Cancer-induced systemic myeloid dysfunction: implications for treatment and a novel nanoparticle approach for its correction

Publication date: Available online 30 May 2018
Source:Seminars in Oncology
Author(s): Rydell Alvarez, Liliana Oliver, Anet Valdes, Circe Mesa
Unlike other regulatory circuits, cancer-induced myeloid dysfunction involves more than an accumulation of impaired dendritic cells (DCs), protumoral macrophages and myeloid derived suppressor cells (MDSCs) in the tumor microenvironment (TME). It is also characterized by "aberrant" myelopoiesis that results in the accumulation and expansion of immature myeloid precursors with a suppressive phenotype in the systemic circulation. The first part of this review briefly describes the evidence for and consequences of this systemic dysfunctional myelopoiesis and the possible reinforcement of this phenomenon by conventional treatments used in patients with cancer, in particular chemotherapy and G-CSF. The second half of this review describes very small size particles (VSSP), a novel immune-modulatory nanoparticle, and the evidence indicating a possible role of this agent in correcting or re-programming the dysfunctional myelopoiesis in different scenarios.



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Targeting myeloid-derived suppressor cells for cancer immunotherapy

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with an immune suppressive phenotype. They represent a critical component of the immune suppressive niche described in cancer, where they support immune escape and tumor progression through direct effects on both the innate and adaptive immune responses, largely by contributing to maintenance of a high oxidative stress environment. The number of MDSCs positively correlates with protumoral activity, and often diminishes the effectiveness of immunotherapies, which is particularly problematic with the emergence of personalized medicine. Approaches targeting MDSCs showed promising results in preclinical studies and are under active investigation in clinical trials in combination with various immune checkpoint inhibitors. In this review, we discuss MDSC targets and therapeutic approaches targeting MDSC that have the aim of enhancing the existing tumor therapies.

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Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC

Future Oncology, Ahead of Print.


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Precise predictive and therapeutic strategy for breast cancer

Future Oncology, Ahead of Print.


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Treatment patterns and medication adherence among patients diagnosed with multiple myeloma and treated with panobinostat

Future Oncology, Ahead of Print.


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Prospective analysis of adoptive TIL therapy in patients with metastatic melanoma: response, impact of anti-CTLA4, and biomarkers to predict clinical outcome

Purpose: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) has consistently demonstrated clinical efficacy in metastatic melanoma. Recent widespread use of checkpoint blockade has shifted the treatment landscape, raising questions regarding impact of these therapies on response to TIL and appropriate immunotherapy sequence. Experimental Design: Seventy-four metastatic melanoma patients were treated with autologous TIL and evaluated for clinical response according to irRC, overall survival and progression free survival. Immunologic factors associated with response were also evaluated. Results: Best overall response for the entire cohort was 42%; 47% in 43 checkpoint naïve patients, 38% when patients were exposed to anti-CTLA4 alone (21 patients) and 33% if also exposed to anti-PD1 (9 patients) prior to TIL ACT. Median overall survival was 17.3 months; 24.6 months in CTLA4 naïve patients and 8.6 months in patients with prior CTLA4 blockade. The latter patients were infused with fewer TIL and experienced a shorter duration of response. Infusion of higher numbers of TIL with CD8 predominance and expression of BTLA correlated with improved response in anti-CTLA-4 naive patients, but not in anti-CTLA-4 refractory patients. Baseline serum levels of IL-9 predicted response to TIL ACT, while TIL persistence, tumor recognition and mutation burden did not correlate with outcome. Conclusions:This study demonstrates the deleterious effects of prior exposure to anti-CTLA4 on TIL ACT response and shows that baseline IL-9 levels can potentially serve as a predictive tool to appropriately select sequence for immunotherapies.

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Inhibition of EphB4-ephrin-B2 signaling enhances response to Cetuximab-radiation therapy in head and neck cancers

Purpose: The clinical success of targeted therapies such as cetuximab and radiation (RT) is hampered by the low response rates and development of therapeutic resistance. In the current study, we investigated the involvement of EphB4-ephrin-B2 pro-tumorigenic signaling in mediating resistance to EGFR inhibition and radiation therapy in head and neck cancers. Experimental Design: We used patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and HNSCC cell lines to test our hypothesis. Tumor tissues were subjected to PhosphoRTK array, and western blotting to detect changes in EphB4-ephrin-B2 targets. mRNA sequencing and microarray data analysis was performed on PDX tumors and HNSCC cell lines respectively to determine differences in gene expression of molecules involved in tumor cell growth, proliferation, and survival pathways. Effects on cell growth were determined by MTT assay on HNSCC cells downregulated for EphB4/ephrin-B2 expression, with and without EGFR inhibitor and radiation. Results: Our data from locally-advanced HNSCC patients treated with standard of care definitive chemo-RT show elevated EphB4 and ephrin-B2 levels after failure of treatment. We observed significant response towards cetuximab and radiation therapy following EphB4-ephrin-B2 inhibition resulting in improved survival in tumor-bearing mice. Tumor growth inhibition was accompanied by decrease in the levels of proliferation and pro-survival molecules and increased apoptosis. Conclusions: Our findings underscore the importance of adopting rational drug combinations to enhance therapeutic effect. Our study documenting enhanced response of HNSCC to cetuximab-RT therapy with EphB4-ephrin-B2 blockade has the potential to translate into clinic to benefit this patient population.

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Phase 1 Trials of anti-ENPP3 antibody drug conjugates in advanced refractory renal cell carcinomas

Purpose: To determine the safety, pharmacokinetics, and recommendedphase2 dose of an antibody drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Experimental Design: Two phase 1 studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma derived AGS-16M8F and Chinese Hamster Ovary derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kguntil unacceptable toxicity or progression. The study was terminated before reaching the maximum tolerated dose (MTD). A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. Results: The AGS-16M8F study (n=26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7 - 83 weeks). One subject had durable partial remission (PR) (83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n=34), the protocol defined MTD was 3.6 mg/kg but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose de-escalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range 100-143 weeks). Eight (8) subjects at 2.7 mg/kg and 1.8 mg/kg had disease control > 37 weeks (37.5 - 141 weeks). Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks.

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Comprehensive molecular profiling of intra- and extrahepatic cholangiocarcinomas: potential targets for intervention

Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response. Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher's exact tests were performed to identify associations between clinical characteristics and genetic alterations.

Results: 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma (IHC) were IDH1(30%), ARID1A(23%) BAP1(20%), TP53(20%) and FGFR2gene fusions (14%). A tendency towards mutual exclusivity was seen between multiple genes in IHC including TP53:IDH1, IDH1:KRAS, TP53:BAP1, IDH1:FGFR2. Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker directed therapy or clinical trial enrollment in 16% of patients. Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/Band ERBB2are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers.

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Radium-223 dichloride in Combination with Vascular Endothelial Growth Factor-Targeting Therapy in Advanced Renal Cell Carcinoma with Bone Metastases

Purpose: This study investigates the biologic activity of radium-223 with vascular endothelial growth factor (VEGF)-targeted therapy in patients with advanced renal cell carcinoma (aRCC) and bone metastases. Experimental Design: Fifteen treatment-naïve patients (n=15) received pazopanib 800 mg orally once-daily and 15 previously-treated patients received sorafenib 400 mg orally twice-daily. Radium-223 55 kilobecquerel/kg was administered concurrently every four weeks for up to 6 infusions in both cohorts. The primary endpoint was decline in bone turnover markers (Procollagen I Intact N-Terminal, N-telopeptide, C-telopeptide, osteocalcin and bone-specific alkaline phosphatase) compared to baseline. Secondary endpoints included safety, rate of symptomatic-skeletal event (SSE) and time to first SSE, objective response rate, change in analgesic use and quality of life. Exploratory analysis of tumor genomic alterations was performed. Results: Of the 30 patients enrolled, 83% had IMDC intermediate- or poor-risk disease, 33% had liver metastases and 83% had a history of SSE prior to enrolment. No dose-limiting toxicity was observed. All bone turnover markers significantly declined from baseline at week 8 and 16. Forty percent of patients experienced treatment-related grade ≥3 adverse events. Response rates were 15% and 18% per RECIST v1.1 and bone response was 50% and 30% per MD Anderson criteria, in the pazopanib and sorafenib cohort, respectively. Median SSE-free interval was 5.8 months and not reached, respectively. Analgesic use remained stable over the study time. Conclusions: Radium-223 combined with VEGF-targeted therapy is biologically active and safe. Randomized-controlled trials are needed to define the role of radium-223 in aRCC with skeletal metastases. NCT02406521

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An Integrative Approach for Deciphering the Causal Associations of Physical Activity and Cancer Risk: The Role of Adiposity

Abstract

Higher physical activity levels have been associated with about 10% to 25% reductions in up to 13 cancers. In isolation, these results are suggestive but not compelling enough to conclude causal associations, except for colon and breast cancer. However, knowledge on the relationships between obesity and cancer, between physical activity and overall and visceral adiposity, and between physical activity and obesity-related mediators of cancer risk can inform the epidemiology of physical activity and cancer. Excluding primarily smoking-related malignancies, for which residual confounding by smoking may occur, all 13 cancers associated with lower physical activity are also obesity-related. Moreover, the magnitude of the inverse association between physical activity and cancer type correlates highly with the association with body mass index (BMI) and cancer type (Spearman r = .79, two-sided P = .004). Physical activity lowers essentially all the obesity-related mediators of cancer, probably mediated largely through reductions in visceral adiposity. These findings strongly suggest that physical activity and adiposity are largely operating through similar carcinogenic mechanisms. That BMI has more robust associations than physical activity with cancer largely reflects that most populations studied have had great variation in BMI and little in physical activity. In populations with higher levels of physical activity and a lower range of BMI, physical activity may appear relatively more important. It may be useful to emphasize to clinicians and the public that physical activity, by acting on the same mechanisms, is likely to reduce risk of obesity-related cancers, even if the impact on lowering BMI is minimal.

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The Antitumor Mechanism of Paeonol on CXCL4/CXCR3-B Signals in Breast Cancer Through Induction of Tumor Cell Apoptosis

Cancer Biotherapy and Radiopharmaceuticals, Ahead of Print.


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Retrospective estimation of heart and lung doses in pediatric patients treated with spinal irradiation

The purpose of this study was to investigate whether treatment information from medical records can be used to estimate radiation doses to heart and lungs retrospectively in pediatric patients receiving spinal irradiation with conventional posterior fields.

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Cardiac dose is associated with immunosuppression and poor survival in locally advanced non-small cell lung cancer

Studies have associated increased radiation therapy (RT) heart dose with cardiac toxicity. Others have correlated RT-related immunosuppression with worsened survival. Given the large vascular volumes irradiated during locally advanced non-small cell lung cancer (LA-NSCLC) treatment, we hypothesized an association between increased heart dose and immunosuppression.

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Radiotherapy utilization in developing countries: An IAEA study

The planning of national radiotherapy (RT) services requires a thorough knowledge of the country's cancer epidemiology profile, the radiotherapy utilization (RTU) rates and a future projection of these data. Previous studies have established RTU rates in high-income countries.

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Prevalence of Enhancer of Zeste Homolog 2 in Patients with Resected Small Cell Lung Cancer

Background/Aim: Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is deeply involved in cancer pathogenesis. Although clinicopathological significance of EZH2 in non-small cell lung cancer has been gradually elucidated, such significance in small cell lung cancer (SCLC) has yet to be fully investigated. Patients and Methods: Forty patients with resected SCLC were analyzed for EZH2. EZH2 expression was evaluated using the Allred score (0-8) and was classified into negative (0-6) and positive (7 and 8). We evaluated the association between EZH2 and the clinicopathological characteristics and postoperative survivals. Results: Among 40 patients, 15 (37.5%) and 25 (62.5%) were classified as being negative and positive for EZH2, respectively. Fisher's exact test demonstrated no significant associations between the positivity for EZH2 and clinicopathological characteristics. No significant differences were observed in recurrence-free and overall survivals between EZH2-negative/low and EZH2-high patients. Conclusion: EZH2 was frequently observed in patients with resected SCLC, but no significant associations were found between its expression and the clinicopathological characteristics and postoperative survivals.

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Potentially Malignant Oral Disorders and Cancer Transformation

Cancer in the oral cavity is often preceded by precursor lesions. Nine oral mucosal disorders are known to have an increased risk of malignant transformation. The etiology varies from disorders caused by exogenous factors such as tobacco and autoimmune inflammation to idiopathic or inherited genetic aberrations. In this review, these potentially malignant disorders (PMDs) are described regarding clinical presentation and histopathological architecture. Special attention is paid to the underlying etiologies of PMDs and the potential pathways leading to cancer. The clinical perspective focuses on the importance of accurate and timely diagnosis.

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Significance of Age in Japanese Patients Receiving Sunitinib as First-line Systemic Therapy for Metastatic Renal Cell Carcinoma: Comparative Assessment of Efficacy and Safety between Patients Aged =75 Years

Background/Aim: To date, it has not been well characterized whether sunitinib is effective in elderly patients with metastatic renal cell carcinoma (mRCC). The objective of this study was to investigate the impact of age on clinical outcomes of mRCC patients receiving sunitinib. Patients and Methods: The efficacy and safety of first-line sunitinib in 154 consecutive mRCC patients were retrospectively compared between patients aged <75 (n=125) and ≥75 (n=29) years. Results: There were no significant differences in the major clinicopathological characteristics between younger and older patients; however, the reduction of the initial dose of sunitinib was significantly more frequent in older than younger patients. No significant difference in response rate, clinical benefit rate or proportion of patients going on to receive second-line therapy was noted between these two groups. Furthermore, there was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two groups, and no significant impact of age on PFS or OS was documented by the Cox proportional hazards regression analyses. Of several adverse events, only anemia and fatigue were significantly more frequently observed in older than younger patients. Although there was no significant difference in the incidence of dose reduction or discontinuation of sunitinib between the two groups, the interruption of sunitinib was more frequently required in older than younger patients. Conclusion: These findings suggest that advanced age alone should not be regarded as a contraindication to the introduction of sunitinib as first-line systemic therapy for mRCC patients.

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Multimodal Anti-tumor Approaches Combined with Immunotherapy to Overcome Tumor Resistance in Esophageal and Gastric Cancer

Upper gastrointestinal malignancies are associated with a high disease burden worldwide, and esophageal and gastric cancers represent the most common entities. Given a lack of early characteristic symptoms and potent screening instruments, the majority of patients present with advanced disease at the time of diagnosis. Complete surgical resection is a first-line curative option, and multimodal approaches involving chemotherapy and radiotherapy further improve patient prognosis. However, response to standard adjuvant and neoadjuvant treatments remains low, and new strategies are warranted to increase tumor control rates. Immunotherapy is emerging in various cancer entities and may be successfully combined with standard therapeutic regimens to improve patient outcome. For the purpose of this review we aimed to assess combined approaches of immunotherapy and standard treatment options such as chemotherapy, radiotherapy and surgery. Current trials evaluating multimodal approaches with immunotherapy in esophageal and gastric cancer are evaluated.

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Second Primary Malignancies in Patients with Well-differentiated/Dedifferentiated Liposarcoma

Background: Well-differentiated/dedifferentiated (WD/DD) liposarcoma is a rare malignancy of putative adipocyte origin. To our knowledge, there have only been isolated case reports describing second primary cancer in patients with this disease. We report on a combined case series of such patients and explore the frequency of this occurrence using a national cancer database. Materials and Methods: Demographics and clinicopathological data were collected from patients with WD/DD liposarcoma who were found to have a concurrent or subsequent second primary cancer, at one of three sarcoma referral centers from 2014-2016. The Surveillance, Epidemiology and End Results (SEER) database was also queried to identify adult patients diagnosed with WD/DD liposarcoma between 1973-2012. Observed/expected (O/E) ratios of second primary malignancies among these cases were calculated by comparison to the age-adjusted cancer incidence in the general population using SEER*stat software. Results: In total, 26 out of 312 consecutive patients (8.3%) with WD/DD liposarcoma at our centers had a second primary cancer identified within 2 years of liposarcoma diagnosis. In the SEER database, among 1,845 patients with WD/DD liposarcoma, 75 (4.1%) had a second cancer within 2 years after liposarcoma diagnosis (O/E ratio=1.81, 99% confidence interval(CI)=1.33-2.40). Patients less than 50 years old at the time of liposarcoma diagnosis had a higher O/E ratio for second primary malignancy compared to older patients. A total of 269 patients (14.6%) developed a second cancer (O/E=1.33, 99% CI=1.15-1.54). Conclusion: In some patients with WD/DD liposarcoma, there appears to be an increased risk of having a second primary cancer. Further validation and investigation is needed, as this finding may have implications (e.g. closer screening) for patients with this disease.

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Hyperfractionated or Accelerated Hyperfractionated Re-irradiation with >=42 Gy in Combination with Paclitaxel for Secondary/Recurrent Head-and-Neck Cancer

Background/Aim: Patients with secondary/ recurrent squamous cell head and neck cancer (SCCHN) have poor prognoses. Outcomes of re-irradiation with ≥42 Gy plus paclitaxel for secondary/recurrent SCCHN are herein presented. Patients and Methods: Two patients re-irradiated for secondary/recurrent SCCHN were evaluated. Patients received 44.4 Gy (2x1.2 Gy/day) or 42.0 Gy (2x1.5 Gy/day), respectively, plus concurrent paclitaxel (35 mg/m² weekly or 20 mg/m² twice per week). Results: One patient developed a locoregional recurrence and additional metastases at 12 months after re-irradiation and died at 13 months. The other patient developed multiple bone metastases at 103 months and died at 104 months. Acute toxicities included grade 2 anemia and mucositis in both patients. Radiation dermatitis was grade 2 in one patient and grade 3 in the other. Conclusion: Re-irradiation with 42.0-44.4 Gy given twice daily plus paclitaxel was well tolerated and achieved a favorable response. The results need to be confirmed in a prospective trial.

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Specifically Targeted Electromagnetic Fields Arrest Proliferation of Glioblastoma Multiforme U-87 Cells in Culture

Background/Aim: Glioblastoma multiforme is an aggressive primary tumor that arises in the glial cells of the brain. Standardized first-line treatment has considerable morbidity and less than one-year median survival after intervention. Ultra-low intensity electromagnetic fields have been shown to interact with biological organisms without anticipated deleterious side-effects. The aim of the study was to determine if a novel, non-invasive application of non-ionizing radiation has an inhibitory effect on proliferation of glioblastoma multiforme cells. Materials and Methods: U-87 MG cells were continuously exposed for 54 h to an electromagnetic field tuned to simultaneously interact with DNA/RNA oligonucleotides (mutated alpha-kinase 2 gene/Hsa-miR-381-5p respectively) and proteins (HSP70/CHI3L1). Results: Exposed cells demonstrated a significant inhibition of cell growth and concurrent increase in cell death. Conclusion: This technology induces cell death by novel non-cytotoxic mechanisms unlikely to induce side-effects in patients; can be customized for individual tumors and may contribute to the emerging strategy of personalized medicine.

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Renal Cell Carcinoma, Unclassified with Medullary Phenotype and Synchronous Renal Clear Cell Carcinoma Present in a Patient with No Sickle Cell Trait/Disease: Diagnostic and Therapeutic Challenges

Renal medullary carcinoma (RMC) is an aggressive high-grade renal cell carcinoma (RCC) associated almost exclusively with sickle cell trait or sickle cell disease. However, RCC with RMC features has rarely been reported in patients with no sickle cell trait or disease. Renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) is a newly-coined term used by an international panel of experts to describe renal cell carcinoma showing morphologic and immunohistochemical features of renal medullary carcinoma in patients without sickle cell trait/disease. So far, only one study in the English literature has described five such cases. Here, we report a case with unique clinical and pathological features in a 76-year-old male patient without sickle cell trait. The patient had a history of colon cancer with liver and lung metastases and was found to have a new renal mass in his right kidney during the follow up. A right nephrectomy was performed and showed two separate masses (tumor 1 and tumor 2). Tumor 1 had histologic features of RMC and the tumor cells were positive for CK7, Pax8, and OCT4 and showed loss of nuclear INI1 expression. Tumor 1 was diagnosed as RCCU-MP (6.3 cm, pT3aNx, WHO/ISUP nuclear grade 3). Tumor 2 showed features of clear cell type of RCC (0.6 cm, pT1aNx, WHO/ISUP grade 2) with intact nuclear INI1 expression. Three-months post-nephrectomy, the patient developed lung metastasis of RCCU-MP. To the best of our knowledge, this was the first documented case with synchronous RCCU-MP and clear cell RCC presenting in a patient without sickle cell trait. Careful histologic assessment with a panel of immunohistochemical biomarkers was helpful to render a correct diagnosis for early aggressive treatment.

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Moesin Up-regulation Is Associated with Enhanced Tumor Progression Imaged Non-invasively in an Orthotopic Mouse Model of Human Glioblastoma

Background/Aim: Glioblastoma is a recalcitrant and poorly understood disease. The aim of the present study was to investigate the effect of moesin up-regulation on tumor progression in an orthotopic nude-mouse model of human glioblastoma. Materials and Methods: U87-GFP glioblastoma cells, transfected with either U87-H4645 (moesin up-regulated) or U87-H149 (vector control) were orthotopically implanted into the brains of nude mice. Moesin expression in the tumors was analyzed with RT-PCR and western blotting. Real-time fluorescence imaging was used to longitudinally and non-invasively quantitate tumor growth. The expression of cancer-related genes β-catenin, CD44, MMP-2, ICAM-1, and PCNA in the tumor was analyzed by RT-PCR, western blotting and immunohistochemistry in both sublines. Results: The expression levels of moesin mRNA and protein were significantly increased in the glioblastoma derived from transfected U87-H4645 cells compared to the vector control and untransfected cells. Tumor growth rate and final tumor weight were significantly increased in the animals with the glioblastoma derived from transfected U87-H4645 cells, compared to untransfected and vector control (p<0.01). mRNA expression of β-catenin, CD44, ICAM-1, and MMP-2 in the glioblastoma derived from the transfected U87-H4645 tumors was significantly increased compared with tumors derived from untransfected and vector-control U87 cells (p<0.01). Furthermore, a similar increase in the expression of these proteins was observed by western blotting or immunohistochemistry. Conclusion: Up-regulation of moesin expression in glioblastoma cells resulted in more aggressive orthotopic glioblastoma growth in nude mice. This effect may be mediated by the regulation of several proliferation-, adhesion-, and invasion-related cancer genes, which may serve as future therapeutic targets for this recalcitrant disease.

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Impact of Pleural Effusion on Outcomes of Patients Receiving Osimertinib for NSCLC Harboring EGFR T790M

Background/Aim: Osimertinib has demonstrated promising efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC). We investigated the efficacy of osimertinib in such patients presenting with pleural effusion, which has been unclear to date. Patients and Methods: The medical records of all patients treated with osimertinib for advanced NSCLC with EGFR T790M between April 2016 and July 2017 at our Institution were retrospectively reviewed. Time to treatment failure (TTF) and overall survival (OS) were determined as endpoints. Results: Twenty-three patients (seven with pleural effusions) were treated with osimertinib. Patients with pleural effusion had significantly shorter median TTF than those without (3.7 vs. 12.8 months, respectively, p=0.021), as well as shorter median OS (7.8 months vs. not attained, respectively, p=0.002). Metastasis to the brain, bone, and liver did not significantly influence our endpoints. Conclusion: Osimertinib monotherapy is less effective in patients with NSCLC with pleural effusions.

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An Agonistic Antibody to EPHA2 Exhibits Antitumor Effects on Human Melanoma Cells

Background/Aim: EPH receptor A2 (EPHA2) is highly expressed in aggressive types of human cancer, and is expected to be an excellent target molecule for antibody treatments. In this study, we investigated the therapeutic potential of antibody to EPHA2 against melanoma in vitro. Materials and Methods: We generated three monoclonal antibodies (mAbs) to EPHA2 and examined cell-surface expression by flow cytometry. To investigate the ability to inhibit tumor cell migration therapy with mAbs to EPHA2, we performed a wound scratch assay and invasion assay. We investigated the therapeutic effects of immunotoxins consisting of toxin-conjugated EPHA2 mAbs. Results: All human melanoma cell lines studied expressed EPHA2. Like natural ligand ephrin-A1, one of EPHA2 mAbs, SHM16, inhibited metastatic behavior of cells, such as migration and invasion. In addition, drastic growth inhibition and cytotoxicity were found using immunotoxin-conjugated SHM16. Conclusion: These observations indicate a promising role for EPHA2 as a target in antibody treatments for melanoma, and demonstrate the potential therapeutic effects of an agonistic antibody to EPHA2.

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Neoadjuvant Platinum-based Chemotherapy Followed by Radical Hysterectomy for Stage Ib2-IIb Adenocarcinoma of the Uterine Cervix - An Italian Multicenter Retrospective Study

Aim: To assess the patterns of recurrence and clinical outcomes of patients with cervical adenocarcinoma who underwent neoadjuvant platinum-based chemotherapy (NACT) followed by radical hysterectomy. Patients and Methods: Data were retrospectively analyzed for 82 patients with International Federation of Gynecology and Obstetrics stage Ib2-IIb cervical adenocarcinoma who underwent this chemo-surgical treatment. The median follow-up of survivors was 89 months (range=5-208 months). Results: Pathological complete response, optimal response and suboptimal response with intra-cervical residual disease were obtained in five (6%), 10 (12%) and 36 (44%) patients, respectively. Adjuvant external-beam radiotherapy with or without concurrent chemotherapy was administered to 47 patients. Nineteen (23%) out of the 82 patients experienced recurrence after a median of 12 months (range=5.3-86.8 months). Recurrent disease was pelvic in 12 (63%) patients, extra-pelvic in five (26%), and both pelvic and extra-pelvic in two (10%). According to pathological response, tumor relapsed in 10% of optimal responders, 14% of sub-optimal responders with intra-cervical residual disease, and 36% of sub-optimal responders with extra-cervical residual disease or non-responders. Five-year recurrence-free and overall survival were 77% and 84%, respectively. Patients who achieved an optimal response or sub-optimal response with intra-cervical residual disease had better 5-year recurrence-free (87% vs. 64%, p=0.017) and overall (92% vs. 74%, p=0.012) survival than those who had sub-optimal response with extra-cervical residual disease or no response. The latter had a 1.441-fold higher risk of recurrence and a 1.652-fold higher risk of death than those who obtained an optimal response or a sub-optimal response with intra-cervical residual disease. Conclusion: NACT followed by radical hysterectomy may be an option for patients with stage Ib2-IIb adenocarcinoma of the uterine cervix.

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Quantitative Structure-Cytotoxicity Relationship of Furo[2,3-b]chromones

Background/Aim: The furo[2,3-b]chromone derivatives are natural products that have been used as folklore medicines for various diseases. Here, the cytotoxicity of 12 synthesized furo[2,3-b]chromone derivatives was investigated and subjected to quantitative structure–activity relationship (QSAR) analysis. Materials and Methods: Cytotoxicity against three human oral squamous cell carcinoma cell lines and three types of oral normal mesenchymal cells was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated as the ratio of the mean 50% cytotoxic concentration (CC₅₀) against normal oral cells to that against carcinoma cell lines. Potency-selectivity expression (PSE) was calculated by dividing the TS value by CC₅₀ against tumor cells. Apoptosis induction was evaluated by cell morphology and caspase-3 activation. Morphological changes were monitored under light microscopy. For QSAR analysis, 288 physicochemical, structural and quantum chemical features were calculated from the most stabilized structure optimized using Corina. Results: Four furo[2,3-b]chromone derivatives showed relatively strong tumor selectivity. In particular, the derivatives with phenylethenyl and methoxy groups showed the highest TS, equivalent to that of melphalan, although their PSE values did not reach those of doxorubicin and 5-fluorouracil. Microscopical observation demonstrated that at cytotoxic concentrations, (2R,3aR,9aR)-rac-3a,9a-dihydro-7-methoxy-4-oxo-2-(2-phenylethenyl)-4H-furo[2,3-b][1]benzopyran-3,3(2H)-dicarboxylic acid 3,3-dimethyl ester and (2R,3aR,9aR)-rac-3a,9a-dihydro-7-methoxy-4-oxo-2-(1-propen-1-yl)-4H-furo[2,3-b][1]benzopyran-3,3(2H)-dicarboxylic acid 3,3-dimethyl ester did not produce a population of shrunken cells typical of apoptotic cells, in contrast to cells treated with actinomycin D. Tumor selectivity of furo[2,3-b]chromone derivatives strongly correlated with features related to the number of intramolecular unsaturated bonds, molecular flexibility, molecular density, lipophilicity, molecular size, and molecular shape. Conclusion: Chemical modification of the lead compound may be a potential choice for designing a new type of anticancer drug.

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Usefulness of Preoperative 18F-FDG-PET in Detecting Invasive Intraductal Papillary Neoplasm of the Bile Duct

Background/Aim: Preoperative identification of the invasive component remains challenging in intraductal papillary neoplasm of the bile duct (IPNB). We evaluated the ability of preoperative ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) to differentiate between non-invasive IPNB, invasive IPNB, and papillary cholangiocarcinoma (CCA). Patients and Methods: The maximum standardized uptake values (SUV_max) of 11 patients with IPNB (6 non-invasive and 5 invasive) and 20 with papillary CCA who underwent pre-surgical ¹⁸F-FDG-PET were assessed. The SUV_max cut-off that predicts an invasive component was determined using receiver operating characteristic (ROC) curve analysis. Results: The SUV_max in patients with invasive IPNB and papillary CCA were significantly higher than in patients with non-invasive IPNB (p=0.035 and 0.0025, respectively). ROC curve analysis revealed an optimal SUV_max cut-off of 4.5, which had 94.5% accuracy, 76.0% sensitivity, and 100% specificity. Conclusion: Our data suggest that the preoperative ¹⁸F-FDG-PET SUV_max can differentiate non-invasive IPNB from invasive IPNB and papillary CCA.

https://ift.tt/2kCKB9K

Combination Therapy with Glucan and Coenzyme Q10 in Murine Experimental Autoimmune Disease and Cancer

Background/Aim: Coenzyme Q₁₀ is a well-accepted anti-oxidant agent known to play a protective role in various physiological and disease processes. Recently, Coenzyme Q₁₀ is gaining attention as a substance with significant anti-inflammatory properties. β-Glucan is the most studied immunomodulator with significant synergetic effects with numerous bioactive molecules. We aimed to evaluate the possible synergistic effects of simultaneous use of coenzyme Q₁₀ with the well-established immune modulator, β-glucan, on immune reactions and cancer development. Materials and Methods: Coenzyme Q₁₀ and β-glucan were used, both in vivo and in vitro, and their effects were evaluated using phagocytosis and cytokine secretion. Results: Our study confirmed the strong anti-inflammatory effects of coenzyme Q₁₀ and showed that these effects were further potentiated with the addition of β-glucan. The anticancer effects of coenzyme Q₁₀ were less pronounced, but stronger, with the addition of β-glucan. Conclusion: There is significant synergy between coenzyme Q₁₀ and β-glucan.

https://ift.tt/2H218wF

Radiological Features of Brain Metastases from Non-small Cell Lung Cancer Harboring EGFR Mutation

Aim: To investigate the radiological features on computed tomography (CT) of brain metastasis (BM) from epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Patients and Methods: Thirty-four patients with NSCLC with BMs who underwent surgical resection of the BMs at the Department of Neurosurgery, Kyushu University from 2005 to 2016 were enrolled in the study. The EGFR statuses of the 34 BMs were investigated. Radiological features, including the number, size, and location of the tumor, were delineated by CT. Results: Patients with EGFR-mutated BMs had significantly higher frequencies of multiple metastases than those with the non-EGFR-mutated type (p=0.042). BMs harboring mutations in EGFR were more frequently observed in the central area of the brain compared to those without mutations in EGFR (p=0.037). Conclusion: Careful follow-up of patients with EGFR-mutated NSCLC may be necessary given the high frequencies of multiple BMs and their location in the central area of the brain.

https://ift.tt/2IVDKXr

Hapalindole H Induces Apoptosis as an Inhibitor of NF-ĸB and Affects the Intrinsic Mitochondrial Pathway in PC-3 Androgen-insensitive Prostate Cancer Cells

Background: Prostate cancer presents the highest incidence rates among all cancers in men. Hapalindole H (Hap H), isolated from Fischerella muscicola (UTEX strain number LB1829) as part of our natural product anticancer drug discovery program, was found to be significantly active against prostate cancer cells. Materials and Methods: In this study, Hap H was tested for nuclear factor-kappa B (NF-ĸB) inhibition and selective cytotoxic activity against different cancer cell lines. The apoptotic effect was assessed on PC-3 prostate cancer cells by fluorescence-activated cell sorting analysis. The underlying mechanism that induced apoptosis was studied and the effect of Hap H on mitochondria was evaluated and characterized using western blot and flow cytometric analysis. Results: Hap H was identified as a potent NF-ĸB inhibitor (0.76 μM) with selective cytotoxicity against the PC-3 prostate cancer cell line (0.02 μM). The apoptotic effect was studied on PC-3 cells. The results showed that treatment of PC-3 cells with Hap H reduced the formation of NAD(P)H, suggesting that the function of the outer mitochondrial membrane was negatively affected. Thus, the mitochondrial transmembrane potential was assessed in Hap H treated cells. The results showed that the outer mitochondrial membrane was disrupted as an increased amount of JC-1 monomers were detected in treated cells (78.3%) when compared to untreated cells (10.1%), also suggesting that a large number of treated cells went into an apoptotic state. Conclusion: Hap H was found to have potent NF-ĸB p65-inhibitory activity and induced apoptosis through the intrinsic mitochondrial pathway in hormone-independent PC-3 prostate cancer cells.

https://ift.tt/2H5j6OD

Phase II Trial of Carboplatin and Pemetrexed Plus Bevacizumab with Maintenance Bevacizumab as a First-line Treatment for Advanced Non-squamous Non-small Cell Lung Cancer in Elderly Patients

Background/Aim: The combination of platinum-doublet chemotherapy with bevacizumab has been established as a first-line treatment option in non-elderly patients with non-squamous (non-sq) non-small cell lung cancer (NSCLC). However, the safety and efficacy of this regimen have not yet been fully established in elderly patients. Patients and Methods: Chemo-naïve patients with non-sq NSCLC, aged ≥75 years, having a good performance status (Eastern Cooperative Oncology Group performance status 0-1) and adequate organ function were considered eligible. Patients received carboplatin (area under the curve=5 mg/ml/min), pemetrexed (500 mg/m²), and bevacizumab (15 mg/kg) every 3 weeks for up to 4 cycles, followed by maintenance bevacizumab. The primary endpoint was the objective response rate (ORR; target=50%, threshold=30%; Simon's two-stage design), and the secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). Results: Twelve patients were enrolled from June 2013 to July 2017. The study was closed because of slow patient accrual. The median patient age was 80 years. Eleven patients (92%) completed 4 cycles of induction chemotherapy. Seven patients achieved a partial response (PR), yielding an ORR of 58%. The median PFS was 8.4 [95% confidence interval (CI)=4.4-10.5] months, and the median OS was 33.9 (95%CI=13.2-43.3) months. Toxicities were generally mild and consistent with previous reports. There were no treatment-related deaths. Conclusion: A regimen comprising carboplatin and pemetrexed plus bevacizumab followed by maintenance bevacizumab is feasible and potentially efficacious in elderly patients with non-sq NSCLC.

https://ift.tt/2IVDKGV

MiR-193a-5p and -3p Play a Distinct Role in Gastric Cancer: miR-193a-3p Suppresses Gastric Cancer Cell Growth by Targeting ETS1 and CCND1

Background/Aim: MicroRNAs (miRNAs) are small non-protein-coding RNAs, that can be generated from the 5p or 3p arm of precursor miRNA (pre-miRNA). Differential miRNA arm selection has been reported between tumor and normal tissue in many cancer types; however, the biological function and mechanism of miRNA arm switching in gastric cancer remain unclear. Materials and Methods: Profiles of miRNA expression in gastric cancer were obtained from The Cancer Genome Atlas (TCGA). The biological role of miR-193a-5p/-3p in tumor growth and invasive abilities was assessed through a gain-of-function approach. Target genes of miR-193a-3p were identified using bioinformatics and an experimental approach. Results: The expression levels of miR-193a-5p, and not of miR-193a-3p, were significantly decreased in gastric cancer compared to adjacent normal tissues. Ectopic expressions of miR-193a-5p and miR-193a-3p revealed that they both inhibited gastric cancer cell growth, but only miR-193a-3p significantly suppressed cell invasion ability. Using a bioinformatics approach, we identified 18 putative target genes of miR-193a-3p. Both mRNA and protein levels of cyclin D1 (CCND1) and ETS proto-oncogene 1 (ETS1) were significantly decreased in AGS cells transfected with miR-193a-3p mimics. ETS1 or CCND1 knockdown significantly suppressed gastric cancer cell growth, similar to miR-193a-3p overexpression. Conclusion: Our results indicated that miR-193a-3p suppressed gastric growth and motility, at least partly, by directly targeting CCND1 and ETS1 expression.

https://ift.tt/2H40Zc9

Malignant adnexal tumors of the skin: a single institution experience

Abstract

Background

Malignant adnexal tumors of the skin (MATS) are rare. We aimed to measure the survival of patients with MATS and identify predictors of improved survival.

Methods

A retrospective review of MATS treated at our institution from 1990 to 2012.

Results

There were 50 patients within the time period. Median age was 59.5 years (range 22–95); primary site was the head and neck (52%); most common histologic subtypes were skin appendage carcinoma (20%) and eccrine adenocarcinoma (20%); and the vast majority were T1 (44%). Most patients (98%) underwent surgical treatment. Chemotherapy and radiation were administered to 8 and 14% of patients, respectively. Recurrence rate was 12%. Median OS was 158 months (95% CI, 52–255). OS and recurrence-free survival at 5 years were 62.4 and 47.4% and at 10 years 56.7 and 41.5%, respectively. Five-year and 10-year disease-specific survival (DSS) was 62.9%. Age > 60 years was an unfavorable predictor of OS (HR 12.9, P < .0008) and recurrence-free survival (RFS) (HR 12.53, P < .0003). Nodal metastasis was a negative predictor of RFS (HR 2.37, P < 0.04) and DSS (HR 7.2, P < 0.03) while treatment with chemotherapy was predictive of poor DSS (HR 14.21, P < 0.03).

Conclusions

Younger patients had better OS and RFS. Absence of nodal metastasis translated to better RFS and DSS. Lymph node basin staging is worth considering in the workup and treatment.

https://ift.tt/2xtG3LV

A fast optimization approach for treatment planning of volumetric modulated arc therapy

Volumetric modulated arc therapy (VMAT) is widely used in clinical practice. It not only significantly reduces treatment time, but also produces high-quality treatment plans. Current optimization approaches he...

https://ift.tt/2L7yQTT

The Effect of Temperature and Perfusion Time on Response, Toxicity, and Survival in Patients with In-transit Melanoma Metastases Treated with Isolated Limb Perfusion

Abstract

Background

Isolated limb perfusion (ILP) is used to treat in-transit metastases of melanoma of the extremities when surgical excision is not possible. The optimal setting concerning temperature and perfusion time is unknown. The purpose of this study was to analyze these factors concerning their effects on response, toxicity, and survival.

Methods

A retrospective analysis of 284 consecutive stage III melanoma patients treated with melphalan ILP for the first time in our institution, during a 31-year period (July 1986–May 2017), was performed. Our series was divided in four time periods, according to perfusion temperature and duration. Demographical data, stage, number, and size of lesions were retrieved from our prospective database.

Results

Overall response (OR) rate 83% and a complete response (CR) rate of 59%. Significant predictive factors for CR in multivariate analysis were non-bulky tumor, fewer metastases, and a perfusion time of 120 min. Predictive factors for increased local toxicity were femoral ILP and higher perfusion temperatures. The median overall survival was 30 months, and the independent negative prognostic factors were lymph-node status, bulky tumors, response, upper limb perfusion, and 120 min perfusion at 39–40 °C.

Conclusions

Modern ILP uses diminished perfusion time and lower temperature, leading to a decrease in toxicity. However, our data also show a decrease in response, which indicates that optimal perfusion time and temperature regimen remain to be determined.

https://ift.tt/2H4irNA

Will Palliative Care Ever Be Cool?

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FOLFIRINOX Versus Gemcitabine/Nab-Paclitaxel for Neoadjuvant Treatment of Resectable and Borderline Resectable Pancreatic Head Adenocarcinoma

Abstract

Background

Both FOLFIRINOX and gemcitabine/nab-paclitaxel (G-nP) are used increasingly in the neoadjuvant treatment (NAT) of pancreatic ductal adenocarcinoma (PDA). This study aimed to compare neoadjuvant FOLFIRINOX and G-nP in the treatment of resectable (R) and borderline resectable (BR) head PDA.

Methods

A single-institution retrospective review of R and BR patients undergoing pancreaticoduodenectomy after NAT with FOLFIRINOX or G-nP was performed. Comparative analysis was performed using inverse-probability-weighted (IPW) estimators. The end points of the study were overall survival (OS) and an 80% reduction in CA19-9 with NAT.

Results

In this study, 193 patients were analyzed, with 73 patients receiving FOLFIRINOX and 120 patients receiving G-nP. The median OS was 38.7 months for FOLFIRINOX versus 28.6 months for G-nP (p = 0.214). The patients who received FOLFIRINOX were younger and had fewer comorbidities, more BR disease, and larger tumors than those treated with G-nP (all p < 0.05). The two regimens were equally effective in achieving an 80% decline in CA19-9 (p = 0.8). The R0 resection rates were similar (80%), but FOLFIRINOX was associated with a reduction in pN1 disease (56% vs. 72%; p = 0.028). The receipt of adjuvant therapy was similar (74 vs. 75%; p = 0.79). In the Cox regression analysis with adjustment for baseline and treatment-related variables (FOLFIRINOX vs. G-nP, age, gender, computed tomography (CT) tumor size, BR vs. R, pre-NAT CA19-9), regimen type was not associated with a survival benefit. In the IPW analysis of 166 patients, however, the average treatment effect of FOLFIRINOX was to increase OS by 4.9 months compared with G-nP (p = 0.012).

Conclusions

Both FOLFIRINOX and G-nP are viable options for neoadjuvant treatment of PDA. In this study, neoadjuvant FOLFIRINOX was associated with a 4.9-month improvement in survival compared with G-nP after adjustment for covariates.

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Most Breast Cancer Patients with T1-2 Tumors and One to Three Positive Lymph Nodes Do Not Need Postmastectomy Radiotherapy

Abstract

Background/Objective

Guidelines concur that postmastectomy radiation therapy (PMRT) in T1-2 tumors with one to three positive (+) lymph nodes (LNs) decreases locoregional recurrence (LRR) but advise limiting PMRT to patients at highest risk to balance against potential harms. In this study, we identify the risks of LRR after mastectomy in patients with T1-2N1 disease, treated with modern chemotherapy, and identify predictors of LRR when omitting PMRT.

Methods

Patients with T1-2N1 breast cancer undergoing mastectomy between 1995 and 2006 were categorized by receipt of PMRT. The Chi square test compared the clinicopathologic features between both groups, and Kaplan–Meier and Cox regression analysis was used to determine the rates of LRR, recurrence-free survival (RFS), and overall survival (OS).

Results

Overall, 1087 patients (924 no PMRT, 163 PMRT) were included in the study, with a median follow-up of 10.8 years (range 0–21). We identified 63 LRRs (56 no PMRT, 7 PMRT), and 10-year rates of LRR with and without PMRT were 4.0% and 7.0%, respectively. Patients receiving PMRT were younger (p = 0.019), had larger tumors (p = 0.0013), higher histologic grade (p = 0.029), more positive LNs (p < 0.0001), lymphovascular invasion (LVI) (p < 0.0001), extracapsular nodal extension (p < 0.0001), and macroscopic LN metastases (p < 0.0001). There was no difference in LRR, RFS, or OS between groups. On multivariate analysis, age < 40 years (p < 0.0001) and LVI (p < 0.0001) were associated with LRR in those not receiving PMRT.

Conclusion

Consistent with the guidelines, 85% of patients with T1-2N1 were spared PMRT at our center, while maintaining low LRR. Age < 40 years and the presence of LVI are significantly associated with LRR in those not receiving PMRT.

https://ift.tt/2H2tg2E

Treatment of Isolated Peritoneal Recurrences in Patients with Colorectal Peritoneal Metastases Previously Treated with Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

Abstract

Background

Colorectal peritoneal carcinomatosis (PC) is preferably treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Peritoneal recurrence of disease after treatment can occur without distant metastases, with a variety of treatment options.

Objective

This study aimed to evaluate the management of isolated peritoneal recurrence after primary CRS-HIPEC.

Methods

In two tertiary referral centers, all patients who underwent CRS-HIPEC for colorectal PC between 2004 and 2015 and who developed isolated peritoneal recurrences were retrospectively evaluated. Location, treatment of peritoneal recurrences, and curative or palliative treatment intent were reported, and univariable and multivariable Cox regression analysis and survival analyses were performed.

Results

Of 414 patients treated with CRS-HIPEC for colorectal PC, 106 patients (26%) developed isolated peritoneal recurrence. Forty-three patients (41%) were treated with curative intent and 63 (59%) were treated with palliative intent. Median overall survival (OS) in the patients treated with curative intent was 24.7 months (interquartile range [IQR] 12.1–61.7), compared with 7.6 months (IQR 2.5–15.9) in those treated with palliative intent (p < 0.001). In the patients treated with curative CRS (n = 17) and curative second CRS-HIPEC (n = 15), median OS was 51.7 months (IQR 14.4–NA) and 29.0 months (IQR 18.1–63.0), respectively (p = 0.620). The latter group had a significantly higher region count (median 1 vs. 3; p < 0.001). Postoperative complications and hospital stay did not significantly differ between first and second CRS-HIPEC.

Conclusion

After CRS-HIPEC for colorectal cancer, approximately one of four patients will develop isolated peritoneal recurrences. A substantial amount of these patients can be safely treated with curative intent yielding long-term survival.

https://ift.tt/2IV9Dzn

Is the 8th Edition of the AJCC TNM Staging System Sufficiently Reasonable for All Patients with Noncardia Gastric Cancer? A 12,549-Patient International Database Study

Abstract

Background

The aim of this work is to compare the prognostic ability between the 7th and 8th editions of the American Joint Committee on Cancer (AJCC) tumor–node–metastasis (TNM) classification for gastric cancer (GC).

Methods

A total of 10,194 noncardia GC patients were identified from the Surveillance, Epidemiology, and End Results database from 1988 to 2008. Concordance index (C-index), bayesian information criterion (BIC), and time-dependent receiver operating characteristic (t-ROC) analyses were used. External validation was performed using a dataset (n = 2355) derived from Fujian Medical University Union Hospital.

Results

Overall survival for all five AJCC N categories differed significantly when patients were subgrouped into ≤ 15 versus >15 examined lymph nodes (eLNs). The prognostic ability of the 8th edition (C-index 0.716) was not improved over the 7th edition (C-index 0.716). Subgroup analysis showed superior performance of the 8th over the 7th edition in patients with > 15 eLNs (C-index 0.742 vs. 0.735); however, the two editions showed similar performance for patients with ≤ 15 eLNs (C-index 0.713 vs. 0.713). The BIC and t-ROC analyses were consistent. To better predict the prognosis of patients with ≤ 15 eLNs, we established a novel prognostic model based on independent prognostic factors (C-index 0.735). BIC analysis showed that this new model was better than the 7th and 8th editions. Similar results were obtained from the validation set.

Conclusions

The 8th edition of the AJCC TNM classification shows better prognostic ability than the 7th edition in noncardia GC patients with > 15 eLNs, but no improvement was found in patients with ≤ 15 eLNs; therefore, a novel prognostic model is proposed.

https://ift.tt/2IXZp10

What is the Incidence of Malignancy in Resected IPMN? An Analysis of Over 100 U.S. Institutions in a Single Year

https://ift.tt/2H0vNdL

Predictors of Residual Disease After Breast Conservation Surgery

Abstract

Introduction

Breast-conserving therapy is the standard of care for early-stage breast cancer. In the era of multimodality therapy, the debate on the value of revision surgery for compromised margins continues, and high re-excision rates persist despite updated guidelines. Our study sought to identify the local re-excision rate for compromised margins after lumpectomy, and identify predictors of residual disease at re-excision.

Methods

This population-based retrospective cohort study included women with breast cancer who underwent a lumpectomy between 2009 and 2012 in Manitoba, with close (≤ 2 mm) or positive margins that led to re-excision. Patient demographics and tumor characteristics were identified through provincial cancer registries and chart reviews. For patients with invasive cancer, the six anatomical margins were reported for margin status, width, and pathology type at the margin.

Results

Of the 2494 patients identified, 556 women underwent re-excision, yielding a re-excision rate of 22.29%. Of our 311 patients with invasive cancer who underwent re-excision, 62.7% had residual disease identified on revision. On univariable analysis, the size and grade of the invasive component, nodal stage, and the number of positive margins were associated with residual disease on re-excision (p < 0.05). With the exception of nodal stage, the same variables remained statistically significant on multivariable analysis.

Conclusions

Our results suggest that even in the absence of 'no ink on tumor', the cancer size and grade in lumpectomy specimens are high-risk factors for residual disease, and this subgroup of patients may benefit from re-excision. Long-term follow-up of this cohort is required to determine their risk of recurrence after adjuvant treatment.

https://ift.tt/2kBStbC

The Impact of Metronomic Adjuvant Chemotherapy in Patients with Advanced Oral Cancer

Abstract

Background

This study evaluated the efficacy of tegafur-uracil for advanced oral cancer.

Methods

From January 2008 to December 2013, clinical data from 356 patients with stage III or IV oral squamous cell carcinoma who received curative surgical resection and postoperative concurrent chemoradiotherapy, treated with or without tegafur-uracil, were analyzed from a prospectively designed database. Tegafur-uracil was orally administered to 114 of the 356 patients. Disease-specific survival (DSS), disease-free survival (DFS), and overall survival (OS) rates were studied.

Results

In our study, the 5-year OS (p = 0.0008), DFS (p = 0.0034), and DSS (p = 0.0029) rates were significantly better in the tegafur-uracil group than in the control group. Distant metastasis occurred in 16.28% of patients in the tegafur-uracil group and 45.28% in the control group (odds ratio 4.3). The distant metastasis rate in the tegafur-uracil group was significantly lower than the control group, indicating that administration of tegafur-uracil after curative surgical treatment and concurrent chemoradiotherapy prevented distant metastasis and improved the OS, DFS, and DSS rate.

Conclusions

The result of tegafur-uracil treatment in patients with advanced oral cancer showed significant improvement in the 5-year OS, DFS, and DSS rate, while also showing a decreased distant metastasis rate. Tegafur-uracil treatment is a useful, effective, and well-tolerated anticancer treatment for advanced oral cancer.

https://ift.tt/2swIzeX

Adrenal Incidentalomas During Diagnostic Work-up of Colorectal Cancer Patients: What is the Risk of Metastases?

Abstract

Background

Adrenal incidentalomas (AIs) are regularly discovered on staging computed tomography (CT) of patients with colorectal cancer (CRC). Although CRC is considered unlikely to metastasize to the adrenal gland, it is not known how often an AI appears to be a CRC metastasis. This causes a diagnostic dilemma for many patients with newly diagnosed CRC. This study aimed primarily to describe the incidence of AIs and adrenal metastases in CRC patients.

Methods

A single-center cohort of 475 consecutive patients with newly diagnosed CRC was defined. Retrospectively, all radiology reports and multidisciplinary team meeting reports were assessed for the presence of adrenal abnormalities. All AIs shown on staging CT were reevaluated for the purpose of this study, and the sizes of these adrenal glands were determined. Based on the CT reevaluation, follow-up imaging, and clinical follow-up assessment, conclusions on the presence or absence of adrenal metastases were drawn.

Results

The incidence of AIs in this CRC patient cohort was 10.5% (50/475). In 96% (48/50) of the patients with AIs, adrenal metastases could be ruled out. No solitary adrenal metastases were encountered. In two patients who had widespread systemic disease without curative treatment options, the AIs were considered to be adrenal metastases (cohort incidence, 0.4%).

Conclusion

This is the first study to report on adrenal incidentalomas in CRC patients. In newly diagnosed CRC patients without disseminated disease, AIs can be considered benign, and no additional imaging is indicated to rule out adrenal metastases in this group.

https://ift.tt/2JbndOz

Implementing a Program of Talimogene laherparepvec

Abstract

Background

Oncolytic viruses are genetically engineered or naturally occurring viruses that selectively replicate in cancer cells without harming normal cells. Talimogene laherparepvec (Imlygic^®), the first oncolytic viral therapy approved for treatment of cancer, was approved for treatment of locally advanced melanoma in October 2015.

Purpose

As a biologic product, use of T. laherparepvec in the clinical setting requires pretreatment planning and a unique systematic approach to deliver the therapy. The processes we describe herein could be adopted by other centers that choose to prescribe T. laherparepvec.

Methods

We studied our clinical trial experience with T. laherparepvec before we embarked on using commercially available T. laherparepvec. We created a standard operating procedure (SOP) with multidisciplinary buy-in and oversight from leadership in Infection Control at our institution. We reflected on clinical cases and the actual procedures of administering T. laherparepvec to create the SOP.

Results

The preimplementation planning, patient selection, identification of lesions to treat, the actual procedure, and ongoing assessment of patients are described. Tumoral-related factors that lead to unique challenges are described.

Conclusions

A process to ensure safe and responsible implementation of a program to administer T. laherparepvec for treatment of melanoma may improve the quality of treatment for patients who suffer from advanced melanoma.

https://ift.tt/2IUtbUB

Stage- and Histologic Subtype-Dependent Frequency of Lymph Node Metastases in Patients with Epithelial Ovarian Cancer Undergoing Systematic Pelvic and Paraaortic Lymphadenectomy

Abstract

Purpose

Tumor stage and distinct histological subtypes in epithelial ovarian cancer (EOC) show different prognostic outcome. The aim of this study is to evaluate whether the frequency of lymph node (LN) metastases in patients with different tumor stages and histological subtypes undergoing systematic pelvic and paraaortic lymphadenectomy is coincidentally divergent.

Methods

Patients with EOC treated with upfront staging or debulking surgery between January 2000 and December 2016 were included. Systematic lymphadenectomy was performed in all consecutive patients with optimal debulking and without medical contraindications.

Results

Seven hundred sixty-two patients including 27.2% with early-stage EOC were included. The median number of removed LNs was 69, and metastases to LNs were found in 54.7%. No LN metastases were found in patients with low-grade endometrioid carcinoma, independently of tumor stage. LN metastases in early-stage low-grade serous (N = 5), mucinous (N = 31), and clear cell (N = 28) EOC were found in one (20%), zero, and one (3.6%) patient, respectively. LN metastases were detected in more than 10% of patients with all other histological subtypes. On multivariate analyses, overall survival was significantly impaired in patients with LN metastases, as compared with patients without LN metastases (p = 0.001).

Conclusions

The risk of LN metastases in patients with EOC is dependent on stage and histological subtype. Patients with incidental finding of early mucinous or low-grade endometrioid EOC are at very low risk of retroperitoneal lymph node metastases. Reoperation for lymph node staging only should be discussed individually with caution.

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Together We Make a Difference

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Adjuvant Therapy in the Treatment of Melanoma

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A Novel Physiobiological Parameter-Based Grading System for Resectable Pancreatic Cancer

Abstract

Background

Preoperative methods to estimate disease-specific survival (DSS) for resectable pancreatic cancer are limited.

Objective

The aim of this study was to develop and validate a pretreatment physiobiological prognostic model in patients with radiologically resectable pancreatic cancer.

Methods

A retrospective review of a prospectively maintained institutional database was undertaken to identify patients who underwent potentially curative resection for radiologically resectable pancreatic cancer. Demographics, treatments, and relationships between the potential prognostic factors and survival rate were analyzed, and prognostic nomograms were established.

Results

We identified 240 patients who fulfilled our eligible criteria. The 1-, 3-, and 5-year DSS rates after surgery were 77.8, 40.9, and 31.3%, respectively. On multivariate analysis, increased neutrophil/lymphocyte ratio [hazard ratio (HR) 1.60, 95% confidence interval (CI) 1.17–2.17; p < 0.01], reduced Prognostic Nutritional Index (HR 2.08, 95% CI 1.68–3.20; p < 0.01), and elevated preoperative serum carbohydrate antigen 19-9 level (HR 2.12, 95% CI 1.55–2.88; p < 0.01) were associated with worse DSS. Although curative resection was the operative aim for all patients, 131 (54.6%) patients had recurrence within 12 months after curative resection of resectable pancreatic cancer. There was a significant correlation between recurrence pattern and physiobiological characteristics.

Conclusion

We developed a new grading system for radiologically resectable pancreatic cancer. This system is simple and reliably predicts differences in survival after pancreatic resection.

https://ift.tt/2kysguq

Salvage Abdominoperineal Resection for Squamous Cell Anal Cancer: A 30-Year Single-Institution Experience

ABSTRACT

Background

Failure of chemoradiotherapy (CRT) for anal squamous cell carcinoma (SCC) results in persistent or recurrent anal SCC. Treatment with salvage abdominoperineal resection (APR) can potentially achieve cure. The aims of this study are to analyze oncological and surgical outcomes of our 30-year experience with salvage APR for anal SCC after failed CRT and identify prognostic factors for overall survival (OS).

Methods

All consecutive patients who underwent salvage APR between 1990 and 2016 for histologically confirmed persistent or recurrent anal SCC after failed CRT were retrospectively analyzed.

Results

Forty-seven patients underwent salvage APR for either persistent (n = 24) or recurrent SCC (n = 23). Median OS was 47 months [95% confidence interval (CI) 10.0–84.0 months] and 5-year survival was 41.6%, which did not differ significantly between persistent or recurrent disease (p = 0.551). Increased pathological tumor size (p < 0.001) and lymph node involvement (p = 0.014) were associated with impaired hazard for OS on multivariable analysis, and irradical resection only (p = 0.001) on univariable analysis. Twenty-one patients developed local recurrence after salvage APR, of whom 8 underwent repeat salvage surgery and 13 received palliative treatment. Median OS was 9 months (95% CI 7.2–10.8 months) after repeat salvage surgery and 4 months (95% CI 2.8–5.1 months) following palliative treatment (p = 0.055).

Conclusions

Salvage APR for anal SCC after failed CRT resulted in adequate survival, with 5-year survival of 41.6%. Negative prognostic factors for survival were increased tumor size, lymph node involvement, and irradical resection. Patients with recurrent anal SCC after salvage APR had poor prognosis, irrespective of performance of repeat salvage surgery, which never resulted in cure.

https://ift.tt/2ss6xaU

Clinicopathological Features and Prognosis of Primary GISTs with Tumor Rupture in the Real World

Abstract

Background

Patients with ruptured gastrointestinal stromal tumor (GIST) are recommended for imatinib adjuvant therapy; however, their clinicopathological features and prognosis in the era of imatinib are unknown.

Patients and Methods

The study cohort included 665 patients with histologically proven primary GISTs who underwent R0 or R1 surgery between 2003 and 2007; the validation cohort included 182 patients between 2000 and 2014. The definitions of tumor rupture in the study included perforation at tumor site, tumor fracture, piecemeal resection including open biopsy, and macroscopic injuries to the pseudocapsule.

Results

Tumor rupture occurred in 21 (3.2%) of 665 and 5 (2.9%) of 182 patients in the study and validation cohort, respectively. Ruptured GISTs were more symptomatic, were larger in size, and had higher mitotic count than nonruptured GISTs but were not associated with tumor location or laparoscopic surgery. GISTs with intraoperative rupture had clinicopathological features and prognostic outcomes similar to those with preoperative rupture. Recurrence rates were higher and median recurrence-free survival (RFS) and overall survival (OS) were shorter with ruptured than nonruptured GIST. Tumor rupture was one of the independent prognostic factors for RFS, but not OS, according to multivariate analysis.

Conclusions

Ruptured GISTs were symptomatic larger tumors with high mitotic activity, frequent relapse, and shorter RFS. Tumor rupture was an independent prognostic factor for RFS, but not for OS, in the era of imatinib.

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Rates of TP53 Mutation are Significantly Elevated in African American Patients with Gastric Cancer

Abstract

Background

Gastric adenocarcinoma is a heterogenous disease that results from complex interactions between environmental and genetic factors, which may contribute to the disparate outcomes observed between different patient populations. This study aimed to determine whether genomic differences exist in a diverse population of patients by evaluating tumor mutational profiles stratified by race.

Methods

All patients with gastric adenocarcinoma between 2012 and 2016 who underwent targeted next-generation sequencing of cancer genes by the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets platform were identified. Patient race was categorized as Asian, African American, Hispanic, or Caucasian. Fisher's exact test was used to examine differences in mutation rates between racial designations for the most common mutations identified. The p values in this study were adjusted using the false discovery rate method.

Results

The study investigated 595 mutations in 119 patients. The DNA alterations identified included missense mutations (66%), frame-shift deletions (13%), and nonsense mutations (9%). Silent mutations were excluded. The most frequently mutated genes were ARID1A, CDH1, ERBB3, KRAS, PIK3CA, and TP53. Of these, TP53 was the most frequently mutated gene, affecting 50% of patients. The proportion of patients with TP53 mutations differed significantly between races (p = 0.012). The findings showed TP53 mutations for 89% (16/18) of the African American patients, 56% (10/18) of the Asian patients, 43% (9/21) of the Hispanic patients, and 40% (25/62) of the Caucasian patients.

Conclusions

Significantly higher rates of TP53 mutations were identified among the African American patients with gastric adenocarcinoma. This is the first study to evaluate tumor genomic differences in a diverse population of patients with gastric adenocarcinoma.

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Efficacy of Endoscopic Ultrasonography for Determining Clinical T Category for Esophageal Squamous Cell Carcinoma: Data From 1434 Surgical Cases

Abstract

Background

The efficacy of endoscopic ultrasonography (EUS) for determining T category is variable for esophageal squamous cell carcinoma (ESCC). We aimed to assess the efficacy of EUS in accurately identifying T category for ESCC based on the 8th AJCC Cancer Staging Manual.

Methods

A retrospective analysis was conducted using a prospectively collected ESCC database from January 2003 to December 2015, in which all patients underwent EUS examination followed by esophagectomy. The efficacy of EUS was evaluated by sensitivity, specificity, and accuracy compared with pathological T category as gold standard. Overall survival of different EUS-T (uT) categories was assessed.

Results

In total, 1434 patients were included, of whom 58.2% were correctly classified by EUS, with 17.9% being overstaged and 23.9% being understaged. The sensitivity and accuracy of EUS for Tis, T1a, T1b, T2, T3, and T4a categories were 15.8 and 98.8%, 16.3 and 95.7%, 33.1 and 89.3%, 56.8 and 65.0%, 65.8 and 70.0%, and 27.3 and 97.5%, respectively. The survival difference between uT1a and uT1b was not statistically significant (p = 0.90), nor was that between uT4a and uT4b (p = 0.34). However, when uT category was integrated as uTis, uT1, uT2, uT3, and uT4, overall survival was clearly distinguished between the categories (p < 0.01).

Conclusions

EUS is in general feasible for classifying clinical T category for ESCC. However, EUS should be used with caution for discriminating between Tis, T1a, and T1b disease, as well as T4 disease.

https://ift.tt/2IZJnUk

Postoperative Adjuvant Trans-Arterial Chemoembolization for Patients with Hepatocellular Carcinoma and Portal Vein Tumor Thrombus

Abstract

Background

It remains uncertain whether patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) benefit from postoperative adjuvant trans-arterial chemoembolization (PA-TACE).

Methods

We retrospectively identified 540 patients to form the crude cohort and adopted propensity score matching analysis to assemble another cohort of 464 patients with similar baseline characteristics. Univariate and multivariate Cox analyses were performed in exploratory subgroups to identify the independent effect of PA-TACE on overall survival (OS).

Results

In the overall study population, univariate analysis showed PA-TACE was associated with longer OS [odds ratio (OR) = 0.55, p = 0.001], and stratified analyses indicated an interaction between PVTT types and PA-TACE on OS (p = 0.057 for interaction). After matching, all of the characteristics were well balanced between the PA-TACE and control groups (all p > 0.05). Multivariate Cox analysis validated that the protective role of PA-TACE was significant greater with the expansion of PVTT (type I, OR 0.66; type II, OR 0.33; and type III, OR 0.33, respectively, p = 0.011 for interaction). There also was evidence of treatment effect modification by PVTT type in the crude cohort (type I, OR 0.60; type II, OR 0.32; and type III, OR 0.32, respectively, p = 0.011 for interaction).

Conclusions

In patients with HCC and PVTT, PA-TACE was associated with a lower risk of death, particularly, among those with PVTT involving right/left or main portal vein, after excluding patients who were unsuitable for this procedure at 1 month after surgery.

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Keine Verschlechterung der postoperativen Lebensqualität von Ösophaguskarzinompatienten durch neoadjuvante Radiochemotherapie

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Ketamine Anesthesia Does Not Improve Depression Scores in Electroconvulsive Therapy: A Randomized Clinical Trial

Background: Although interest in ketamine use during electroconvulsive therapy (ECT) has increased, studies have been equivocal with regard to its efficacy. The aims of this clinical trial were to evaluate ketamine's antidepressive effects in ECT as a primary anesthetic, determine ketamine's tolerability when compared with standard anesthesia, and determine if plasma brain-derived neurotrophic factor (BDNF) is necessary for treatment response. Materials and Methods: Adults meeting criteria for treatment-resistant depression undergoing index course ECT received either methohexital (1 to 2 mg/kg) or ketamine (1 to 2 mg/kg) anesthesia in this dual-arm double-blinded randomized clinical trial (NCT02752724). The primary outcome of this study is change in depression questionnaire scores before and after ECT. Seizure data, depression severity using self-reported and clinician-assessed questionnaires, cognitive scoring, and plasma BDNF concentrations were obtained before and after completion of ECT. Results: There were no differences in seizure lengths, hemodynamics, or seizure stimuli between the ketamine (n=23;138 ECTs) and methohexital (n=27;159 ECTs) groups. Depression scores improved similarly after ECT in both groups. In the methohexital group, 15% of patients failed to achieve adequate seizures and were switched to ketamine and 26% were converted to bilateral ECT stimulus, whereas all ketamine patients achieved adequate seizures and only 4% required bilateral stimulus. Plasma BDNF increased after ECT only in the ketamine group. Conclusions: Our data show that ketamine does not significantly improve depression when compared with methohexital as a single induction agent for ECT, increases serum BDNF and does not increase rates of post-ECT agitation. Ketamine use in ECT may have some benefits for some patients that are not captured through standard depression assessment questionnaires alone. This work was supported in part by a Pilot Project Award #850 from the United States Department of Veterans Affairs. The content does not represent the views of the United States Department of Veterans Affairs or the United States Government. The sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The authors have no conflicts of interest to disclose. Address correspondence to: Charles William Carspecken, MD, MSc, MBA, Department of Anesthesiology and Critical Care, University of Pennsylvania, Hospital of the University of Pennsylvania, 3620 Hamilton Walk, Philadelphia, PA 19104 (e-mail: charles.carspecken@uphs.upenn.edu). Received March 2, 2018 Accepted April 23, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved

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Metastatic acral lentiginous melanoma in a tertiary referral center in Switzerland: a systematic analysis

Acral lentiginous melanoma (ALM) is a unique histopathological subtype of melanoma with a poorer prognosis than other cutaneous melanomas. This study aims to evaluate the clinicopathological characteristics, metastatic pattern, prognostic factors, response to systemic therapy, and overall survival (OS) of ALM in a White population. This is a retrospective study of patients who were diagnosed and/or treated for ALM at the Department of Dermatology of the University Hospital Zurich, Switzerland, from January 2005 to December 2015. Overall, 172 patients with histologically confirmed ALM were included in the study. In univariate Cox regression, Breslow thickness (P

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What Does a Red Meat Allergy Have to Do With Anesthesia? Perioperative Management of Alpha-Gal Syndrome

Over the past decade, there has been a growing awareness of a new allergic syndrome known as alpha-gal allergy or alpha-gal syndrome, commonly recognized as a red meat allergy. We performed a review of the literature to identify articles that provide both background on this syndrome in general and any reports of reactions to medications or medical devices related to alpha-gal syndrome. Alpha-gal syndrome results from IgE to the oligosaccharide galactose-α-1,3-galactose, expressed in the meat and tissues of noncatarrhine mammals. It is triggered by the bite of the lone star tick and has been implicated in immediate-onset hypersensitivity to the monoclonal antibody cetuximab and delayed-onset hypersensitivity reactions after the consumption of red meat. There is growing recognition of allergic reactions in these patients to other drugs and medical devices that contain alpha-gal. Many of these reactions result from inactive substances that are part of the manufacturing or preparation process such as gelatin or stearic acid. This allergy may be documented in a variety of ways or informally reported by the patient, requiring vigilance on the part of the anesthesiologist to detect this syndrome, given its serious implications. This allergy presents a number of unique challenges to the anesthesiologist, including proper identification of a patient with alpha-gal syndrome and selection of anesthetic and adjunctive medications that will not trigger this allergy. Accepted for publication April 16, 2018. Funding: Institutional and/or departmental. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to W. Jonathan Dunkman, MD, Department of Anesthesiology, Duke University Medical Center, Box 3094, Durham, NC 27710. Address e-mail to william.dunkman@duke.edu. © 2018 International Anesthesia Research Society

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Automated Assessment of Existing Patient’s Revised Cardiac Risk Index Using Algorithmic Software

BACKGROUND: Previous work in the field of medical informatics has shown that rules-based algorithms can be created to identify patients with various medical conditions; however, these techniques have not been compared to actual clinician notes nor has the ability to predict complications been tested. We hypothesize that a rules-based algorithm can successfully identify patients with the diseases in the Revised Cardiac Risk Index (RCRI). METHODS: Patients undergoing surgery at the University of California, Los Angeles Health System between April 1, 2013 and July 1, 2016 and who had at least 2 previous office visits were included. For each disease in the RCRI except renal failure—congestive heart failure, ischemic heart disease, cerebrovascular disease, and diabetes mellitus—diagnosis algorithms were created based on diagnostic and standard clinical treatment criteria. For each disease state, the prevalence of the disease as determined by the algorithm, International Classification of Disease (ICD) code, and anesthesiologist's preoperative note were determined. Additionally, 400 American Society of Anesthesiologists classes III and IV cases were randomly chosen for manual review by an anesthesiologist. The sensitivity, specificity, accuracy, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve were determined using the manual review as a gold standard. Last, the ability of the RCRI as calculated by each of the methods to predict in-hospital mortality was determined, and the time necessary to run the algorithms was calculated. RESULTS: A total of 64,151 patients met inclusion criteria for the study. In general, the incidence of definite or likely disease determined by the algorithms was higher than that detected by the anesthesiologist. Additionally, in all disease states, the prevalence of disease was always lowest for the ICD codes, followed by the preoperative note, followed by the algorithms. In the subset of patients for whom the records were manually reviewed, the algorithms were generally the most sensitive and the ICD codes the most specific. When computing the modified RCRI using each of the methods, the modified RCRI from the algorithms predicted in-hospital mortality with an area under the receiver operating characteristic curve of 0.70 (0.67–0.73), which compared to 0.70 (0.67–0.72) for ICD codes and 0.64 (0.61–0.67) for the preoperative note. On average, the algorithms took 12.64 ± 1.20 minutes to run on 1.4 million patients. CONCLUSIONS: Rules-based algorithms for disease in the RCRI can be created that perform with a similar discriminative ability as compared to physician notes and ICD codes but with significantly increased economies of scale. Accepted for publication March 5, 2018. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. I. S. Hofer and A. Mahajan are working with counsel to patent the algorithms for the diseases described in this article. Reprints will not be available from the authors. Address correspondence to Ira S. Hofer, MD, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at University of California, Los Angeles, 757 Westwood Plaza, Los Angeles, CA 90095. Address e-mail to ihofer@mednet.ucla.edu. © 2018 International Anesthesia Research Society

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Pain Medicine Board Review

No abstract available

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Assessing the Association Between Blood Loss and Postoperative Hemoglobin After Cesarean Delivery: A Prospective Study of 4 Blood Loss Measurement Modalities

BACKGROUND: Visual estimation and gravimetric methods are commonly used to quantify the volume of blood loss during cesarean delivery (CD). However, the correlation between blood loss and post-CD hemoglobin (Hb) is poorly studied, and it is unclear whether the correlation varies according to how blood loss is measured. METHODS: After obtaining Institutional Review Board approval, we performed a prospective study of 61 women undergoing CD to assess the relations between post-CD Hb and blood loss measured using 4 modalities: gravimetric blood loss measurement (gBL), visual blood loss estimation by a blinded obstetrician (oBL) and anesthesiologist (aBL), and the Triton System (tBL). Hb was measured preoperatively and within 10 minutes after CD. gBL was quantified as blood volume in a suction canister in addition to the weight of blood-soaked sponges. tBL was measured with the Triton System by photographing blood-soaked sponges and suction canister contents. To assess the relation between blood loss and post-CD Hb, we performed correlation analyses and compared the magnitude of the correlations across the 4 measurement modalities using William t test. A Bonferroni correction was set to identify a statistically significant correlation (P

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Phentolamine Reverses Epinephrine-Enhanced Skin Antinociception of Dibucaine in Rats

BACKGROUND: The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction between dibucaine and epinephrine, phentolamine, a nonselective α-adrenergic antagonist, was added to the mixture. METHODS: We assessed sensory blockade with these drugs by injecting 0.6 mL of drug-in-saline in the dorsal thoracolumbar area of rats; pinprick of the "wheal" formed by the injectate was the area targeted for stimulation to elicit a cutaneous trunci muscle reflex. The sensory block of dibucaine was compared with that of bupivacaine or epinephrine. Drug–drug interactions were analyzed by isobologram. Phentolamine was added to investigate the antinociceptive effect of dibucaine coinjected with epinephrine. RESULTS: We demonstrated that dibucaine, epinephrine, and bupivacaine produced dose-dependent skin antinociception. On the median effective dose (ED50) basis, the potency was higher for epinephrine (mean, 0.011 [95% confidence interval {CI}, 0.007–0.015] μmol) than for dibucaine (mean, 0.493 [95% CI, 0.435–0.560] μmol) (P

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Intraoperative Methadone in Same-Day Ambulatory Surgery: A Randomized, Double-Blinded, Dose-Finding Pilot Study

BACKGROUND: Approximately 50 million US patients undergo ambulatory surgery annually. Postoperative opioid overprescribing is problematic, yet many patients report inadequate pain relief. In major inpatient surgery, intraoperative single-dose methadone produces better analgesia and reduces opioid use compared with conventional repeated dosing of short-duration opioids. This investigation tested the hypothesis that in same-day ambulatory surgery, intraoperative methadone, compared with short-duration opioids, reduces opioid consumption and pain, and determined an effective intraoperative induction dose of methadone for same-day ambulatory surgery. METHODS: A double-blind, dose-escalation protocol randomized 60 patients (2:1) to intraoperative single-dose intravenous methadone (initially 0.1 then 0.15 mg/kg ideal body weight) or conventional as-needed dosing of short-duration opioids (eg, fentanyl, hydromorphone; controls). Intraoperative and postoperative opioid consumption, pain, and opioid side effects were assessed before discharge. Patient home diaries recorded pain, opioid use, and opioid side effects daily for 30 days postoperatively. Primary outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30 days opioid consumption, pain intensity, and opioid side effects. RESULTS: Median (interquartile range) methadone doses were 6 (5–6) and 9 (8–9) mg in the 0.1 and 0.15 mg/kg methadone groups, respectively. Total opioid consumption (morphine equivalents) in the postanesthesia care unit was significantly less compared with controls (9.3 mg, 1.3–11.0) in subjects receiving 0.15 mg/kg methadone (0.1 mg, 0.1–3.3; P

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Mixing Studies in Patients With Prolonged Activated Partial Thromboplastin Time or Prothrombin Time

BACKGROUND: Patients presenting for surgery may have isolated or combined prolonged activated partial thromboplastin time (aPTT) and/or prothrombin time (PT). In patients not receiving anticoagulants or with no identifiable cause for abnormal clot formation, a mixing study is performed. The index of circulating anticoagulant (ICA) has been used to predict the presence of an inhibitor, usually a lupus anticoagulant. METHODS: We retrospectively reviewed the results of mixing studies performed at Northwestern Memorial Hospital, between January 1, 2010 and February 29, 2012. We determined the number of samples that normalized or remained prolonged, the clotting factors associated with prolonged test results, and the presence of coagulation inhibitors. We calculated the ICA in the samples with prolonged aPTT and PT to determine its ability to predict a lupus anticoagulant. The primary comparison of interest was the diagnostic utility of the ICA at cutoff values of 11% for predicting the presence of lupus anticoagulant. RESULTS: There were 269 mixing studies performed: 131 samples with prolonged aPTT; 95 with prolonged PT; and 43 with both prolonged aPTT and prolonged PT. Of the samples with a prolonged aPTT, 55 of 131 (42%) normalized, 36 of 131 (27%) partially corrected, and 40 of 131 (31%) remained prolonged. Thirty-three of 95 samples (35%) with prolonged PT normalized, while 62 of 95 (65%) remained prolonged. Eight of 43 (19%) mixing studies of patients with prolonged PT and aPTT normalized; the aPTT normalized, but the PT remained prolonged in 17 of 43 (39%); the PT normalized, but the aPTT remained prolonged in 7 of 43 (16%); and both tests remained prolonged in 11 of 43 (26%) samples. Prolongations in the aPTT were primarily associated with low activities of CF XII, while the majority of the prolongations in PT were secondary to low activities in CF VII. Combined prolongations were secondary to deficiencies in both the intrinsic and extrinsic as well as the common pathways. An ICA >11% had 100% (95% CI, 59%–100%) sensitivity, 53% (95% CI, 35%–70%) specificity, and 77% (95% CI, 62%–92%) accuracy in predicting the presence of lupus anticoagulant in patients with prolonged aPTT. CONCLUSIONS: Normalization of the aPTT and PT in a mixing study was associated with low clotting factor activity. The ICA may be helpful in predicting the presence of a lupus anticoagulant. As anesthesiologists take ownership of the perioperative surgical home, we need to understand the clinical implications of the results of mixing studies. Accepted for publication April 12, 2018. Funding: Departmental. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Honorio T. Benzon, MD, Northwestern University Feinberg School of Medicine, 251 E Huron, Feinberg Pavilion, 5–704, Chicago, IL 60611. Address e-mail to h-benzon@northwestern.edu. © 2018 International Anesthesia Research Society

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Opening the Black Box: Understanding the Science Behind Big Data and Predictive Analytics

Big data, smart data, predictive analytics, and other similar terms are ubiquitous in the lay and scientific literature. However, despite the frequency of usage, these terms are often poorly understood, and evidence of their disruption to clinical care is hard to find. This article aims to address these issues by first defining and elucidating the term big data, exploring the ways in which modern medical data, both inside and outside the electronic medical record, meet the established definitions of big data. We then define the term smart data and discuss the transformations necessary to make big data into smart data. Finally, we examine the ways in which this transition from big to smart data will affect what we do in research, retrospective work, and ultimately patient care. Accepted for publication March 22, 2018. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Ira S. Hofer, MD, Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine at UCLA, 757 Westwood Plaza, Los Angeles, CA 90095. Address e-mail to ihofer@mednet.ucla.edu. © 2018 International Anesthesia Research Society

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Reversing Cholinergic Bronchoconstriction by Common Inotropic Agents: A Randomized Experimental Trial on Isolated Perfused Rat Lungs

BACKGROUND: The ability of inotropic agents to alter airway reactivity and lung tissue mechanics has not been compared in a well-controlled experimental model. Therefore, we compared the potential to alter lung tissue viscoelasticity and bronchodilator effects of commonly used inotropic agents in an isolated perfused rat lung model. METHODS: After achieving steady state lung perfusion, sustained bronchoconstriction was induced by acetylcholine (ACh). Isolated rat lungs were then randomly allocated to 6 groups treated with either saline vehicle (n = 8) or incremental concentrations of inotropes (adrenaline, n = 8; dopamine, n = 7; dobutamine, n = 7; milrinone, n = 8; or levosimendan, n = 6) added to the whole-blood perfusate. Airway resistance (Raw), lung tissue damping (G), and elastance were measured under baseline conditions, during steady-state ACh-induced constriction and for each inotrope dose. RESULTS: No change in Raw was observed after addition of the saline vehicle. Raw was significantly lower after addition of dopamine (maximum difference [95% CI] of 29 [12–46]% relative to the saline control, P = .004), levosimendan (58 [39–77]%, P

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The Effect of Labor Epidural Analgesia on Breastfeeding Outcomes: A Prospective Observational Cohort Study in a Mixed-Parity Cohort

BACKGROUND: The effect of labor epidural analgesia (LEA) on successful breastfeeding has been evaluated in several studies with divergent results. We hypothesized that LEA would not influence breastfeeding status 6 weeks postpartum in women who intended to breastfeed in an environment that encourages breastfeeding. METHODS: In this prospective observational cohort study, a total of 1204 women intending to breastfeed, delivering vaginally with or without LEA, were included; breastfeeding was recorded at 3 days and 6 weeks postpartum. Primary outcome was breastfeeding at 6 weeks, and the χ2 test was used for comparisons between women delivering with and without LEA, according to parity status and previous breastfeeding experience. Total epidural fentanyl dose and oxytocin use (yes/no) were recorded. A multivariable logistic regression was performed to assess factors affecting breastfeeding at 6 weeks. RESULTS: The overall breastfeeding rate at 6 weeks was 76.9%; it was significantly lower among women delivering with LEA (74.0%) compared with women delivering without LEA (83.4%; P

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Readiness for Discharge After Foot and Ankle Surgery Using Peripheral Nerve Blocks: A Randomized Controlled Trial Comparing Spinal and General Anesthesia as Supplements to Nerve Blocks

BACKGROUND: Neuraxial anesthesia is often viewed as superior to general anesthesia but may delay discharge. Comparisons do not typically use multimodal analgesics and nerve blockade. Combining nerve blockade with general anesthesia may reduce pain, opioid consumption, and nausea. We hypothesized that general anesthesia (with nerve blocks) would lead to earlier readiness for discharge, compared to spinal anesthesia (with nerve blocks). METHODS: All patients underwent ambulatory foot and ankle surgery, with a predicted case duration of 1–3 hours. All patients received popliteal and adductor canal nerve blocks using bupivacaine and dexamethasone. No intraoperative opioids were administered. All patients received ondansetron, dexamethasone, ketamine, and ketorolac. Patients, data collectors, and the data analyst were not informed of group assignment. Patients were randomized to spinal or general anesthesia with concealed allocation. Spinal anesthesia was performed with mepivacaine and accompanied with propofol sedation. After general anesthesia was induced with propofol, a laryngeal mask airway was inserted, followed by sevoflurane and propofol. Time until ready for discharge, the primary outcome, was compared between groups after adjusting for age and surgery time using multivariable unconditional quantile regression. Secondary outcomes compared at multiple timepoints were adjusted for multiple comparisons using the Holm–Bonferroni step-down procedure. RESULTS: General anesthesia patients were ready for discharge at a median of 39 minutes earlier (95% confidence interval, 2–75; P = .038) versus spinal anesthesia patients. Patients in both groups met readiness criteria for discharge substantially before actual discharge. Pain scores at rest were higher among general anesthesia patients 1 hour after leaving the operating room (adjusted difference in means, 2.1 [95% confidence interval, 1.0–3.2]; P

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In Response

No abstract available

https://ift.tt/2Jd4rWS

Opioid Use Disorders: Perioperative Management of a Special Population

Opioid-related overdose deaths have reached epidemic levels within the last decade. The efforts to prevent, identify, and treat opioid use disorders (OUDs) mostly focus on the outpatient setting. Despite their frequent overrepresentation, less is known about the inpatient management of patients with OUDs. Specifically, the perioperative phase is a very vulnerable time for patients with OUDs, and little has been studied on the optimal management of acute pain in these patients. The preoperative evaluation should aim to identify those with OUDs and assess factors that may interfere with OUD treatment and pain management. Efforts should be made to provide education and assistance to patients and their support systems. For those who are actively struggling with opioid use, the perioperative phase can be an opportunity for engagement and to initiate treatment. Buprenorphine, methadone, and naltrexone medication treatment for OUD and opioid tolerance complicate perioperative pain management. A multidisciplinary team approach is crucial to provide clinically balanced pain relief without jeopardizing the patient's recovery. This article reviews the existing literature on the perioperative management of patients with OUDs and provides clinical suggestions for the optimal care of this patient population. Accepted for publication March 22, 2018. Funding:None. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (https://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Emine Nalan Ward, MD, Department of Psychiatry, Massachusetts General Hospital, 16 Blossom St, Boston, MA 02114. Address e-mail to enward@partners.org. © 2018 International Anesthesia Research Society

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