I–III breast cancer between June 2000 and May 2013, recorded in the combined Waikato and Auckland Breast Cancer Registers, who had complete data on ER, PR and HER2 status. Five ER/PR/HER2 subtypes were defined. Kaplan–Meier method and Cox proportional hazards model were used to examine ethnic disparities in breast cancer-specific survival.

Results

Of the 9,015 women, 891 were Māori, 548 were Pacific and 7,576 others. Both Māori and Pacific women were less likely to have triple negative breast cancer compared to others (8.6, 8.9 vs. 13.0%). Pacific women were more than twice as likely to have ER−, PR− and HER2+ cancer than Māori and others (14.2 vs. 6.0%, 6.7%). After adjustment for age, year of diagnosis, stage, grade and treatment, the hazard ratios of breast cancer-specific mortality for Māori and Pacific women with ER+, PR+ and HER2− were 1.52 (95% CI 1.06–2.18) and 1.55 (95% CI 1.04–2.31) compared to others, respectively. Māori women with HER2+ cancer were twice more likely to die of their cancer than others.

Conclusions

Outcomes for Māori and Pacific women could be improved by better treatment regimens especially for those with HER2+ breast cancer and for women with ER+, PR+ and HER2− breast cancer.

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Impact of the National Cervical Screening Programme in New Zealand by age: analysis of cervical cancer trends 1985–2013 in all women and in Māori women

Abstract

Background

New Zealand is an example of a country with a well-established cytology-based screening program. New Zealand's National Cervical Screening Programme (NCSP) commenced in 1990, and recommends three-yearly cytology-based screening for women aged 20–69 years. In 2018, the NCSP will transition to five-yearly HPV-based screening for women aged 25–69 years. The aim of this study was to assess the impact of the program to date in different groups, to provide a benchmark for the new program.

Methods

Analysis of cervical cancer trends in New Zealand by age and ethnicity over the period 1985–2013, and by morphology over the period 1997–2013, using data from the New Zealand Cancer Registry was conducted.

Results

The overall incidence of cervical cancer was 56% (95% CI 51–60%) lower in 2009–2013 than in 1985–1989, and significant reductions were observed in women aged 25–49, 50–69, and 70 + years. Relative reductions in cervical cancer were very similar for Māori and non-Māori women aged 25–49 (50% in Māori; 52% in non-Māori) and 50–69 years (65% in Māori; 69% in non-Māori). In contrast, incidence appeared to increase after around 1996 in women aged 20–24. The increasing trend was significant for women aged 20–24 overall and for non-Māori women (p < 0.01 in both cases).

Conclusion

There have been substantial reductions in cervical cancer among women aged 25 + years in New Zealand since the inception of the NCSP, and these reductions are similar in Māori and non-Māori women. Cervical cancer incidence among women 20–24 years has not declined since the NCSP began, and appears to be increasing.

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Economic and disease burden of breast cancer associated with suboptimal breastfeeding practices in Mexico

Abstract

Purpose

Exclusive breastfeeding and longer breastfeeding reduce women's breast cancer risk but Mexico has one of the lowest breastfeeding rates worldwide. We estimated the lifetime economic and disease burden of breast cancer in Mexico if 95% of parous women breastfeed each child exclusively for 6 months and continue breastfeeding for over a year.

Methods

We used a static microsimulation model with a cost-of-illness approach to simulate a cohort of Mexican women. We estimated breast cancer incidence, premature mortality, disability-adjusted life years (DALYs), medical costs, and income losses due to breast cancer and extrapolated the results to 1.116 million Mexican women of age 15 in 2012. Costs were expressed in 2015 US dollars and discounted at a 3% annual rate.

Results

We estimated that 2,186 premature deaths (95% CI 2,123–2,248), 9,936 breast cancer cases (95% CI 9,651–10,220), 45,109 DALYs (95% CI 43,000–47,217), and $245 million USD (95% CI 234–256) in medical costs and income losses owing to breast cancer could be saved over a cohort's lifetime. Medical costs account for 80% of the economic burden; income losses and opportunity costs for caregivers account for 15 and 5%, respectively.

Conclusions

In Mexico, the burden of breast cancer due to suboptimal breastfeeding in women is high in terms of morbidity, premature mortality, and the economic costs for the health sector and society.

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Sedentary time and postmenopausal breast cancer incidence

Abstract

Purpose

The objective of this study was to evaluate the prospective association between sedentary time and postmenopausal breast cancer incidence, and whether associations differ by race/ethnicity, physical activity levels, and body measurements.

Methods

The Women's Health Initiative Observational Study is a prospective cohort among women ages 50–79 years at baseline (1994–1998) (analytic cohort = 70,233). Baseline questionnaire data were used to estimate time spent sitting and total sedentary time. Associations between time spent sitting and invasive breast cancer incidence overall (n = 4,115 cases through September 2015), and by hormone receptor subtypes, were investigated using Cox proportional hazards regression. Analyses were replicated stratified by race/ethnicity, body measurements, and physical activity.

Results

Among women in this study, 34.5% reported ≤ 5 h/day sitting, 40.9% reported 6–9 h/day and 24.7% reported ≥ 10 h/day. Time spent sitting (≥ 10 vs. ≤5 h/day adjusted HR = 1.00, 95% CI 0.92–1.09) was not associated with breast cancer incidence, regardless of hormone receptor subtype. Associations did not differ by race/ethnicity, physical activity, or body measurements.

Conclusions

Results from this study do not support an association between sedentary time and breast cancer incidence.

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Hybrid Simulation in Teaching Clinical Breast Examination to Medical Students

Abstract

Clinical breast examination (CBE) is traditionally taught to third-year medical students using a lecture and a tabletop breast model. The opportunity to clinically practice CBE depends on patient availability and willingness to be examined by students, especially in culturally sensitive environments. We propose the use of a hybrid simulation model consisting of a standardized patient (SP) wearing a silicone breast simulator jacket and hypothesize that this, compared to traditional teaching methods, would result in improved learning. Consenting third-year medical students (N = 82) at a university-affiliated tertiary care center were cluster-randomized into two groups: hybrid simulation (breast jacket + SP) and control (tabletop breast model). Students received the standard lecture by instructors blinded to the randomization, followed by randomization group-based learning and practice sessions. Two weeks later, participants were assessed in an Objective Structured Clinical Examination (OSCE), which included three stations with SPs blinded to the intervention. The SPs graded the students on CBE completeness, and students completed a self-assessment of their performance and confidence during the examination. CBE completeness scores did not differ between the two groups (p = 0.889). Hybrid simulation improved lesion identification grades (p < 0.001) without increasing false positives. Hybrid simulation relieved the fear of missing a lesion on CBE (p = 0.043) and increased satisfaction with the teaching method among students (p = 0.002). As a novel educational tool, hybrid simulation improves the sensitivity of CBE performed by medical students without affecting its specificity. Hybrid simulation may play a role in increasing the confidence of medical students during CBE.

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Same Time Next Year!

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Widening Access; Developing an eLearning Resource for Health and Social Care Professionals Caring for Children and Young People with Cancer

Abstract

Cancer is a key priority worldwide, and caring for children and young people with cancer requires a range of specific knowledge, skills and experience in order to deliver the complex care regimes both within the hospital or community environment. The aim of this paper is to disseminate work undertaken to design and develop pedagogical practice and innovation through an eLearning resource for health care professionals caring for children and young people with cancer across the globe. The work undertaken evaluated an existing cancer course (which has been withdrawn) that was developed and delivered through the Paediatric Oncology Nurses Forum, Royal College Nursing (Nurse Educators) and Warwick University. The evaluation consisted of 26 open and closed questions relating to the previous resource and was circulated to all health and social care professionals involved directly within specialist oncology services through the Children's Cancer and Leukaemia Group. Questionnaires were sent out to a convenience sample of 773 health care professionals and the response rate was 14%. The findings identified that the course was predominantly accessed by nurses, but other health care professionals also found it useful. Participants highlighted several areas where they believed content could be developed or was lacking. This included areas such as palliative and end of life care, nutrition, sepsis and teenagers and young people. This feedback was then used to develop a site dedicated to the care of children and young people with cancer.

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Una Mano Amiga: Pilot Test of a Patient Navigator Program for Southwest New Mexico

Abstract

We conducted a pilot test of a patient navigation intervention (Una Mano Amiga) to address cancer health disparities in three rural counties in southwest New Mexico. We trained two bilingual lay health workers (promotoras) as patient navigators (PNs) to help adult cancer patients and their participating families in Grant, Luna, and Hidalgo counties "navigate" the health care system, including appropriate access to social and financial services. Our hypothesized outcome was a reduction in time from diagnosis to treatment initiation compared to the average time without PNs in each of the three counties (2000–2009). We enrolled 85 eligible patients and 43 eligible family members who had completed psychosocial and demographic forms in this PN intervention. Mean time from cancer diagnosis to treatment initiation among 41 study patients was 59.6 days across the three counties. Mean time from non-intervention comparison data was 47.1 days. In the intervention group, on a 0–10 satisfaction scale (higher = more), patient mean scores for three items ranged from 9.3 to 9.6, family members, 8.9–9.3. Caregiver stress as measured by a Caregiver Self-Assessment score ≥ 10 (highest stress = 16) decreased from 23.8% of caregivers at study entry to 14.3% at follow-up (not statistically significantly different). Although the PN intervention did not decrease time from diagnosis to treatment initiation compared to three comparison counties, positive reactions of patients and family members support further research with larger samples.

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Knowledge and Attitudes Toward Cancer Pain Management Among Nurses at Oncology Units

Abstract

Nurses have major responsibilities to treat cancer pain in an optimal way. Their knowledge and attitudes are the key to success cancer pain management (CPM) process and impact the outcomes of pain treatment. This study aimed to evaluate the knowledge and attitudes toward CPM among Jordanian nurses working at oncology units. A cross-sectional descriptive design was used to collect data from 135 nurses who were working at four oncology units using Knowledge and Attitudes Survey Regarding Pain. The percentage of correct answers was 51.5% indicating that participants had fair knowledge and attitudes toward CPM. Nurses appeared knowledgeable about CPM guidelines but were unfamiliar regarding pharmacological management and had negative attitudes toward opioids addiction and pain assessment. Significantly, knowledge and attitudes were higher among nurses who had previous education programs (P < .001) and worked in a pain team (P < .001). Therefore, including CPM topics in nursing curricula and postgraduate educational programs is needed. Additionally, initiating pain management teams and using CPM guidelines will contribute to effective treatment of cancer pain.

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The Impact of a Primary Care Education Program Regarding Cancer Survivorship Care Plans: Results from an Engineering, Primary Care, and Oncology Collaborative for Survivorship Health

Abstract

Survivorship care plans (SCPs) have been recommended as tools to improve care coordination and outcomes for cancer survivors. SCPs are increasingly being provided to survivors and their primary care providers. However, most primary care providers remain unaware of SCPs, limiting their potential benefit. Best practices for educating primary care providers regarding SCP existence and content are needed. We developed an education program to inform primary care providers of the existence, content, and potential uses for SCPs. The education program consisted of a 15-min presentation highlighting SCP basics presented at mandatory primary care faculty meetings. An anonymous survey was electronically administered via email (n = 287 addresses) to evaluate experience with and basic knowledge of SCPs pre- and post-education. A total of 101 primary care advanced practice providers (APPs) and physicians (35% response rate) completed the baseline survey with only 23% reporting prior receipt of a SCP. Only 9% could identify the SCP location within the electronic health record (EHR). Following the education program, primary care physicians and APPs demonstrated a significant improvement in SCP knowledge, including improvement in their ability to locate one within the EHR (9 vs 59%, p < 0.0001). A brief educational program containing information about SCP existence, content, and location in the EHR increased primary care physician and APP knowledge in these areas, which are prerequisites for using SCP in clinical practice.

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Sphingosine-1-phosphate/sphingosine kinase 1-dependent lymph node metastasis in esophageal squamous cell carcinoma

Abstract

Purpose

To establish whether Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SphK1) contribute to lymph node metastasis in esophageal squamous cell carcinoma.<?oxy_comment_start comment="Author: Author details: Kindly check and confirm whether the corresponding affiliation is correctly identified and amend if necessary."?><?oxy_comment_end ?><?oxy_comment_start comment="There is no correction point."?><?oxy_comment_end ?>

Methods

Immunohistochemical analysis of SphK1 expression was performed using a tissue microarray containing 177 thoracic squamous cell esophageal cancer specimens resected at surgery, to investigate the association between intratumoral SphK1 expression and lymph node metastasis. Serum S1P levels and intratumoral SphK1 mRNA and protein expression were also evaluated in mice with vs. mice without lymph node metastasis in a murine lymph node metastasis model.<?oxy_comment_start comment="Author: Please check the edits made to the article title and amend if necessary."?><?oxy_comment_end ?><?oxy_comment_start comment="There is no correction point."?><?oxy_comment_end ?>

Results

Among 177 esophageal cancer patients, 127 (72%) were defined as being SphK1-positive. In univariate and multivariate analyses, SphK1 expression status was a significant factor contributing to lymph node metastasis and poorer 5-year overall survival. In the murine lymph node metastasis model, there was no difference in tumor volume or weight between the lymph node metastasis-negative and lymph node metastasis-positive groups. However, levels of SphK1 mRNA and protein and serum S1P levels were all much higher in the metastasis-positive group.

Conclusions

S1P/SphK1 may be novel targets for inhibiting lymph node metastasis in esophageal squamous cell carcinoma, and may provide the basis for a therapeutic strategy to suppress lymph node metastasis.

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The features of adipose-derived stem cells in patients with inflammatory bowel diseases

Abstract

Purpose

The treatment outcomes for inflammatory bowel disease (IBD) have been improving, but the development of better therapies is needed. Stem cell therapy is promising, but little is known about the differences in adipose-derived stem cells (ADSCs) between IBD patients and healthy individuals.

Methods

ADSCs were isolated from subcutaneous adipose tissue (SAT) in IBD (Crohn's disease, 3; ulcerative colitis, 2) and non-IBD (colorectal cancer, 5; breast cancer, 1) patients. We also analyzed the effects of tumor necrosis factor (TNF)-α on murine ADSCs.

Results

The numbers of stromal vascular fraction (SVF) cells per gram of SAT were 7.72 ± 3.03 × 10⁵ in IBD and 8.51 ± 8.80 × 10⁵ in non-IBD patients (p > 0.05). The proportions of ADSCs in SVF cells were 4.98 ± 2.61% in IBD and 1.02 ± 0.67% in non-IBD patients. The numbers of ADSCs per gram of SAT were 4.16 ± 2.96 × 10⁴ in IBD and 0.88 ± 1.04 × 10⁴ in non-IBD patients. The proportions and numbers of ADSCs were significantly higher in IBD patients than in non-IBD patients. TNF-α significantly facilitated the proliferation and motility of murine ADSCs.

Conclusion

These results showed the potential advantage of freshly isolated autologous ADSCs in IBD patients.

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Combined analysis of the preoperative and postoperative prognostic nutritional index offers a precise predictor of the prognosis of patients with gastric cancer

Abstract

Purpose

The prognostic nutritional index (PNI) is considered useful for predicting the prognosis of patients with gastric cancer (GC). This retrospective study investigated the relationship between both the pre- and postoperative PNI and the prognosis of GC patients.

Methods

The subjects of this study were 254 patients who underwent curative surgery for histopathologically diagnosed GC.

Results

Patients were divided according to their pre- and postoperative PNI as follows: preoperative PNI of ≥ 52 (pre-PNI^High), preoperative PNI of < 52 (pre-PNI^Low), postoperative PNI of ≥ 49 (post-PNI^High), and postoperative PNI of < 49 (pre-PNI^Low). Both pre- and postoperative PNI were significantly associated with GC prognosis. Patients were then divided as follows: group A, patients with pre-PNI^High and post-PNI^High; group B, patients with either pre-PNI^High and post-PNI^Low or pre-PNI^Low and post-PNI^High; and group C, patients with pre-PNI^Low and post-PNI^Low. The 5-year survival rates were 100.0, 83.0, and 67.1% for groups A, B, and C, respectively. Multivariate analysis indicated that the combination of pre- and postoperative PNI was an independent prognostic indicator.

Conclusions

Combined analysis of the pre- and postoperative PNI offers accurate information about the prognosis of patients with GC.

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Oxidized regenerated cellulose induces pleural thickening in patients with pneumothorax: possible involvement of the mesothelial–mesenchymal transition

Abstract

Purpose

The pleural covering technique, i.e., wrapping a part of or the entire surface of the lung with oxidized regenerative cellulose (ORC), reinforces visceral pleura through pleural thickening for patients with pneumothorax and cystic lung diseases. However, it remains undetermined how ORC induces pleural thickening.

Methods

A histopathological examination was performed for lung specimens from patients who had recurrent pneumothoraces after pleural covering and re-operation (n = 5). To evaluate the influence of ORC on the pleura in vitro, we used MeT-5A cells (a human pleural mesothelial cell line).

Results

Pleural thickening was confirmed in all lung specimens examined. Three months after covering, the thickened pleura showed inflammatory cell infiltration, proliferation of myofibroblasts, and expression of fibronectin and TGF-β. However, after 1 year, those findings virtually disappeared, and the thickened pleura was composed mainly of abundant collagen. When MeT-5A cells were cultured in ORC-immersed medium, their morphology changed from a cobblestone to spindle-shaped appearance. The expression of E-cadherin decreased, whereas that of N-cadherin, α-smooth muscle actin, and fibronectin increased, suggesting mesothelial–mesenchymal transition (Meso–MT).

Conclusions

Our results suggest that Meso–MT may be involved as a mechanism of pleural thickening induced by pleural covering with ORC.

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Laparoscopic lymph node dissection around the inferior mesenteric artery for left-sided colon and rectal cancer

Abstract

Lymph node dissection is a critical part of surgery for colorectal cancer. Japanese D3 and complete mesocolic excision are two unique principles for lymph node dissection in colorectal cancer. Laparoscopic surgery magnifies the targets and provides insight about the micro-anatomy through high-quality, high-definition imaging, which benefits the surgeon. Although laparoscopic colorectal resection is feasible, there is no universal procedure. We describe in detail the anatomy viewed during lymph node dissection around the inferior mesenteric artery. Visual recognition of two folds on both sides of Landzert's fossa is the critical first step, as recognizing these structures allows laparoscopic procedures to be performed safely. Our findings suggest that this procedure is feasible and effective for the surgical treatment of patients with left-sided colon or rectal cancer.

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Complementary and Integrative Medicine in Hematologic Malignancies: Questions and Challenges

Abstract

Hematologic malignancies represent 9.7% of all cancers, making them the fourth most common type of cancer in the United States. The aggressive and complex treatments administered in hematologic malignancies result in a high burden of psychological needs. Complementary and integrative medicine (CIM) is becoming one of the options that patients use to address their distress during and after cancer treatments. It is not clear whether appropriate CIM can relieve distress in patients affected by these malignancies. This review covers the potential benefits of CIM as relates to nutrition, nutritional supplements, exercise, circadian rhythm, methods for reducing distress during bone marrow aspiration, massage therapy, and acupuncture, in treating patients with hematological malignancies. This review may provide a framework to enhance patient-doctor dialogue regarding CIM use in hematologic malignancies.

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The Role of Next-Generation Sequencing in Sarcomas: Evolution From Light Microscope to Molecular Microscope

Abstract

Purpose of Review

Sarcomas are rare, heterogeneous group of soft tissue and bone tumors. Precise diagnosis of specific subtypes is challenging using conventional methods. Herein, we review the role of next-generation sequencing (NGS) technology that is used for rapid sequencing of DNA and RNA.

Recent Findings

Recent sarcoma specific studies recommend that molecular genetic testing should be added at diagnosis for appropriate clinical management in addition to diagnosis by expert pathologists. NGS has already been used to identify potentially actionable mutations, copy number alterations, and gene fusions. Rationally, choosing a drug based on an individual patient profile aka: "precision oncology" has been so far limited to few case reports in sarcomas.

Summary

As we improve our ability to deliver personalized medicine using all modalities including conventional therapy, more patients may eventually benefit. As the cost and capacity of NGS outpace Moore's law, so does the probability of success.

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Treatment-Free Remission: a New Therapeutic Goal in Chronic Myelogenous Leukemia

Abstract

Purpose of Review

Chronic myelogenous leukemia (CML) is a chronic myeloproliferative neoplasm characterized by the presence of Philadelphia chromosome [t(9:22)] leading to the presence of pathognomonic fusion gene product, BCR-ABL1. This leads to constitutive activation of ABL1 kinase. CML was a difficult-to-treat illness until the advent of small molecule tyrosine kinase inhibitor (TKI), imatinib which revolutionized therapy of CML. Since then, multiple second- and third-generation TKIs have been formulated which have proven effective and has led to marked improvement in survival. In this article, we review currently available data on possibility of holding TKI therapy in patients in deep remission [treatment-free remission (TFR)] and safety of this approach.

Recent Findings

As CML treatment has become more effective, new questions have emerged, most important being whether the treatment with TKIs can ever be stopped. This is especially relevant in patient experiencing side effects from therapy or who may be subject to increased health risks due to treatment. There is now evidence that some CML patients who have achieved stable deep molecular response can safely stop TKI. Furthermore, patients can safely re-establish remission after restarting their TKI therapy in the situation of relapse.

Summary

CML is highly treatable disease, but the treatment has untoward physical and socioeconomic consequences. The idea of TFR is hence attractive. There is a growing body of evidence that some CML patients who have achieved stable deep molecular response can safely stop TKI.

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B Vitamin Complex and Chemotherapy-Induced Peripheral Neuropathy

Abstract

Purpose of Review

The purpose of this mini review is to evaluate the literature on B vitamins and chemotherapy-induced peripheral neuropathy.

Recent Findings

One hundred and five journal articles were evaluated and nine manuscripts were included. There was one in vitro, one was an animal and seven were human studies. The in vitro study was a safety study on vitamin B₆ and oxaliplatin which was not directly related to CIPN. The animal study evaluated vitamin B₃ on paclitaxel administration with positive results. The human studies varied using a vitamin B complex, vitamin B₁₂ only and vitamin B₆.

Summary

Chemotherapy-induced peripheral neuropathy (CIPN) continues to plague patients and the medical fraternity. Currently, there are still no conclusive protective or treatment options. B vitamins have been found to play a role in CIPN prevention, but further studies are required to ascertain possible protection and treatment options.

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Using Geriatric Assessment Strategies to Lead End-of-Life Care Discussions

Abstract

End-of-life discussions with geriatric oncology patients are a vital part of the comprehensive care of the senior adult patient. Developing a roadmap for these conversations can be challenging. Patients and caregivers may have expectations that are not concordant with what is reasonably achievable if the patient is frail. Measuring baseline cognition, nutritional status, and physical function and discussing goals of care are all essential pieces of information that can be obtained through a comprehensive geriatric assessment (CGA). Objective findings from the CGA can be crucial in developing end-of-life care plans that reflect both the patient's health status and personal values.

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Cancer risk management in Tasmanian women with BRCA1 and BRCA2 mutations

Abstract

Women carrying germline mutations in BRCA1 or BRCA2 have significantly increased lifetime risks of breast and tubo-ovarian cancer. To manage the breast cancer risk women may elect to have breast screening by MRI/mammogram from age 30, to take risk-reducing medication, or to have a prophylactic bilateral mastectomy. To manage the tubo-ovarian cancer risk, the only effective strategy is to have a bilateral salpingo-oophorectomy, recommended by age 40 (BRCA1) or 'around' age 40 (BRCA2). Early studies suggested that uptake of these cancer risk-reducing strategies was low. More recent studies have revealed higher rates of uptake, however it is unclear whether uptake is genuinely improving or whether the higher uptake rates reflect changes in the populations studied. In this study we surveyed 193 BRCA1/2 mutation carriers in the state of Tasmania to determine the uptake of cancer risk-reducing strategies and what factors might influence women's decisions in relation to both gynaecological and breast surgery. We observed that uptake of risk management strategies varied depending on the strength of the recommendation in the national guidelines. Uptake rates were > 90% for strategies which are strongly recommended, such as breast screening by MRI/mammogram and bilateral salpingo-oophorectomy, and were unaffected by demographic factors such as socio-economic disadvantage and educational achievement. Uptake rates were much lower for strategies which are presented in the guidelines as options for consideration and where patient choice and shared decision making are encouraged, such as prophylactic mastectomy (29%) and chemoprevention (1%) and in the case of prophylactic mastectomy, were influenced by both socio-economic advantage and educational achievement.

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Penetrance of a rare familial mutation predisposing to papillary thyroid cancer

Abstract

Familial non-medullary thyroid cancer (FNMTC) is clinically defined as two or more first-degree relatives with NMTC and appears to follow an autosomal dominant inheritance pattern. Approximately 5–7% of NMTC is hereditary and affects multiple generations with a young age of onset. The primary aim of this study was to determine the age-specific penetrance of NMTC in individuals from a large family with FNMTC with a previously identified private mutation at 4q32, with a secondary aim to determine the penetrance for benign thyroid disease in this family. We present a large family with NMTC in which we had previously described a culpable mutation. Participants provided their personal medical history and family history. The germline 4q32 A > C mutation was detected in 34 of 68 tested individuals. Age-specific penetrance of thyroid cancer and benign thyroid disease was determined using the inverted Kaplan–Meier method of segregation analysis. Individuals who tested positive for the 4q32 mutation have a 68.9% (95% CI 46.5–88.7) risk of developing thyroid cancer by age 70 and a 65.3% (95% CI 46.0–83.8) risk of developing benign thyroid disease by age 70. The 4q32 A > C mutation significantly increases the risk to develop thyroid cancer but not benign thyroid disease in members of this family. The female:male sex ratio of 1.33 that we observed in affected mutation carriers differs greatly from the ratio of approximately 3:1 observed in PTC, supporting a central role of the mutation. Early thyroid surveillance with annual ultrasound is recommended to individuals testing positive for this private familial mutation.

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Family history influences the tumor characteristics and prognosis of breast cancers developing during postmenopausal hormone therapy

Abstract

Long term use of postmenopausal hormone therapy (HT) has been reported to increase breast cancer risk. On the other hand, observational studies suggest that breast cancers diagnosed during HT may have a more favorable prognosis. While family history is a risk factor for breast cancer, and genetic factors also influence prognosis, the role of family history in combination with HT use has been little studied. We investigated the relationship between HT, family history, and prognosis in 584 (267 exposed) familial and 952 (460 exposed) non-familial breast cancer cases, using three survival end points: death from breast cancer (BCS), distant disease free survival (DDFS), and local recurrence free survival (LRFS). Among non-familial cases, HT was associated with better BCS (HR 0.63, 95% CI 0.41–0.94; p = 0.025), and DDFS (HR 0.58, 95% CI 0.40–0.85; p = 0.005), with a consistent but not statistically significant effect in LRFS. This effect was not seen in familial cases (HR > 1.0), and family history was found to interact with HT in BCS (p_{(interaction)} = 0.0067) (BC-death) and DDFS (p_{(interaction)} = 0.0070). There was phenotypic heterogeneity between HT-associated tumors in familial and non-familial cases, particularly on estrogen receptor (ER) status, although the interaction between HT and family history appears to be at least partially independent of these markers (p = 0.0370 after adjustment for standard prognostic factors). If confirmed by further studies, our results suggest that family history should be taken into consideration in clinical counseling before beginning a HT regimen.

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Whole body magnetic resonance imaging (WB-MRI) and brain MRI baseline surveillance in TP53 germline mutation carriers: experience from the Li-Fraumeni Syndrome Education and Early Detection (LEAD) clinic

Abstract

Individuals with Li-Fraumeni syndrome (LFS) have a significantly increased lifetime cancer risk affecting multiple organ sites. Therefore, novel comprehensive screening approaches are necessary to improve cancer detection and survival in this population. The objective of this study was to determine the diagnostic performance of whole body MRI (WB-MRI) and dedicated brain MRI screening as part of a comprehensive screening clinic called Li-Fraumeni Education and Early Detection (LEAD) at MD Anderson Cancer Center. Adult (≥21 year old) and pediatric (<21 year old) patients were referred to the LEAD clinic by healthcare providers or self-referred and screened at 6 month intervals. During the study period, 63 LFS individuals were seen in the LEAD clinic including 49 adults (11 male, 38 female) and 14 children (7 male, 7 female). Fifty-three of 63 potentially eligible individuals underwent baseline WB-MRI (41 adults and 12 children) with primary tumors detected in six patients, tumor recurrence in one patient and cancer metastases in one patient. Thirty-five of 63 patients (24 adults and 11 children) underwent baseline brain MRI with primary brain tumors detected in three individuals, also noted on subsequent WB-MRI scans. Three additional tumors were diagnosed that in retrospect review were missed on the initial scan (false negatives) and one tumor noted, but not followed up clinically, was prospectively found to be malignant. The high incidence of asymptomatic tumors identified in this initial screening (13%), supports the inclusion of WB-MRI and brain MRI in the clinical management of individuals with LFS.

http://ift.tt/2ykWRnI

Inherited DNA repair gene mutations detected by tumor next generation sequencing in urinary tract cancers

Abstract

Interpretation of next-generation sequencing (NGS) of tumor tissue in patients with advanced Urinary Tract Cancer (UTC) is performed to guide treatment selection but may reveal pathogenic variants with germline implications. We identified three patients with UTC with unexpected germline DNA repair gene mutations. Specific testing for these was prompted by the detection of these mutations by tumor NGS. All three patients were nonsmokers with a strong family history of cancer. Two patients had upper tract UTC with age at diagnosis in the 40 s. One had a family history suggestive of hereditary breast/ovarian predisposition and a FANCA mutation detected on NGS was confirmed to be germline. The second patient had a family history suggestive of Lynch syndrome but was found to have a germline BRCA2 mutation that was suggested by NGS. The third patient had bladder cancer at an advanced age, a family history of late-onset gastrointestinal malignancies that did not meet criteria for clinical testing for a hereditary cancer predisposition syndrome. NGS identified an MUTYH mutation, and targeted testing confirmed a monoallelic germline MUTYH mutation. Detection of variants with germline implications by tumor NGS may be clinically relevant for patients and their families and warrant genetic counseling and germline genetic testing. The prevalence of germline DNA repair defects in the context of inherited predisposition to UTC merits further study.

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Predictive and prognostic value of tumor volume and its changes during radical radiotherapy of stage III non-small cell lung cancer

Abstract

Purpose

Lung cancer remains the leading cause of cancer-related mortality worldwide. Stage III non-small cell lung cancer (NSCLC) includes heterogeneous presentation of the disease including lymph node involvement and large tumour volumes with infiltration of the mediastinum, heart or spine. In the treatment of stage III NSCLC an interdisciplinary approach including radiotherapy is considered standard of care with acceptable toxicity and improved clinical outcome concerning local control. Furthermore, gross tumour volume (GTV) changes during definitive radiotherapy would allow for adaptive replanning which offers normal tissue sparing and dose escalation.

Methods

A literature review was conducted to describe the predictive value of GTV changes during definitive radiotherapy especially focussing on overall survival. The literature search was conducted in a two-step review process using PubMed®/Medline® with the key words "stage III non-small cell lung cancer" and "radiotherapy" and "tumour volume" and "prognostic factors".

Results

After final consideration 17, 14 and 9 studies with a total of 2516, 784 and 639 patients on predictive impact of GTV, GTV changes and its impact on overall survival, respectively, for definitive radiotherapy for stage III NSCLC were included in this review. Initial GTV is an important prognostic factor for overall survival in several studies, but the time of evaluation and the value of histology need to be further investigated. GTV changes during RT differ widely, optimal timing for re-evaluation of GTV and their predictive value for prognosis needs to be clarified. The prognostic value of GTV changes is unclear due to varying study qualities, re-evaluation time and conflicting results.

Conclusion

The main findings were that the clinical impact of GTV changes during definitive radiotherapy is still unclear due to heterogeneous study designs with varying quality. Several potential confounding variables were found and need to be considered for future studies to evaluate GTV changes during definitive radiotherapy with respect to treatment outcome.

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Concurrent radiotherapy with temozolomide vs. concurrent radiotherapy with a cisplatinum-based polychemotherapy regimen

Abstract

Purpose

As the efficacy of all pediatric high-grade glioma (HGG) treatments is similar and still disappointing, it is essential to also investigate the toxicity of available treatments.

Methods

Prospectively recorded hematologic and nonhematologic toxicities of children treated with radiochemotherapy in the HIT GBM-C/D and HIT-HGG-2007 trials were compared. Children aged 3–18 years with histologically proven HGG (WHO grade III and IV tumors) or unequivocal radiologic diagnosis of diffuse intrinsic pontine glioma (DIPG) were included in these trials. The HIT-HGG-2007 protocol comprised concomitant radiochemotherapy with temozolomide, while cisplatinum/etoposide (PE) and PE plus ifosfamide (PEI) in combination with weekly vincristine injections were applied during radiochemotherapy in the HIT GBM-C/D protocol.

Results

Regular blood counts and information about cellular nadirs were available from 304 patients (leukocytes) and 306 patients (thrombocytes), respectively. Grade 3–4 leukopenia was much more frequent in the HIT GBM-C/D cohort (n = 88, 52%) vs. HIT-HGG-2007 (n = 13, 10%; P <0.001). Grade 3–4 thrombopenia was also more likely in the HIT GBM-C/D cohort (n = 21, 12% vs. n = 3,2%; P <0.001). Grade 3–4 leukopenia appeared more often in children aged 3–7 years (n = 38/85, 45%) than in children aged 8–12 years (n = 39/120, 33%) and 13–18 years (24/100, 24%; P =0.034). In addition, sickness was more frequent in the HIT GBM-C/D cohort (grade 1–2: 44%, grade 3–4: 6% vs. grade 1–2: 28%, grade 3–4: 1%; P <0.001).

Conclusion

Radiochemotherapy involving cisplatinum-based polychemotherapy is more toxic than radiotherapy in combination with temozolomide. Without evidence of differences in therapeutic efficacy, the treatment with lower toxicity, i. e., radiotherapy with temozolomide should be used.

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Postoperative radiotherapy for prostate cancer

Abstract

Purpose

The aim of this work was to characterise actuarial incidence and prevalence of early and late side effects of local versus pelvic three-dimensional conformal postoperative radiotherapy for prostate cancer.

Materials and methods

Based on a risk-adapted protocol, 575 patients received either local (n = 447) or local-plus-pelvic (n = 128) radiotherapy. Gastrointestinal (GI) and genitourinary (GU) side effects (≥grade 2 RTOG/EORTC criteria) were prospectively assessed. Maximum morbidity, actuarial incidence rate, and prevalence rates were compared between the two groups.

Results

For local radiotherapy, median follow-up was 68 months, and the mean dose was 66.7 Gy. In pelvic radiotherapy, the median follow-up was 49 months, and the mean local and pelvic doses were 66.9 and 48.3 Gy respectively. Early GI side effects ≥ G2 were detected in 26% and 42% of patients respectively (p < 0.001). Late GI adverse events were detected in 14% in both groups (p = 0.77). The 5‑year actuarial incidence rates were 14% and 14%, while the prevalence rates were 2% and 0% respectively. Early GU ≥ G2 side effects were detected in 15% and 16% (p = 0.96), while late GU morbidity was detected in 18% and 24% (p = 0.001). The 5‑year actuarial incidence rates were 16% and 35% (p = 0.001), while the respective prevalence rates were 6% and 8%.

Conclusions

Despite the low prevalence of side effects, postoperative pelvic radiotherapy results in significant increases in the actuarial incidence of early GI and late GU morbidity using a conventional 4‑field box radiotherapy technique. Advanced treatment techniques like intensity-modulated radiotherapy (IMRT) or volumetric modulated arc radiotherapy (VMAT) should therefore be considered in pelvic radiotherapy to potentially reduce these side effects.

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Treatment and survival disparities by ethnicity in New Zealand women with stage I–III breast cancer tumour subtypes

Abstract

Purpose

This study aims to look at the distribution of different subtypes of stage I–III breast cancer in Māori and Pacific versus non-Māori/Pacific women, and to examine cancer outcomes by ethnicity within these different subtypes.

Method

This study included 9,015 women diagnosed with stage I–III breast cancer between June 2000 and May 2013, recorded in the combined Waikato and Auckland Breast Cancer Registers, who had complete data on ER, PR and HER2 status. Five ER/PR/HER2 subtypes were defined. Kaplan–Meier method and Cox proportional hazards model were used to examine ethnic disparities in breast cancer-specific survival.

Results

Of the 9,015 women, 891 were Māori, 548 were Pacific and 7,576 others. Both Māori and Pacific women were less likely to have triple negative breast cancer compared to others (8.6, 8.9 vs. 13.0%). Pacific women were more than twice as likely to have ER−, PR− and HER2+ cancer than Māori and others (14.2 vs. 6.0%, 6.7%). After adjustment for age, year of diagnosis, stage, grade and treatment, the hazard ratios of breast cancer-specific mortality for Māori and Pacific women with ER+, PR+ and HER2− were 1.52 (95% CI 1.06–2.18) and 1.55 (95% CI 1.04–2.31) compared to others, respectively. Māori women with HER2+ cancer were twice more likely to die of their cancer than others.

Conclusions

Outcomes for Māori and Pacific women could be improved by better treatment regimens especially for those with HER2+ breast cancer and for women with ER+, PR+ and HER2− breast cancer.

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Impact of the National Cervical Screening Programme in New Zealand by age: analysis of cervical cancer trends 1985–2013 in all women and in Māori women

Abstract

Background

New Zealand is an example of a country with a well-established cytology-based screening program. New Zealand's National Cervical Screening Programme (NCSP) commenced in 1990, and recommends three-yearly cytology-based screening for women aged 20–69 years. In 2018, the NCSP will transition to five-yearly HPV-based screening for women aged 25–69 years. The aim of this study was to assess the impact of the program to date in different groups, to provide a benchmark for the new program.

Methods

Analysis of cervical cancer trends in New Zealand by age and ethnicity over the period 1985–2013, and by morphology over the period 1997–2013, using data from the New Zealand Cancer Registry was conducted.

Results

The overall incidence of cervical cancer was 56% (95% CI 51–60%) lower in 2009–2013 than in 1985–1989, and significant reductions were observed in women aged 25–49, 50–69, and 70 + years. Relative reductions in cervical cancer were very similar for Māori and non-Māori women aged 25–49 (50% in Māori; 52% in non-Māori) and 50–69 years (65% in Māori; 69% in non-Māori). In contrast, incidence appeared to increase after around 1996 in women aged 20–24. The increasing trend was significant for women aged 20–24 overall and for non-Māori women (p < 0.01 in both cases).

Conclusion

There have been substantial reductions in cervical cancer among women aged 25 + years in New Zealand since the inception of the NCSP, and these reductions are similar in Māori and non-Māori women. Cervical cancer incidence among women 20–24 years has not declined since the NCSP began, and appears to be increasing.

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Economic and disease burden of breast cancer associated with suboptimal breastfeeding practices in Mexico

Abstract

Purpose

Exclusive breastfeeding and longer breastfeeding reduce women's breast cancer risk but Mexico has one of the lowest breastfeeding rates worldwide. We estimated the lifetime economic and disease burden of breast cancer in Mexico if 95% of parous women breastfeed each child exclusively for 6 months and continue breastfeeding for over a year.

Methods

We used a static microsimulation model with a cost-of-illness approach to simulate a cohort of Mexican women. We estimated breast cancer incidence, premature mortality, disability-adjusted life years (DALYs), medical costs, and income losses due to breast cancer and extrapolated the results to 1.116 million Mexican women of age 15 in 2012. Costs were expressed in 2015 US dollars and discounted at a 3% annual rate.

Results

We estimated that 2,186 premature deaths (95% CI 2,123–2,248), 9,936 breast cancer cases (95% CI 9,651–10,220), 45,109 DALYs (95% CI 43,000–47,217), and $245 million USD (95% CI 234–256) in medical costs and income losses owing to breast cancer could be saved over a cohort's lifetime. Medical costs account for 80% of the economic burden; income losses and opportunity costs for caregivers account for 15 and 5%, respectively.

Conclusions

In Mexico, the burden of breast cancer due to suboptimal breastfeeding in women is high in terms of morbidity, premature mortality, and the economic costs for the health sector and society.

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Sedentary time and postmenopausal breast cancer incidence

Abstract

Purpose

The objective of this study was to evaluate the prospective association between sedentary time and postmenopausal breast cancer incidence, and whether associations differ by race/ethnicity, physical activity levels, and body measurements.

Methods

The Women's Health Initiative Observational Study is a prospective cohort among women ages 50–79 years at baseline (1994–1998) (analytic cohort = 70,233). Baseline questionnaire data were used to estimate time spent sitting and total sedentary time. Associations between time spent sitting and invasive breast cancer incidence overall (n = 4,115 cases through September 2015), and by hormone receptor subtypes, were investigated using Cox proportional hazards regression. Analyses were replicated stratified by race/ethnicity, body measurements, and physical activity.

Results

Among women in this study, 34.5% reported ≤ 5 h/day sitting, 40.9% reported 6–9 h/day and 24.7% reported ≥ 10 h/day. Time spent sitting (≥ 10 vs. ≤5 h/day adjusted HR = 1.00, 95% CI 0.92–1.09) was not associated with breast cancer incidence, regardless of hormone receptor subtype. Associations did not differ by race/ethnicity, physical activity, or body measurements.

Conclusions

Results from this study do not support an association between sedentary time and breast cancer incidence.

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Hybrid Simulation in Teaching Clinical Breast Examination to Medical Students

Abstract

Clinical breast examination (CBE) is traditionally taught to third-year medical students using a lecture and a tabletop breast model. The opportunity to clinically practice CBE depends on patient availability and willingness to be examined by students, especially in culturally sensitive environments. We propose the use of a hybrid simulation model consisting of a standardized patient (SP) wearing a silicone breast simulator jacket and hypothesize that this, compared to traditional teaching methods, would result in improved learning. Consenting third-year medical students (N = 82) at a university-affiliated tertiary care center were cluster-randomized into two groups: hybrid simulation (breast jacket + SP) and control (tabletop breast model). Students received the standard lecture by instructors blinded to the randomization, followed by randomization group-based learning and practice sessions. Two weeks later, participants were assessed in an Objective Structured Clinical Examination (OSCE), which included three stations with SPs blinded to the intervention. The SPs graded the students on CBE completeness, and students completed a self-assessment of their performance and confidence during the examination. CBE completeness scores did not differ between the two groups (p = 0.889). Hybrid simulation improved lesion identification grades (p < 0.001) without increasing false positives. Hybrid simulation relieved the fear of missing a lesion on CBE (p = 0.043) and increased satisfaction with the teaching method among students (p = 0.002). As a novel educational tool, hybrid simulation improves the sensitivity of CBE performed by medical students without affecting its specificity. Hybrid simulation may play a role in increasing the confidence of medical students during CBE.

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Same Time Next Year!

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Widening Access; Developing an eLearning Resource for Health and Social Care Professionals Caring for Children and Young People with Cancer

Abstract

Cancer is a key priority worldwide, and caring for children and young people with cancer requires a range of specific knowledge, skills and experience in order to deliver the complex care regimes both within the hospital or community environment. The aim of this paper is to disseminate work undertaken to design and develop pedagogical practice and innovation through an eLearning resource for health care professionals caring for children and young people with cancer across the globe. The work undertaken evaluated an existing cancer course (which has been withdrawn) that was developed and delivered through the Paediatric Oncology Nurses Forum, Royal College Nursing (Nurse Educators) and Warwick University. The evaluation consisted of 26 open and closed questions relating to the previous resource and was circulated to all health and social care professionals involved directly within specialist oncology services through the Children's Cancer and Leukaemia Group. Questionnaires were sent out to a convenience sample of 773 health care professionals and the response rate was 14%. The findings identified that the course was predominantly accessed by nurses, but other health care professionals also found it useful. Participants highlighted several areas where they believed content could be developed or was lacking. This included areas such as palliative and end of life care, nutrition, sepsis and teenagers and young people. This feedback was then used to develop a site dedicated to the care of children and young people with cancer.

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Una Mano Amiga: Pilot Test of a Patient Navigator Program for Southwest New Mexico

Abstract

We conducted a pilot test of a patient navigation intervention (Una Mano Amiga) to address cancer health disparities in three rural counties in southwest New Mexico. We trained two bilingual lay health workers (promotoras) as patient navigators (PNs) to help adult cancer patients and their participating families in Grant, Luna, and Hidalgo counties "navigate" the health care system, including appropriate access to social and financial services. Our hypothesized outcome was a reduction in time from diagnosis to treatment initiation compared to the average time without PNs in each of the three counties (2000–2009). We enrolled 85 eligible patients and 43 eligible family members who had completed psychosocial and demographic forms in this PN intervention. Mean time from cancer diagnosis to treatment initiation among 41 study patients was 59.6 days across the three counties. Mean time from non-intervention comparison data was 47.1 days. In the intervention group, on a 0–10 satisfaction scale (higher = more), patient mean scores for three items ranged from 9.3 to 9.6, family members, 8.9–9.3. Caregiver stress as measured by a Caregiver Self-Assessment score ≥ 10 (highest stress = 16) decreased from 23.8% of caregivers at study entry to 14.3% at follow-up (not statistically significantly different). Although the PN intervention did not decrease time from diagnosis to treatment initiation compared to three comparison counties, positive reactions of patients and family members support further research with larger samples.

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Knowledge and Attitudes Toward Cancer Pain Management Among Nurses at Oncology Units

Abstract

Nurses have major responsibilities to treat cancer pain in an optimal way. Their knowledge and attitudes are the key to success cancer pain management (CPM) process and impact the outcomes of pain treatment. This study aimed to evaluate the knowledge and attitudes toward CPM among Jordanian nurses working at oncology units. A cross-sectional descriptive design was used to collect data from 135 nurses who were working at four oncology units using Knowledge and Attitudes Survey Regarding Pain. The percentage of correct answers was 51.5% indicating that participants had fair knowledge and attitudes toward CPM. Nurses appeared knowledgeable about CPM guidelines but were unfamiliar regarding pharmacological management and had negative attitudes toward opioids addiction and pain assessment. Significantly, knowledge and attitudes were higher among nurses who had previous education programs (P < .001) and worked in a pain team (P < .001). Therefore, including CPM topics in nursing curricula and postgraduate educational programs is needed. Additionally, initiating pain management teams and using CPM guidelines will contribute to effective treatment of cancer pain.

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The Impact of a Primary Care Education Program Regarding Cancer Survivorship Care Plans: Results from an Engineering, Primary Care, and Oncology Collaborative for Survivorship Health

Abstract

Survivorship care plans (SCPs) have been recommended as tools to improve care coordination and outcomes for cancer survivors. SCPs are increasingly being provided to survivors and their primary care providers. However, most primary care providers remain unaware of SCPs, limiting their potential benefit. Best practices for educating primary care providers regarding SCP existence and content are needed. We developed an education program to inform primary care providers of the existence, content, and potential uses for SCPs. The education program consisted of a 15-min presentation highlighting SCP basics presented at mandatory primary care faculty meetings. An anonymous survey was electronically administered via email (n = 287 addresses) to evaluate experience with and basic knowledge of SCPs pre- and post-education. A total of 101 primary care advanced practice providers (APPs) and physicians (35% response rate) completed the baseline survey with only 23% reporting prior receipt of a SCP. Only 9% could identify the SCP location within the electronic health record (EHR). Following the education program, primary care physicians and APPs demonstrated a significant improvement in SCP knowledge, including improvement in their ability to locate one within the EHR (9 vs 59%, p < 0.0001). A brief educational program containing information about SCP existence, content, and location in the EHR increased primary care physician and APP knowledge in these areas, which are prerequisites for using SCP in clinical practice.

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Sphingosine-1-phosphate/sphingosine kinase 1-dependent lymph node metastasis in esophageal squamous cell carcinoma

Abstract

Purpose

To establish whether Sphingosine-1-phosphate (S1P) and sphingosine kinase 1 (SphK1) contribute to lymph node metastasis in esophageal squamous cell carcinoma.<?oxy_comment_start comment="Author: Author details: Kindly check and confirm whether the corresponding affiliation is correctly identified and amend if necessary."?><?oxy_comment_end ?><?oxy_comment_start comment="There is no correction point."?><?oxy_comment_end ?>

Methods

Immunohistochemical analysis of SphK1 expression was performed using a tissue microarray containing 177 thoracic squamous cell esophageal cancer specimens resected at surgery, to investigate the association between intratumoral SphK1 expression and lymph node metastasis. Serum S1P levels and intratumoral SphK1 mRNA and protein expression were also evaluated in mice with vs. mice without lymph node metastasis in a murine lymph node metastasis model.<?oxy_comment_start comment="Author: Please check the edits made to the article title and amend if necessary."?><?oxy_comment_end ?><?oxy_comment_start comment="There is no correction point."?><?oxy_comment_end ?>

Results

Among 177 esophageal cancer patients, 127 (72%) were defined as being SphK1-positive. In univariate and multivariate analyses, SphK1 expression status was a significant factor contributing to lymph node metastasis and poorer 5-year overall survival. In the murine lymph node metastasis model, there was no difference in tumor volume or weight between the lymph node metastasis-negative and lymph node metastasis-positive groups. However, levels of SphK1 mRNA and protein and serum S1P levels were all much higher in the metastasis-positive group.

Conclusions

S1P/SphK1 may be novel targets for inhibiting lymph node metastasis in esophageal squamous cell carcinoma, and may provide the basis for a therapeutic strategy to suppress lymph node metastasis.

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The features of adipose-derived stem cells in patients with inflammatory bowel diseases

Abstract

Purpose

The treatment outcomes for inflammatory bowel disease (IBD) have been improving, but the development of better therapies is needed. Stem cell therapy is promising, but little is known about the differences in adipose-derived stem cells (ADSCs) between IBD patients and healthy individuals.

Methods

ADSCs were isolated from subcutaneous adipose tissue (SAT) in IBD (Crohn's disease, 3; ulcerative colitis, 2) and non-IBD (colorectal cancer, 5; breast cancer, 1) patients. We also analyzed the effects of tumor necrosis factor (TNF)-α on murine ADSCs.

Results

The numbers of stromal vascular fraction (SVF) cells per gram of SAT were 7.72 ± 3.03 × 10⁵ in IBD and 8.51 ± 8.80 × 10⁵ in non-IBD patients (p > 0.05). The proportions of ADSCs in SVF cells were 4.98 ± 2.61% in IBD and 1.02 ± 0.67% in non-IBD patients. The numbers of ADSCs per gram of SAT were 4.16 ± 2.96 × 10⁴ in IBD and 0.88 ± 1.04 × 10⁴ in non-IBD patients. The proportions and numbers of ADSCs were significantly higher in IBD patients than in non-IBD patients. TNF-α significantly facilitated the proliferation and motility of murine ADSCs.

Conclusion

These results showed the potential advantage of freshly isolated autologous ADSCs in IBD patients.

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Highlights from Recent Cancer Literature

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T Cells Deficient in Diacylglycerol Kinase {zeta} Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia

Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ−/−) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ−/− T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676–86. ©2017 AACR.

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Structurally Novel Antiestrogens Elicit Differential Responses from Constitutively Active Mutant Estrogen Receptors in Breast Cancer Cells and Tumors

Many estrogen receptor α (ERα)–positive breast cancers develop resistance to endocrine therapy via mutation of ERs whose constitutive activation is associated with shorter patient survival. Because there is now a clinical need for new antiestrogens (AE) against these mutant ERs, we describe here our development and characterization of three chemically novel AEs that effectively suppress proliferation of breast cancer cells and tumors. Our AEs are effective against wild-type and Y537S and D538G ERs, the two most commonly occurring constitutively active ERs. The three new AEs suppressed proliferation and estrogen target gene expression in WT and mutant ER-containing cells and were more effective in D538G than in Y537S cells and tumors. Compared with WT ER, mutants exhibited approximately 10- to 20-fold lower binding affinity for AE and a reduced ability to be blocked in coactivator interaction, likely contributing to their relative resistance to inhibition by AE. Comparisons between mutant ER–containing MCF7 and T47D cells revealed that AE responses were compound, cell-type, and ERα-mutant dependent. These new ligands have favorable pharmacokinetic properties and effectively suppressed growth of WT and mutant ER–expressing tumor xenografts in NOD/SCID-γ mice after oral or subcutaneous administration; D538G tumors were more potently inhibited by AE than Y537S tumors. These studies highlight the differential responsiveness of the mutant ERs to different AEs and make clear the value of having a toolkit of AEs for treatment of endocrine therapy–resistant tumors driven by different constitutively active ERs. Cancer Res; 77(20); 5602–13. ©2017 AACR.

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Cancer Self-Defense: An Immune Stealth

The hurdles in realizing successful cancer immunotherapy stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment/secretion of a "decoy flare," for example, anomalous cancer-associated antigens by the tumor cells. The cancer secretome, which resembles the parent cell make-up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs, etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents, resulting in a "cancer-stealth" effect. Immunotherapy, or any treatment that relies on antigens' expression/function, could be improved by the understanding of the properties of the cancer secretome, as its clinical evaluation may change the therapeutic landscape. Cancer Res; 77(20); 5441–4. ©2017 AACR.

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Highlights from Recent Cancer Literature

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The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors, defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase-activating proteins also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anticancer agents, including targeted therapies, as well as to the suppression of antitumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting. Cancer Res; 77(20); 5445–51. ©2017 AACR.

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CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy

Expression of the ectonucleotidase CD73 by tumor cells, stromal cells, and immune cells is associated in cancer with immune suppression. In this study, we investigated the role of CD73 on the activity of the anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab. In a prospective, randomized phase III clinical trial evaluating the activity of trastuzumab, high levels of CD73 gene expression were associated significantly with poor clinical outcome. In contrast, high levels of PD-1 and PD-L1 were associated with improved clinical outcome. In immunocompetent mouse models of HER2/ErbB2–driven breast cancer, CD73 expression by tumor cells and host cells significantly suppressed immune-mediated responses mediated by anti-ErbB2 mAb. Furthermore, anti-CD73 mAb therapy enhanced the activity of anti-ErbB2 mAb to treat engrafted or spontaneous tumors as well as lung metastases. Gene ontology enrichment analysis from gene-expression data revealed a positive association of CD73 expression with extracellular matrix organization, TGFβ genes, epithelial-to-mesenchymal transition (EMT) transcription factors and hypoxia-inducible-factor (HIF)-1 gene signature. Human mammary cells treated with TGFβ or undergoing EMT upregulated CD73 cell-surface expression, confirming roles for these pathways. In conclusion, our findings establish CD73 in mediating resistance to trastuzumab and provide new insights into how CD73 is regulated in breast cancer. Cancer Res; 77(20); 5652–63. ©2017 AACR.

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HIF-2{alpha} Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells in vitro. We also found that HIF-2α strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452–63. ©2017 AACR.

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ATM Deficiency Generating Genomic Instability Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Therapy-Induced DNA Damage

Pancreatic ductal adenocarcinomas (PDAC) harbor recurrent functional mutations of the master DNA damage response kinase ATM, which has been shown to accelerate tumorigenesis and epithelial–mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements, and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC. Cancer Res; 77(20); 5576–90. ©2017 AACR.

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STRAP Promotes Stemness of Human Colorectal Cancer via Epigenetic Regulation of the NOTCH Pathway

NOTCH signaling exerts essential roles in normal and malignant intestinal physiology and the homeostasis of cancer stem-like cells (CSC), but the basis for this latter role remains obscure. The signaling scaffold protein STRAP is upregulated in several cancers, where it promotes tumorigenicity and metastasis. Here we report a novel oncogenic function for STRAP in maintaining CSC subpopulations in a heterogeneous mixture by antagonizing formation of the chromatin modifier PRC2 and by epigenetically activating NOTCH signals in human colorectal cancer. Silencing STRAP sensitized colorectal cancer cells to chemotherapeutic drugs in vitro and in vivo. STRAP depletion also contributed to a reduced stem-like phenotype of colorectal cancer cells, as indicated by reduced expression of the CSC signature and NOTCH signaling regulators in vitro and by diminished tumorigenesis in vivo. Genes encoding some upstream activators of NOTCH were highly enriched for H3K27me3, which forms repressive chromatin domains upon STRAP silencing. Mechanistically, STRAP competitively disrupted association of the PRC2 subunits EZH2 and SUZ12, thereby inhibiting PRC2 assembly. Restoring the NOTCH pathway by lentiviral expression of NICD1 or HES1 in STRAP-depleted tumor cells reversed the CSC phenotype. In 90 colorectal cancer clinical specimens, a significant positive correlation was documented between the expression of STRAP and HES1. Overall, our findings illuminated a novel STRAP–NOTCH1–HES1 molecular axis as a CSC regulator in colorectal cancer, with potential implications to improve treatment of this disease. Cancer Res; 77(20); 5464–78. ©2017 AACR.

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Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

Myeloid-derived suppressor cells (MDSC) are a major obstacle to promising forms of cancer immunotherapy, but tools to broadly limit their immunoregulatory effects remain lacking. In this study, we assessed the therapeutic effect of the humanized anti–Jagged1/2-blocking antibody CTX014 on MDSC-mediated T-cell suppression in tumor-bearing mice. CTX014 decreased tumor growth, affected the accumulation and tolerogenic activity of MDSCs in tumors, and inhibited the expression of immunosuppressive factors arginase I and iNOS. Consequently, anti-Jagged therapy overcame tumor-induced T-cell tolerance, increased the infiltration of reactive CD8+ T cells into tumors, and enhanced the efficacy of T-cell–based immunotherapy. Depletion of MDSC-like cells restored tumor growth in mice treated with anti-Jagged, whereas coinjection of MDSC-like cells from anti–Jagged-treated mice with cancer cells delayed tumor growth. Jagged1/2 was induced in MDSCs by tumor-derived factors via NFkB-p65 signaling, and conditional deletion of NFkB-p65 blocked MDSC function. Collectively, our results offer a preclinical proof of concept for the use of anti-Jagged1/2 to reprogram MDSC-mediated T-cell suppression in tumors, with implications to broadly improve the efficacy of cancer therapy. Cancer Res; 77(20); 5628–38. ©2017 AACR.

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LSD1-Mediated Epigenetic Reprogramming Drives CENPE Expression and Prostate Cancer Progression

Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479–90. ©2017 AACR.

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T Cells Deficient in Diacylglycerol Kinase {zeta} Are Resistant to PD-1 Inhibition and Help Create Persistent Host Immunity to Leukemia

Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKζ) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKζ-deficient (DGKζ−/−) mice than wild-type mice. T cells transferred from DGKζ-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKζ−/− T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKζ-deficient T cells increased the levels of IFNγ and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKζ may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKζ targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade. Cancer Res; 77(20); 5676–86. ©2017 AACR.

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Human Pluripotent Stem Cell-Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation–bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/− mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491–502. ©2017 AACR.

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Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer. Cancer Res; 77(20); 5564–75. ©2017 AACR.

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De Novo Lipid Synthesis Facilitates Gemcitabine Resistance through Endoplasmic Reticulum Stress in Pancreatic Cancer

Pancreatic adenocarcinoma is moderately responsive to gemcitabine-based chemotherapy, the most widely used single-agent therapy for pancreatic cancer. Although the prognosis in pancreatic cancer remains grim in part due to poor response to therapy, previous attempts at identifying and targeting the resistance mechanisms have not been very successful. By leveraging The Cancer Genome Atlas dataset, we identified lipid metabolism as the metabolic pathway that most significantly correlated with poor gemcitabine response in pancreatic cancer patients. Furthermore, we investigated the relationship between alterations in lipogenesis pathway and gemcitabine resistance by utilizing tissues from the genetically engineered mouse model and human pancreatic cancer patients. We observed a significant increase in fatty acid synthase (FASN) expression with increasing disease progression in spontaneous pancreatic cancer mouse model, and a correlation of high FASN expression with poor survival in patients and poor gemcitabine responsiveness in cell lines. We observed a synergistic effect of FASN inhibitors with gemcitabine in pancreatic cancer cells in culture and orthotopic implantation models. Combination of gemcitabine and the FASN inhibitor orlistat significantly diminished stemness, in part due to induction of endoplasmic reticulum (ER) stress that resulted in apoptosis. Moreover, direct induction of ER stress with thapsigargin caused a similar decrease in stemness and showed synergistic activity with gemcitabine. Our in vivo studies with orthotopic implantation models demonstrated a robust increase in gemcitabine responsiveness upon inhibition of fatty acid biosynthesis with orlistat. Altogether, we demonstrate that fatty acid biosynthesis pathway manipulation can help overcome the gemcitabine resistance in pancreatic cancer by regulating ER stress and stemness. Cancer Res; 77(20); 5503–17. ©2017 AACR.

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Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter

Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of MCT1 in vivo inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. Cancer Res; 77(20); 5591–601. ©2017 AACR.

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Sensitivity to BUB1B Inhibition Defines an Alternative Classification of Glioblastoma

Glioblastoma multiforme (GBM) remains a mainly incurable disease in desperate need of more effective treatments. In this study, we develop evidence that the mitotic spindle checkpoint molecule BUB1B may offer a predictive marker for aggressiveness and effective drug response. A subset of GBM tumor isolates requires BUB1B to suppress lethal kinetochore–microtubule attachment defects. Using gene expression data from GBM stem-like cells, astrocytes, and neural progenitor cells that are sensitive or resistant to BUB1B inhibition, we created a computational framework to predict sensitivity to BUB1B inhibition. Applying this framework to tumor expression data from patients, we stratified tumors into BUB1B-sensitive (BUB1BS) or BUB1B-resistant (BUB1BR) subtypes. Through this effort, we found that BUB1BS patients have a significantly worse prognosis regardless of tumor development subtype (i.e., classical, mesenchymal, neural, proneural). Functional genomic profiling of BUB1BR versus BUB1BS isolates revealed a differential reliance of genes enriched in the BUB1BS classifier, including those involved in mitotic cell cycle, microtubule organization, and chromosome segregation. By comparing drug sensitivity profiles, we predicted BUB1BS cells to be more sensitive to type I and II topoisomerase inhibitors, Raf inhibitors, and other drugs, and experimentally validated some of these predictions. Taken together, the results show that our BUB1BR/S classification of GBM tumors can predict clinical course and sensitivity to drug treatment. Cancer Res; 77(20); 5518–29. ©2017 AACR.

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Therapeutic Effects of XPO1 Inhibition in Thymic Epithelial Tumors

Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro. Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry–based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors. Cancer Res; 77(20); 5614–27. ©2017 AACR.

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Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells

Sister chromatids are held together by cohesin, a tripartite ring with a peripheral SA1/2 subunit, where SA1 is required for telomere cohesion and SA2 for centromere cohesion. The STAG2 gene encoding SA2 is often inactivated in human cancer, but not in in a manner associated with aneuploidy. Thus, how these tumors maintain chromosomal cohesion and how STAG2 loss contributes to tumorigenesis remain open questions. Here we show that, despite a loss in centromere cohesion, sister chromatids in STAG2 mutant tumor cells maintain cohesion in mitosis at chromosome arms and telomeres. Telomere maintenance in STAG2 mutant tumor cells occurred by either telomere recombination or telomerase activation mechanisms. Notably, these cells were refractory to telomerase inhibitors, indicating recombination can provide an alternative means of telomere maintenance. STAG2 silencing in normal human cells that lack telomerase led to increased recombination at telomeres, delayed telomere shortening, and postponed senescence onset. Insofar as telomere shortening and replicative senescence prevent genomic instability and cancer by limiting the number of cell divisions, our findings suggest that extending the lifespan of normal human cells due to inactivation of STAG2 could promote tumorigenesis by extending the period during which tumor-driving mutations occur. Cancer Res; 77(20); 5530–42. ©2017 AACR.

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{beta}-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T-cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies—physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8+ T-cell to CD4+ regulatory T-cell ratio (IFNγ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639–51. ©2017 AACR.

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Shrimp miR-S8 Suppresses the Stemness of Human Melanoma Stem-like Cells by Targeting the Transcription Factor YB-1

Cross-species regulation of gene expression by microRNA is a possible untapped opportunity for miRNA-based therapy. In this study, we report a novel approach to ablate melanoma stem-like cells by targeting the transcription factor YB-1, which is significantly and selectively upregulated in these cells in melanoma. Silencing YB-1 expression was sufficient to significantly inhibit the stemness of melanoma stem-like cells. In exploring YB-1 targeting, we discovered that the shrimp microRNA miR-S8 could suppress human YB-1 expression in melanoma stem-like cells. Mechanistic investigations revealed that miR-S8 recognized the 3′UTR of YB-1 mRNA and mediated its degradation. In tumor cell and xenograft experiments, miR-S8 suppressed the tumorigenic capacity of melanoma stem-like cells by targeting human YB-1. Overall, our results illuminated a novel aspect of miRNA-mediated cross-species gene expression and its use in regulating cancer stem-like cells. Cancer Res; 77(20); 5543–53. ©2017 AACR.

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Human Pluripotent Stem Cell-Derived TSC2-Haploinsufficient Smooth Muscle Cells Recapitulate Features of Lymphangioleiomyomatosis

Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation–bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/− mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491–502. ©2017 AACR.

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Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter

Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of MCT1 in vivo inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. Cancer Res; 77(20); 5591–601. ©2017 AACR.

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Shrimp miR-S8 Suppresses the Stemness of Human Melanoma Stem-like Cells by Targeting the Transcription Factor YB-1

Cross-species regulation of gene expression by microRNA is a possible untapped opportunity for miRNA-based therapy. In this study, we report a novel approach to ablate melanoma stem-like cells by targeting the transcription factor YB-1, which is significantly and selectively upregulated in these cells in melanoma. Silencing YB-1 expression was sufficient to significantly inhibit the stemness of melanoma stem-like cells. In exploring YB-1 targeting, we discovered that the shrimp microRNA miR-S8 could suppress human YB-1 expression in melanoma stem-like cells. Mechanistic investigations revealed that miR-S8 recognized the 3′UTR of YB-1 mRNA and mediated its degradation. In tumor cell and xenograft experiments, miR-S8 suppressed the tumorigenic capacity of melanoma stem-like cells by targeting human YB-1. Overall, our results illuminated a novel aspect of miRNA-mediated cross-species gene expression and its use in regulating cancer stem-like cells. Cancer Res; 77(20); 5543–53. ©2017 AACR.

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Cancer Self-Defense: An Immune Stealth

The hurdles in realizing successful cancer immunotherapy stem from the fact that cancer patients are either refractory to immune response and/or develop resistance. Here, we propose that these phenomena are due, in part, to the deployment/secretion of a "decoy flare," for example, anomalous cancer-associated antigens by the tumor cells. The cancer secretome, which resembles the parent cell make-up, is composed of soluble macromolecules (proteins, glycans, lipids, DNAs, RNAs, etc.) and insoluble vesicles (exosomes), thus hindering cancer detection/recognition by immunotherapeutic agents, resulting in a "cancer-stealth" effect. Immunotherapy, or any treatment that relies on antigens' expression/function, could be improved by the understanding of the properties of the cancer secretome, as its clinical evaluation may change the therapeutic landscape. Cancer Res; 77(20); 5441–4. ©2017 AACR.

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{beta}-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy

The immune context of tumors has significant prognostic value and is predictive of responsiveness to several forms of therapy, including immunotherapy. We report here that CD8+ T-cell frequency and functional orientation within the tumor microenvironment is regulated by β2-adrenergic receptor (β-AR) signaling in host immune cells. We used three strategies—physiologic (manipulation of ambient thermal environment), pharmacologic (β-blockers), and genetic (β2-AR knockout mice) to reduce adrenergic stress signaling in two widely studied preclinical mouse tumor models. Reducing β-AR signaling facilitated conversion of tumors to an immunologically active tumor microenvironment with increased intratumoral frequency of CD8+ T cells with an effector phenotype and decreased expression of programmed death receptor-1 (PD-1), in addition to an elevated effector CD8+ T-cell to CD4+ regulatory T-cell ratio (IFNγ+CD8+:Treg). Moreover, this conversion significantly increased the efficacy of anti-PD-1 checkpoint blockade. These data highlight the potential of adrenergic stress and norepinephrine-driven β-AR signaling to regulate the immune status of the tumor microenvironment and support the strategic use of clinically available β-blockers in patients to improve responses to immunotherapy. Cancer Res; 77(20); 5639–51. ©2017 AACR.

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The Rac GTPase in Cancer: From Old Concepts to New Paradigms

Rho family GTPases are critical regulators of cellular functions that play important roles in cancer progression. Aberrant activity of Rho small G-proteins, particularly Rac1 and their regulators, is a hallmark of cancer and contributes to the tumorigenic and metastatic phenotypes of cancer cells. This review examines the multiple mechanisms leading to Rac1 hyperactivation, particularly focusing on emerging paradigms that involve gain-of-function mutations in Rac and guanine nucleotide exchange factors, defects in Rac1 degradation, and mislocalization of Rac signaling components. The unexpected pro-oncogenic functions of Rac GTPase-activating proteins also challenged the dogma that these negative Rac regulators solely act as tumor suppressors. The potential contribution of Rac hyperactivation to resistance to anticancer agents, including targeted therapies, as well as to the suppression of antitumor immune response, highlights the critical need to develop therapeutic strategies to target the Rac pathway in a clinical setting. Cancer Res; 77(20); 5445–51. ©2017 AACR.

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Therapeutic Targeting of the CBP/p300 Bromodomain Blocks the Growth of Castration-Resistant Prostate Cancer

Resistance invariably develops to antiandrogen therapies used to treat newly diagnosed prostate cancers, but effective treatments for castration-resistant disease remain elusive. Here, we report that the transcriptional coactivator CBP/p300 is required to maintain the growth of castration-resistant prostate cancer. To exploit this vulnerability, we developed a novel small-molecule inhibitor of the CBP/p300 bromodomain that blocks prostate cancer growth in vitro and in vivo. Molecular dissection of the consequences of drug treatment revealed a critical role for CBP/p300 in histone acetylation required for the transcriptional activity of the androgen receptor and its target gene expression. Our findings offer a preclinical proof of concept for small-molecule therapies to target the CBP/p300 bromodomain as a strategy to treat castration-resistant prostate cancer. Cancer Res; 77(20); 5564–75. ©2017 AACR.

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HIF-2{alpha} Promotes Dissemination of Plasma Cells in Multiple Myeloma by Regulating CXCL12/CXCR4 and CCR1

Disease progression and relapse in multiple myeloma is dependent on the ability of the multiple myeloma plasma cells (PC) to reenter the circulation and disseminate throughout the bone marrow. Increased bone marrow hypoxia is associated with increased recirculation of multiple myeloma PCs. Accordingly, we hypothesized that during chronic hypoxia, activation of HIF-2α may overcome the bone marrow retention signal provided by stromal-derived CXCL12, thereby enabling dissemination of multiple myeloma PCs. Here we demonstrate that HIF-2α upregulates multiple myeloma PC CXCL12 expression, decreasing migration toward CXCL12 and reducing adhesion to mesenchymal stromal cells in vitro. We also found that HIF-2α strongly induced expression of the chemokine receptor CCR1 in multiple myeloma PCs. CCR1 activation potently induces multiple myeloma PC migration toward CCL3 while abrogating the multiple myeloma PC migratory response to CXCL12. In addition, increased CCR1 expression by multiple myeloma PCs conferred poor prognosis in newly diagnosed multiple myeloma patients and was associated with an increase in circulating multiple myeloma PCs in these patients. Taken together, our results suggest a role for hypoxia-mediated CCR1 upregulation in driving the egress of multiple myeloma PCs from the bone marrow. Targeting CCR1 may represent a novel strategy to prevent dissemination and overt relapse in multiple myeloma. Cancer Res; 77(20); 5452–63. ©2017 AACR.

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