Effects of insistent screening for contralateral patent processus vaginalis in laparoscopic percutaneous extraperitoneal closure to prevent metachronous contralateral onset of pediatric inguinal hernia

Abstract

Purpose

Laparoscopic percutaneous extraperitoneal closure (LPEC) is known to reduce the incidence of metachronous contralateral hernia (MCH) compared to conventional hernia repair. We herein describe the effects of insistent screening for an irregular orifice of the contralateral patent processus vaginalis (CPPV).

Methods

All patients who underwent LPEC between 2003 and 2013 were reviewed. We started insistent screening for a CPPV in July 2010. The surgically treated cases before June 2010 were assigned to the former group, while those treated after July 2010 were in the latter group. The data were retrospectively collected from medical records. The statistical analysis was performed using the Mann–Whitney U test or Chi square test. A value of P < 0.05 was considered to be significant.

Result

A total of 1113 patients (514 males and 599 females) ranging in age from 3 months old to 15 years old (median 4.6 years old), were reviewed. Of the 626 patients in the former group, a CPPV was detected in 227 patients. Of the 487 patients in the latter group, a CPPV was detected in 271 patients. The incidence of a CPPV significantly increased over time (P < 0.001). We encountered five cases of MCH, all of which belonged to the former group (P = 0.048).

Conclusions

The increased detection of a CPPV by insistent screening seemed to cause a decrease in the incidence of MCH.

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Beneficial effects of a cardiac support device on left ventricular remodeling after posterior myocardial infarction: an evaluation by echocardiography, pressure–volume curves and ventricular histology

Abstract

Purpose

Posterior myocardial infarction (MI) can induce LV remodeling and ischemic mitral regurgitation (IMR). The protective effects of a cardiac support device (CSD) against LV remodeling and IMR after posterior MI have been poorly documented.

Methods

Posterior MI was induced by ligation of the left circumflex coronary artery in beagle dogs. After 7 days, the dogs were randomized to a CSD placement (CSD group, n = 8) or no treatment (CTL group, n = 8).

Results

At 3 months after MI, the LV remodeling was less marked and the LV and RV systolic functions were better in the CSD group than in the CTL group. Neither the RV nor LV diastolic function (min dP/dt, Tau and EDPVR) was disturbed by the CSD. IMR was consistently prevented in our canine model.

Conclusion

Early application of a CSD after posterior MI can attenuate LV remodeling without causing any deterioration of the biventricular diastolic function.

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Comparisons of financial and short-term outcomes between laparoscopic and open hepatectomy: benefits for patients and hospitals

Abstract

Purposes

This retrospective analysis compared the cost outcomes for both patients and hospitals, as well as the short-term outcomes, for laparoscopic hepatectomy (LH) and open hepatectomy (OH).

Methods

The subjects comprised 70 patients who underwent LH or OH. The total hospital charge was calculated using the Japanese lump-sum payment system according to the diagnosis procedure combination.

Results

Of the 70 patients, 10 in the LH group and 16 in the OH group underwent primary single limited/anatomic resection or left lateral sectoriectomy. The operation time, blood loss, and postoperative complications did not differ significantly between the two groups. The median [range] time of inflow occlusion was significantly longer [120 (50–194) vs. 57 (17–151) min, P = 0.03] and the postoperative hospital stay was significantly shorter [5 (4–6) vs. 9 (5–12) days, P < 0.01] in the LH group than in the OH group, respectively. The mean ± standard deviation surgical costs (1307 ± 596 vs. 1054 ± 365 US$, P = 0.43) and total hospital charges (12046 ± 1174 vs. 11858 ± 2096 US$, P > 0.99) were similar in the LH and OH groups, respectively, although the charges per day were significantly higher in the LH group than in the OH group (1388 ± 217 vs. 1016 ± 134 US$, P < 0.01).

Conclusions

The costs to patients for LH are similar to those for OH. However, LH provides a financial advantage to hospitals due to a reduced hospital stay and comparable surgical costs.

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Correlation between histological invasiveness and the computed tomography value in pure ground-glass nodules

Abstract

Purpose

The purpose of this study was to evaluate the correlation between histological invasiveness and the computed tomography (CT) value and size in pure ground-glass nodules (GGNs) to determine optimal "follow-up or resection" strategies.

Methods

Between 2001 and 2014, 78 resected, pure GGNs were retrospectively evaluated. The maximum diameter and CT value of pure GGNs were measured using a computer graphics support system.

Results

All GGNs with a maximum diameter ≤10 mm and CT value ≤−600 Hounsfield units (HU) were considered to be noninvasive lesions, while 21 of 26 (81 %) with a maximum diameter >10 mm and CT value >−600 HU were considered to be invasive lesions. With respect to the correlation between each histological type and pure GGN with a maximum diameter ≤10 mm and CT value ≤−600 HU, the specificity was 90 % and the sensitivity and negative predictive value were both 100 % in atypical adenomatous hyperplasia (AAH), while the specificity was 58 % and the sensitivity and positive predictive value were 0 % in minimally invasive and invasive adenocarcinoma.

Conclusion

Pure GGNs with a maximum diameter of ≤10 mm and CT value of ≤−600 HU are nearly always pre-invasive lesions; therefore, surgery should be carefully selected in such patients.

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Endoscopic thyroidectomy using the EZ-VANS method

Abstract

Purpose

Several video-assisted and robotic surgery techniques have been reported for resection of the thyroid and parathyroid glands. Our institute has started performing endoscopic thyroidectomy using the Lap-protector and E·Z-access system, referred to as E·Z-access using video-assisted neck surgery (EZ-VANS). In this report, we evaluate the safety and efficacy of this technique.

Methods

From January 2007 to September 2014, 110 patients underwent resection of a primary thyroid tumor, 73 who underwent a cervical collar incision (the Open group) and 37 underwent EZ-VANS (the EZ-VANS group).

Results

The average operating time was 159 and 172 min in the Open group and EZ-VANS group, respectively; the amount of blood loss was 46.5 and 54.7 ml, respectively; and the length of hospital stay after surgery was 4.3 and 5.2 days, respectively, with no significant differences observed between the two groups. The learning curve for the EZ-VANS technique was shorter than for open surgery.

Conclusions

We confirmed that the EZ-VANS technique is a safe and useful method for resection of benign and early malignant thyroid tumors.

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Functional outcome assessment of swallowing (FOAMS) scoring and videofluoroscopic evaluation of perioperative swallowing rehabilitation in radical esophagectomy

Abstract

Purpose

Oropharyngeal swallowing dysfunction following esophagectomy has been associated with the surgical disruption of muscle strength and flexibility of the oropharyngeal structures. We assessed the value of perioperative swallowing rehabilitation (SR) in patients who underwent radical esophagectomy.

Methods

We instituted routine perioperative SR for patients with esophageal cancer and retrospectively compared postoperative swallowing function between the patients who received (n = 12) vs. those who did not receive (n = 14) SR.

Results

The average duration of pre- and postoperative SR was 23.0 and 26.0 days, respectively. Preoperatively, the functional outcome assessment of the swallowing (FOAMS) score was 7 (full marks) in all 26 patients, whereas the average score at hospital discharge was 6.3 vs. 5.5 in the patients who received vs. those who did not receive SR, respectively (p = 0.049). Videofluoroscopic examination (n = 12) demonstrated that the maximum superior excursion of hyoid bone increased significantly with preoperative SR (p = 0.030), as well as postoperative SR (p = 0.046). However, perioperative SR did not reduce the incidence of postoperative aspiration pneumonia or the duration of hospital stay.

Conclusions

Swallowing function after radical esophagectomy was improved by perioperative SR; however, further investigations are needed to assess the clinical significance of SR in reducing surgical complications.

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Reconstruction after proximal gastrectomy for gastric cancer in the upper third of the stomach: a review of the literature published from 2000 to 2014

Abstract

Proximal gastrectomy (PG) is occasionally performed to preserve the physiological function of the remnant stomach with the aim of maintaining a gastric reservoir for patients with early gastric cancer in the upper third of the stomach. Many reconstructive procedures after PG have been reported, including esophagogastrostomy (EG), jejunal interposition, jejunal pouch interposition, and double tract. However, no general agreement exists regarding the optimal reconstructive procedure. This article reviews the current reconstructive procedures available for PG. We examined the surgical outcomes, postoperative complications, endoscopic findings, and quality of life (QOL) according to the reconstructive procedures. We found no significant difference in anastomotic leakage and anastomotic stricture among the procedures. The frequency of reflux esophagitis was higher with simple EG compared with the other reconstructive procedures. Some additional procedures, such as fundoplication, the use of a narrow gastric conduit, and placement of a gastric tube in the lower mediastinum on EG, could decrease the frequency of reflux esophagitis and reflux symptoms. These additional procedures may improve the QOL; however, the previous studies were small and could not adequately compare the reconstructive procedures. Prospective randomized controlled trials that involve a longer trial period and more institutions are needed to clarify the optimal reconstructive procedures after PG.

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Mesenteric ischemia in acute aortic dissection

Abstract

Mesenteric ischemia complicated by acute aortic dissection (AAD) is uncommon, but serious, as there is no established treatment strategy and it can progress rapidly to multi-organ failure. Diagnosing mesenteric ischemia before necrotic change is difficult, not only for primary care physicians, but even for gastrointestinal or cardiovascular surgeons as it can occur at any time during surgery. Thus, measures need to be in place at the bedside to enable us to obtain information on visceral perfusion. It is often difficult to decide which of laparotomy or aortic repair should be performed first, especially when there is associated shock or malperfusion of other vital organs. The standard surgical procedures for mesenteric ischemia are prompt revascularization of the mesenteric artery and, if needed, resection of necrotic intestine. However, the development of endovascular treatment and the introduction of hybrid ORs have improved the treatment strategies for mesenteric ischemia. This article reviews the issues of "diagnosis" in relation to the mechanism of mesenteric ischemia, and discusses the current "treatment strategies".

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Akt is a downstream effector of Trop-2

Purpose: Inhibition of Akt is a key target area for personalized cancer medicine. However, predictive markers of response to Akt inhibitors are lacking. Correspondingly unclear remains the Akt-dependent chain of command for tumor growth, which will mediate Akt-dependent therapeutic responses. Experimental design: Proteomic profilingwas utilized to identify nodal hubs of the Trop-2 cancer growth-driving network. Kinase-specific inhibitors were used to dissect Trop-2-dependent from Trop-2-independent pathways. In vitro assays, in vivo preclinical models and case series of primary human breast cancers were utilized to define the mechanisms of Trop-2-driven growth and the mode of action of Trop-2-predicted Akt inhibitors. Results: Trop-2 and Akt expression was shown to be tightly coordinated in human breast cancers, with virtual overlap with Akt activation profiles at T308 and S473, consistent with functional interaction in vivo. Akt allosteric inhibitors were shown to only block the growth of Trop-2-expressing tumor cells, both in vitro and in preclinical models, being ineffective on Trop-2-null cells. Consistent, Akt-targeted siRNA only impacted on Trop-2-expressing cells. Lentiviral down-regulation of endogenous Trop-2 abolished tumor response to Akt blockade, indicating Trop-2 as a mandatory activator of Akt. Conclusion: Our findings indicate that the expression of Trop-2 is a stringent predictor of tumor response to Akt inhibitors. They also support the identification of target-activatory pathways, as efficient predictors of response in precision cancer therapy.

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New Strategy for Treating Advanced Ovarian Cancer Shows Promise in Mice

An experimental strategy for treating advanced ovarian cancer has caused tumor regression in animal models, according to a new study. The strategy uses a protein fragment, or peptide, to stimulate normal cells in the tissues surrounding cancer cells—the tumor microenvironment—to block the growth of the cancer cells.

Suming Wang, Ph.D., and Anna Blois, Ph.D., of Boston Children's Hospital's Vascular Biology Program and their colleagues, reported the results March 9 in Science Translational Medicine. Based on the findings, the researchers said they would continue to explore this strategy as a potential treatment for ovarian cancer that has spread to other parts of the body, or metastasized.

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Characteristics, rates, and trends of melanoma incidence among Hispanics in the USA

Abstract

Purpose

The purpose of this study is to describe the epidemiology of melanoma among Hispanics using data that cover nearly 100 % of the US population.

Methods

The study used population-based cancer incidence data from the National Program of Cancer Registries and the Surveillance, Epidemiology and End Results Program to examine melanoma incidence rates and trends among Hispanics by sex, age, race, histology, anatomic location, stage, and tumor thickness.

Results

From 2008 to 2012, 6,623 cases of melanoma were diagnosed among Hispanics. Rates were higher among males (4.6) than among females (4.0), but females younger than age 55 had higher rates than males. The most common histologic subtype was superficial spreading melanoma (23 %). Melanomas with poorer outcomes, such as nodular (NM) and acral lentiginous melanoma (ALM), were more common among males. Hispanic females had the highest proportion of melanoma on the lower limb and hip (33.7 %), while Hispanic males had the highest proportion on the trunk (29.9 %). Incidence rates for later-stage diagnosis and thicker tumors were significantly higher among Hispanic men than among women. Incidence rates decreased significantly during 2003–2012 (AAPC = −1.4).

Conclusions

Clinicians and public health practitioners will need to reach the growing Hispanic population in the USA with strategies for primary prevention and early diagnosis of melanoma. Results suggest Hispanics and providers need education to increase awareness about the characteristics of melanoma among Hispanics, including types that occur on non-sun-exposed areas (ALM and NM). Skin cancer prevention and awareness interventions targeting Hispanics should be culturally relevant.

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Pharmacology of SERD inhibitor in breast cancer models

Fulvestrant is an estrogen receptor (ER) antagonist administered to breast cancer patients by monthly intramuscular injection. Given its present limitations of dosing and route of administration, a more flexible orally available compound has been sought to pursue the potential benefits of this drug in patients with advanced metastatic disease. Here we report the identification and characterization of AZD9496, a non-steroidal small molecule inhibitor of ERα which is a potent and selective antagonist and down-regulator of ERα in vitro and in vivo in ER-positive models of breast cancer. Significant tumour growth inhibition was observed as low as 0.5 mg/kg dose in the estrogen-dependent MCF-7 xenograft model, where this effect was accompanied by a dose-dependent decrease in PR protein levels demonstrating potent antagonist activity. Combining AZD9496 with PI3K pathway and CDK4/6 inhibitors led to further growth inhibitory effects compared to monotherapy alone. Tumour regressions were also seen in a long-term estrogen-deprived breast model, where significant down-regulation of ERα protein was observed. AZD9496 bound and down-regulated clinically relevant ESR1 mutants in vitro and inhibited tumour growth in an ESR1-mutant patient-derived xenograft model that included a D538G mutation. Collectively, the pharmacological evidence showed that AZD9496 is an oral, non-steroidal, selective estrogen receptor antagonist and down-regulator in ER-positive breast cells that could provide meaningful benefit to ER-positive breast cancer patients. AZD9496 is currently being evaluated in a Phase 1 clinical trial. -

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AMPK Activation and Metabolic Reprogramming by Tamoxifen

Tamoxifen is the most widely used adjuvant chemotherapeutic for the treatment of estrogen receptor (ER) positive breast cancer, yet a large body of clinical and preclinical data indicates that tamoxifen can modulate multiple cellular processes independently of ER status. Here, we describe the ER-independent effects of tamoxifen on tumor metabolism. Using combined pharmacological and genetic knockout approaches, we demonstrate that tamoxifen inhibits oxygen consumption via inhibition of mitochondrial complex I, resulting in an increase in the AMP/ATP ratio and activation of the AMPK signaling pathway in vitro and in vivo. AMPK in turn promotes glycolysis, and alters fatty acid metabolism. We also show that tamoxifen-induced cytotoxicity is modulated by isoform-specific effects of AMPK signaling, in which AMPKα1 promotes cell death through inhibition of the mTOR pathway and translation. By using agents which concurrently target distinct adaptive responses to tamoxifen-mediated metabolic reprogramming, we demonstrate increased cytotoxicity through synergistic therapeutic approaches. Our results demonstrate novel metabolic perturbations by tamoxifen in tumor cells which can be exploited to expand the therapeutic potential of tamoxifen treatment beyond ER+ breast cancer.

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CD4+ T-cell help in therapeutic cancer vaccination

While showing promise, vaccination strategies to treat cancer require further optimization. Likely barriers to efficacy involve cancer-associated immunosuppression and peripheral tolerance, which limit the generation of effective vaccine-specific cytotoxic T lymphocytes (CTL). Since CD4+ T cells improve CTL responsiveness, next-generation vaccines include helper epitopes. Here we demonstrate in mice how CD4+ T cell help optimizes the CTL response to a clinically relevant DNA vaccine engineered to combat HPV-expressing tumors. Inclusion of tumor-unrelated helper epitopes greatly increased CTL priming, effector and memory T cell programming. CD4+ T cell help optimized the CTL response in all these aspects via CD27/CD70 co-stimulation. Notably, administration of an agonistic CD27 antibody could largely replace helper epitopes in promoting primary and memory CTL responses, acting directly on CD8+ T cells. CD27 agonism also improved efficacy of the vaccine without helper epitopes, more so than combined PD-1 and CTLA-4 blockade. Combining CD27 agonism with CTLA-4 blockade improved vaccine-induced CTL priming and tumor infiltration, but only combination with PD-1 blockade was effective at eradicating tumors, thereby fully recapitulating the effect of CD4+ T cell help on vaccine efficacy. PD-1 blockade alone did not affect CTL priming or tumor infiltration, so these results implied that it cooperated with CD4+ T cell help by alleviating immune suppression against CTL in the tumor. Helper epitope inclusion or CD27 agonism did not stimulate regulatory T cells and vaccine efficacy was also improved by CD27 agonism in presence of CD4+ T cell help. Our findings provide a preclinical rationale to apply CD27 agonist antibodies, either alone or combined with PD-1 blockade, to improve the therapeutic efficacy of cancer vaccines and immunotherapy generally.

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PTP1B is a diet-dependent tumor suppressor in Pten-null PCa

Diet affects the risk and progression of prostate cancer (PCa), but the interplay between diet and genetic alterations in this disease is not understood. Here we present genetic evidence in the mouse showing that PCa progression driven by loss of the tumor suppressor Pten is mainly unresponsive to a high fat diet (HFD), but that coordinate loss of the protein tyrosine phosphatase Ptpn1 (PTP1B in human) enables a highly invasive disease. PCa in Pten-/-Ptpn1-/- mice was characterized by increased cell proliferation and Akt activation, interpreted to reflect a heightened sensitivity to IGF-1 stimulation upon HFD feeding. Prostate-specific overexpression of PTP1B was not sufficient to initiate PCa, arguing that it acted as a diet-dependent modifier of prostate cancer development in Pten-/- mice. Our findings offer a preclinical rationale to investigate the anticancer effects of PTP1B inhibitors currently being studied clinically for diabetes treatment as a new modality for management of prostate cancer.

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Genetic Nrf2 activation in chemical lung carcinogenesis

Nrf2 activation promotes resistance to chemical carcinogenesis in animal models, but activating mutations in Nrf2 also confer malignant characters to human cells by activating anti-oxidative/detoxifying enzymes and metabolic reprogramming. In this study, we examined how these contradictory activities of Nrf2 - cancer chemoprevention and cancer cell growth enhancement - can be reconciled in an established mouse model of urethane-induced lung carcinogenesis. Using Keap1-knockdown (kd) mice which express high levels of Nrf2, we found that urethane was rapidly excreted into the urine, consistent with an upregulation in the expression of urethane detoxification genes. Consequently, urethane-induced tumors were significantly smaller and less frequent in Keap1-kd mice than in wild-type mice. In contrast, tumor cells derived from Keap1-kd mice and transplanted into nude mice exhibited higher tumorigenicity compared with cells derived from wild-type mice. To identify the factors contributing to the tumor growth phenotype in the transplantation model, we performed a microarray analysis and found that many antioxidative stress genes were upregulated in the Keap1-kd-derived tumors. Therefore, we suggest that Nrf2 activation in cancer cells enhances their tumorigenicity, but global Nrf2 activation, as in Keap1-kd mice, simultaneously enhances anticancer immunity, thereby suppressing the growth potential of Keap1-kd tumors. Our findings provide relevant insight into the dual role of Nrf2 in cancer and warrant further studies of Nrf2 function during different stages of carcinogenesis.

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Early Adaption and Acquired Palbociclib Resistance

Small-molecule inhibitors of the CDK4/6 cell-cycle kinases have shown clinical efficacy in estrogen receptor (ER)-positive metastatic breast cancer, although their cytostatic effects are limited by primary and acquired resistance. Here we report that ER-positive breast cancer cells can adapt quickly to CDK4/6 inhibition and evade cytostasis, in part, via noncanonical cyclin D1-CDK2–mediated S-phase entry. This adaptation was prevented by cotreatment with hormone therapies or PI3K inhibitors, which reduced the levels of cyclin D1 (CCND1) and other G1–S cyclins, abolished pRb phosphorylation, and inhibited activation of S-phase transcriptional programs. Combined targeting of both CDK4/6 and PI3K triggered cancer cell apoptosis in vitro and in patient-derived tumor xenograft (PDX) models, resulting in tumor regression and improved disease control. Furthermore, a triple combination of endocrine therapy, CDK4/6, and PI3K inhibition was more effective than paired combinations, provoking rapid tumor regressions in a PDX model. Mechanistic investigations showed that acquired resistance to CDK4/6 inhibition resulted from bypass of cyclin D1–CDK4/6 dependency through selection of CCNE1 amplification or RB1 loss. Notably, although PI3K inhibitors could prevent resistance to CDK4/6 inhibitors, they failed to resensitize cells once resistance had been acquired. However, we found that cells acquiring resistance to CDK4/6 inhibitors due to CCNE1 amplification could be resensitized by targeting CDK2. Overall, our results illustrate convergent mechanisms of early adaptation and acquired resistance to CDK4/6 inhibitors that enable alternate means of S-phase entry, highlighting strategies to prevent the acquisition of therapeutic resistance to these agents. Cancer Res; 1–13. ©2016 AACR.

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miR-29b/HDAC4 epigenetic loop in multiple myeloma

Epigenetic abnormalities are common in hematologic malignancies, including multiple myeloma (MM), and their effects can be efficiently counteracted by a class of tumor suppressor microRNAs, named epi-miRNAs. Given the oncogenic role of histone deacetylases (HDACs) in MM, we investigated if their activity could be antagonized by miR-29b, a well-established epi-miRNA. We demonstrated here that miR-29b specifically targets HDAC4 and we highlighted that both molecules are involved in a functional loop. In fact, silencing of HDAC4 by shRNAs inhibited MM cell survival and migration and triggered apoptosis and autophagy, along with induction of miR-29b expression by promoter hyperacetylation, leading to downregulation of pro-survival miR-29b targets (SP1, MCL-1). Moreover, treatment with the pan-HDAC inhibitor SAHA upregulated miR-29b, overcoming the negative control exerted by HDAC4. Importantly, overexpression or inhibition of miR-29b respectively potentiated or antagonized SAHA activity on MM cells, as also shown in vivo by a strong synergism between miR-29b synthetic mimics and SAHA in a murine xenograft model of human MM. Altogether, our results shed light on a novel epigenetic circuitry regulating MM cell growth and survival, and open new avenues for miR-29b-based epi-therapeutic approaches in the treatment of this malignancy.

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Awareness of Undergraduate Dental and Medical Students Towards Oral Cancer

Abstract

Oral cancer is a common malignancy in Nepal and many other South East Asian countries, which is predisposed by a variety of potentially malignant oral diseases. Considering the importance of knowledge of health professionals and their role in early diagnosis and reduction of cancer statistics, this study aims to evaluate the awareness of undergraduate dental and medical students towards oral cancer. The study involved undergraduate dental and medical students of BP Koirala Institute of Health Sciences, Nepal. A self-administered questionnaire adapted from Carter to Ogden was distributed. One hundred forty-three dental and 311 medical students responded to the questionnaire. Significantly more dental (80.4 %) than medical students (36.0 %) were found to routinely examine the oral mucosa. Tobacco smoking and chewing were the most commonly recognized risk factors by both medical and dental students. Most of the students found ulcer as the common change associated with oral cancer. Only 30 out of the total students felt very well informed about oral cancer. This study has demonstrated a lack of awareness in some aspects of oral cancer among medical and dental students which highlights the need to frame new teaching methodologies. Similar studies from other health institutions would provide an insight regarding the same and could be a base for formulating a uniform curriculum in the implementation of knowledge regarding oral cancer.

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In Memoriam—Richard F. Bakemeier, MD, MSc

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Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma

Abstract

Background

Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10–15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.

Materials and Methods

Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.

Results

Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.

Discussion

Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential.

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Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model

Abstract

Fibroblast activation protein α (FAPα) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAPα. This vaccine successfully reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses which could kill CAFs, and the decrease in FAPα-expressing CAFs resulted in markedly attenuated expression of collagen I and other stromal factors that benefit the tumor progression. Based on these results, a DNA vaccine targeting human FAPα may be an attractive and effective cancer immunotherapy strategy.

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Mmu-miR-125b overexpression suppresses NO production in activated macrophages by targeting eEF2K and CCNA2

Abstract

Background

MicroRNAs have been shown to be important regulators of the immune response and the development of the immune system. It was reported that microRNA-125b (miR-125b) was down-regulated in macrophages challenged with endotoxin. However, little is known about the function and mechanism of action of miR-125b in macrophage activation. Macrophages use L-arginine to synthesize nitric oxide (NO) through inducible NO synthase (iNOS), and the released NO contributes to the tumoricidal activity of macrophages.

Methods

Luciferase reporter assays were employed to validate regulation of a putative target of miR-125b. The effect of miR-125b on endogenous levels of this target were subsequently confirmed via Western blot. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to determine the expression level of miR-125b in macrophage. MTS assays were conducted to explore the impact of miR-125b overexpression on the cell viability of 4T1 cells.

Results

Here, we demonstrate that mmu-miR-125b overexpression suppresses NO production in activated macrophages and that LPS-activated macrophages with overexpressed mmu-miR-125b promote 4T1 tumor cell proliferation in vitro and 4T1 tumor growth in vivo. CCNA2 and eEF2K are the direct and functional targets of mmu-miR-125b in macrophages; CCNA2 and eEF2K expression was knocked down, which mimicked the mmu-miR-125b overexpression phenotype.

Conclusions

These data suggest that mmu-miR-125b decreases NO production in activated macrophages at least partially by suppressing eEF2K and CCNA2 expression.

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Antitumor effects of cecropin B-LHRH’ on drug-resistant ovarian and endometrial cancer cells

Abstract

Background

Luteinizing hormone-releasing hormone receptor (LHRHr) represents a promising therapeutic target for treating sex hormone-dependent tumors. We coupled cecropin B, an antimicrobial peptide, to LHRH', a form of LHRH modified at carboxyl-terminal residues 4–10, which binds to LHRHr without interfering with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. This study aimed to assess the antitumor effects of cecropin B-LHRH' (CB-LHRH') in drug-resistant ovarian and endometrial cancers.

Methods

To evaluate the antitumor effects of CB-LHRH', three drug resistant ovarian cancer cell lines (SKOV-3, ES-2, NIH:OVCAR-3) and an endometrial cancer cell line (HEC-1A) were treated with CB-LHRH'. Cell morphology changes were assessed using inverted and electron microscopes. In addition, cell growth and cell cytotoxicity were measured by MTT assay and LDH release, respectively. In addition, hemolysis was measured. Furthermore, radioligand receptor binding, hypersensitization and minimal inhibitory concentrations (against Staphylococcus aureus, Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, and Acinetobacter baumannii) were determined. Finally, the impact on tumor growth in BALB/c-nu mice was assessed in an ES-2 xenograft model.

Results

CB-LHRH' bound LHRHr with high-affinity (dissociation constant, Kd = 0.252 ± 0.061nM). Interestingly, CB-LHRH' significantly inhibited the cell viability of SKOV-3, ES-2, NIH:OVCAR-3 and HEC-1A, but not that of normal eukaryotic cells. CB-LHRH' was active against bacteria at micromolar concentrations, and caused no hypersensitivity in guinea pigs. Furthermore, CB-LHRH' inhibited tumor growth with a 23.8 and 20.4 % reduction in tumor weight at 50 and 25 mg/kg.d, respectively.

Conclusions

CB-LHRH' is a candidate for targeted chemotherapy against ovarian and endometrial cancers.

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Tumour infiltrating lymphocytes correlate with improved survival in patients with oesophageal adenocarcinoma

Abstract

Background

Oesophageal adenocarcinoma (OAC) is increasingly common in the west, and survival remains poor at 10–15 % at 5 years. Immune responses are increasingly implicated as a determining factor of tumour progression. The ability of lymphocytes to recognise tumour antigens provides a mechanism for a host immune attack against cancer providing a potential treatment strategy.

Materials and Methods

Tumour infiltrating lymphocytes (TILs: CD3+, CD4+, CD8+ and FOXp3+) were assessed by immunohistochemistry using tissue microarrays in a contemporary and homogeneous cohort of OAC patients (n = 128) undergoing curative treatment.

Results

Multivariate analysis identified three independent prognostic factors for improved cancer-specific survival (CSS): increased CD8+ TILs (p = 0.003), completeness of resection (p < 0.0001) and lower pathological N stage (p < 0.0001). Independent prognostic factors for favourable disease-free survival included surgery-only treatment (p = 0.015), completeness of resection (p = 0.001), increased CD8+ TILs (p < 0.0001) and reduced pathological N stage (p < 0.0001). Higher levels of TILs in the pathological specimen were associated with significant pathological response to neoadjuvant chemotherapy (NAC). On multivariate analysis increased levels of CD4+ (p = 0.017) and CD8+ TILs (p = 0.005) were associated with significant local tumour regression and lymph node downstaging, respectively.

Discussion

Our results establish an association of TILs and survival in OAC, as seen in other solid tumours, and identify particular TIL subsets that are present at higher levels in patients who responded to NAC compared to non-responders. These findings highlight potential therapeutic strategies in EAC based on utilising the host immunological response and highlight the immune responses biomarker potential.

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Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model

Abstract

Fibroblast activation protein α (FAPα) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAPα. This vaccine successfully reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses which could kill CAFs, and the decrease in FAPα-expressing CAFs resulted in markedly attenuated expression of collagen I and other stromal factors that benefit the tumor progression. Based on these results, a DNA vaccine targeting human FAPα may be an attractive and effective cancer immunotherapy strategy.

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Progression and metastasis of lung cancer

Abstract

Metastasis in lung cancer is a multifaceted process. In this review, we will dissect the process in several isolated steps such as angiogenesis, hypoxia, circulation, and establishment of a metastatic focus. In reality, several of these processes overlap and occur even simultaneously, but such a presentation would be unreadable. Metastasis requires cell migration toward higher oxygen tension, which is based on changing the structure of the cell (epithelial-mesenchymal transition), orientation within the stroma and stroma interaction, and communication with the immune system to avoid attack. Once in the blood stream, cells have to survive trapping by the coagulation system, to survive shear stress in small blood vessels, and to find the right location for extravasation. Once outside in the metastatic locus, tumor cells have to learn the communication with the "foreign" stroma cells to establish vascular supply and again express molecules, which induce immune tolerance.

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A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer

BACKGROUND

The mammalian target of rapamycin (mTOR) pathway is up-regulated in castration-resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up-regulation of the androgen receptor (AR) pathway.

METHODS

Patients who were eligible for this study had to have progressive CRPC with serum testosterone levels <50 ng/dL. No prior bicalutamide (except to prevent flare) or everolimus was allowed. Treatment included oral bicalutamide 50 mg and oral everolimus 10 mg, both once daily, with a cycle defined as 4 weeks. The primary endpoint was the prostate-specific antigen (PSA) response (≥30% reduction) from baseline. A sample size of 23 patients would have power of 0.8 and an α error of .05 (1-sided) if the combination had a PSA response rate of 50% versus a historic rate of 25% with bicalutamide alone.

RESULTS

Twenty-four patients were enrolled. The mean age was 71.1 years (range, 53.0-87.0 years), the mean PSA level at study entry was 43.4 ng/dL (range, 2.5-556.9 ng/dL), and the mean length of treatment was 8 cycles (range, 1.0-23.0 cycles). Of 24 patients, 18 had a PSA response (75%; 95% confidence interval [CI], 0.53-0.90), whereas 15 (62.5%; 95% CI, 0.41-0.81) had a PSA decrease ≥50%. The median overall survival was 28 months (95% CI, 14.1-42.7 months). Fourteen patients (54%; 95% CI, 0.37-0.78) developed grade 3 (13 patients) or grade 4 (1 patient with sepsis) adverse events that were attributable to treatment.

CONCLUSIONS

The combination of bicalutamide and everolimus has encouraging efficacy in men with bicalutamide-naive CRPC, thus warranting further investigation. A substantial number of patients experienced everolimus-related toxicity. Cancer 2016. © 2016 American Cancer Society.

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Genetic testing for Lynch syndrome in the province of Ontario

BACKGROUND

In November 2001, genetic testing for Lynch syndrome (LS) was introduced by the Ministry of Health and Long-Term Care (MOH) in Ontario for individuals at high risk for LS cancers according to either tumor immunohistochemistry staining or their family history. This article describes the outcomes of the program and makes recommendations for improving it and informing other public health care programs.

METHODS

Subjects were referred for molecular testing of the mismatch repair (MMR) genes MutL homolog 1, MutS homolog 2, and MutS homolog 6 if they met 1 of 7 MOH criteria. Testing was conducted from January 2001 to March 2015 at the Molecular Diagnostic Laboratory of Mount Sinai Hospital in Toronto.

RESULTS

A total of 1452 subjects were tested. Of the 662 subjects referred for testing because their tumor was immunodeficient for 1 or more of the MMR genes, 251 (37.9%) carried a germline mutation. In addition, 597 subjects were tested for a known family mutation, and 298 (49.9%) were positive; 189 of these 298 subjects (63.4%) were affected with cancer at the time of testing. An additional 193 subjects were referred because of a family history of LS, and 34 of these (17.6%) had a mutation identified.

CONCLUSIONS

These results indicate that the provincial criteria are useful in identifying LS carriers after an MMR-deficient tumor is identified. Placing greater emphasis on testing unaffected relatives in families with a known mutation may identify more unaffected carriers and facilitate primary prevention in those individuals. Cancer 2016. © 2016 American Cancer Society.

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Treatment trends and survival effects of chemotherapy for hypopharyngeal cancer: Analysis of the National Cancer Data Base

BACKGROUND

The current study was performed to characterize trends and survival outcomes for chemotherapy in the definitive and adjuvant treatment of hypopharyngeal cancer in the United States.

METHODS

A total of 16,248 adult patients diagnosed with primary hypopharyngeal cancer without distant metastases between 1998 and 2011 were identified in the National Cancer Data Base. The association between treatment modality and overall survival was analyzed using Kaplan-Meier survival curves and 5-year survival rates. A multivariate Cox regression analysis was performed on a subset of 3357 cases to determine the treatment modalities that predict improved survival when controlling for demographic and clinical factors.

RESULTS

There was a significant increase in the use of chemotherapy with radiotherapy both as definitive treatment (P<.001) and as adjuvant chemoradiotherapy with surgery (P=.001). This was accompanied by a decrease in total laryngectomy/pharyngectomy rates (P<.001). Chemoradiotherapy was associated with improved 5-year survival compared with radiotherapy alone in the definitive setting (31.8% vs 25.2%; log rank P<.001). Similarly, in multivariateanalysis, definitive radiotherapy was found to be associated with compromised survival compared with definitive chemoradiotherapy (hazard ratio, 1.51; P<.001).

CONCLUSIONS

Survival analysis revealed that overall 5-year survival rates were higher for chemoradiotherapy compared with radiotherapy alone in the definitive setting, but were comparable between surgery with chemoradiotherapy and surgery with radiotherapy. Cancer 2016. © 2016 American Cancer Society.

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Cognitive testing of tobacco use items for administration to patients with cancer and cancer survivors in clinical research

BACKGROUND

To the authors' knowledge, there are currently no standardized measures of tobacco use and secondhand smoke exposure in patients diagnosed with cancer, and this gap hinders the conduct of studies examining the impact of tobacco on cancer treatment outcomes. The objective of the current study was to evaluate and refine questionnaire items proposed by an expert task force to assess tobacco use.

METHODS

Trained interviewers conducted cognitive testing with cancer patients aged ≥21 years with a history of tobacco use and a cancer diagnosis of any stage and organ site who were recruited at the National Institutes of Health Clinical Center in Bethesda, Maryland. Iterative rounds of testing and item modification were conducted to identify and resolve cognitive issues (comprehension, memory retrieval, decision/judgment, and response mapping) and instrument navigation issues until no items warranted further significant modification.

RESULTS

Thirty participants (6 current cigarette smokers, 1 current cigar smoker, and 23 former cigarette smokers) were enrolled from September 2014 to February 2015. The majority of items functioned well. However, qualitative testing identified wording ambiguities related to cancer diagnosis and treatment trajectory, such as "treatment" and "surgery"; difficulties with lifetime recall; errors in estimating quantities; and difficulties with instrument navigation. Revisions to item wording, format, order, response options, and instructions resulted in a questionnaire that demonstrated navigational ease as well as good question comprehension and response accuracy.

CONCLUSIONS

The Cancer Patient Tobacco Use Questionnaire (C-TUQ) can be used as a standardized item set to accelerate the investigation of tobacco use in the cancer setting. Cancer 2016. © 2016 American Cancer Society.

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Radiation therapy (with or without neck surgery) for phenotypic human papillomavirus–associated oropharyngeal cancer

BACKGROUND

Favorable outcomes for human papillomavirus–associated oropharyngeal cancer have led to interest in identifying a subgroup of patients with the lowest risk of disease recurrence after therapy. De-intensification of therapy for this group may result in survival outcomes that are similar to those associated with current therapy but with less toxicity. To advance this effort, this study analyzed the outcomes of oropharyngeal cancer patients treated with or without systemic therapy.

METHODS

This was a retrospective study of patients with oropharyngeal cancer treated between 1985 and 2012. The criteria for inclusion were ≤10 pack-years of cigarette smoking and stage III/IVA cancer limited to T1-3, N1-N2b, and T3N0 disease. A survival analysis was performed with the primary endpoint of progression-free survival (PFS).

RESULTS

The cohort included 857 patients. Systemic therapy was given to 439 patients (51%). The median survival was 80 months. The 2-year PFS rate was 91%. When the analysis was limited to 324 patients irradiated without systemic therapy, the 2- and 5-year PFS rates were 90% and 85%, respectively. Furthermore, for these 324 patients, the 5-year PFS rates for T1, T2, and T3 disease were 90%, 83%, and 70%, respectively. The 5-year PFS rate for patients treated with systemic therapy for T3 disease was 77% (P = .07).

CONCLUSIONS

According to the low-risk definition currently established in cooperative trials, the patients had a 2-year PFS rate approximating 90%. When patients who were treated with radiation alone were evaluated, no compromise was observed in this high rate of PFS, which is higher than the 2-year PFS thresholds used in current cooperative trials. Cancer 2016. © 2016 American Cancer Society.

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Long-term follow-up of patients with acute myeloid leukemia surviving and free of disease recurrence for at least 2 years after autologous stem cell transplantation: A report from the acute leukemia working party of the European Society for Blood and Marrow Transplantation

BACKGROUND

Leukemia recurrence is a major cause of treatment failure after autologous stem cell transplantation for acute myeloid leukemia (AML). It usually occurs within the first 2 years after transplantation. The goal of the current retrospective study was to assess the follow-up of and characterize risk factors for outcome among patients who survived free of disease recurrence after this period.

METHODS

The analysis included 3567 adults (median age, 45 years) with AML who underwent autografting during the first (86% of patients) or second (14% of patients) complete remission between 1990 and 2008. The stem cell source was the bone marrow in 32% of patients or the peripheral blood in 68% of patients. The median follow-up was 6.9 years.

RESULTS

At 5 years and 10 years after transplantation, the probability of leukemia-free survival was 86% and 76%, respectively; the recurrence incidence was 11% and 16%, respectively; and the nonrecurrence mortality rate was 3% and 8%, respectively. The observed survival was decreased compared with the expected survival of the general European population. In a multivariate analysis, decreased probability of leukemia-free survival was demonstrated for patients who underwent peripheral blood autologous stem cell transplantation; had French-American-British subtypes M0, M6, or M7; and were of an older age. The same factors were found to be associated with an increased risk of disease recurrence. Nonrecurrence mortality was found to be affected by older age.

CONCLUSIONS

The results of the current analysis indicate that late recurrences remain a major concern after autologous stem cell transplantation among patients with AML, indicating the need for close monitoring of minimal residual disease and additional leukemic control measures after transplantation. Cancer 2016. © 2016 American Cancer Society.

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Contract research organizations in oncology clinical research: Challenges and opportunities

Contract research organizations (CROs) represent a multibillion dollar industry that is firmly embedded in the contemporary clinical trial process. Over the past 30 years, and especially within the last decade, the reach of CROs has extended to service all phases of drug trials in an increasingly global research environment. The presence of CROs is particularly noticeable in medical oncology because of the large number of investigational compounds developed to treat cancer that are currently undergoing testing in human subjects. Although limited data are available with which to objectively define the effects that CROs have had on the clinical trial process, with the expansion of these organizations, several reports have called into question whether ethical and professional standards in research conduct are at times secondary to economic considerations. CROs can add considerable value to the clinical trial process, but difficulty communicating with CRO representatives and time spent answering trivial data queries generated by CROs are current obstacles for study site personnel interacting with CROs. Further study of the effect of the CRO industry on the clinical trial process is needed to ensure efficient data collection and patient safety while collaboratively developing novel therapies in an expedited fashion. Cancer 2016. © 2016 American Cancer Society.

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Intratumoral heterogeneity: Role of differentiation in a potentially lethal phenotype of testicular cancer

BACKGROUND

Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype.

METHODS

In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations.

RESULTS

Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected.

CONCLUSIONS

The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016. © 2016 American Cancer Society.

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The cytomorphological features of low-grade urothelial neoplasms vary by specimen type

BACKGROUND

Urinary tract (UT) cytology has been used successfully to diagnose high-grade urothelial carcinoma but is reported to have poor sensitivity for low-grade urothelial neoplasms (LGUNs). However, the literature has shown that LGUN may be associated with atypical findings in UT specimens. The authors determined which features were most commonly observed, and whether the method of specimen procurement had an effect.

METHODS

A total of 326 specimens were identified over an 8-year period. One hundred fifty-three specimens were reviewed and graded for cellularity, number of tissue fragments (TFs), degeneration, inflammation, hyperchromasia, nuclear pleomorphism, nuclear border irregularity, nuclear size, cytoplasmic tails, nuclear eccentricity, and high-grade features.

RESULTS

Of the 153 specimens, 86 specimens (56.2%) demonstrated cellular atypia; of those, 51.2% were voided urine (VU) and 31.4% were UT washing (UW) specimens. The majority of specimens had many cells (46.5%), many single cells (44.2%), few to moderate TFs (46.5% and 27.9%, respectively), mild hyperchromasia (52.3%), mild nuclear pleomorphism (51.2%), mild nuclear border irregularity (60.5%), cytoplasmic tails (51.2%), and few to moderate eccentric nuclei (37.2% and 36.1%, respectively). The presence of TFs, cytoplasmic tails, and eccentric and enlarged nuclei were significantly more common in UW versus VU specimens (P = .036, .012, .014, and .027, respectively) and in UW versus benign UW controls (P = .001, .002, .002, and .003, respectively).

CONCLUSIONS

Approximately 50% of UT specimens with LGUN on follow-up demonstrated atypical features. Based on comparison with benign UW controls, TFs, cytoplasmic tails, nuclear eccentricity, and enlarged nuclei were more pronounced in neoplastic UW than VU specimens, suggesting that the method of urine specimen procurement affects the presence of certain low-grade features. Cancer Cytopathol 2016. © 2016 American Cancer Society.

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Comparison of dose distributions with TG-43 and collapsed cone convolution algorithms applied to accelerated partial breast irradiation patient plans

Publication date: Available online 28 March 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Sara L. Thrower, Simona F. Shaitelman, Elizabeth Bloom, Mohammad Salehpour, Kent Gifford
Purpose/ObjectiveBrachytherapy dose calculation algorithms that account for heterogeneous patient geometries have recently become commercially available. However, a retrospective comparison of the new collapsed cone convolution (CCC) with the current standard on a large cohort of patients treated with either a Strut-Adjusted Volume Implant (SAVI) or Contura® balloon device has not yet been completed. We compared the treatment plans for accelerated partial breast irradiation calculated by the new commercially available CCC and current standard TG-43-based algorithms for 50 patients treated at our institution with either a SAVI or Contura® device.Methods and MaterialsWe recalculated target coverage, volume of highly dosed normal tissue, and dose to organs at risk (ribs, skin, and lung) with each algorithm. For one case, an artificial air pocket was added to simulate 10% nonconformance. We performed a Wilcoxon signed rank test to determine the median differences in the clinical indices V90, V95, V100, V150, V200, and highest-dosed 0.1 cc and 1.0 cc of rib, skin, and lung between the two algorithms.ResultsThe CCC algorithm calculated lower values on average for all dose-volume histogram parameters. Across the entire patient cohort, the median difference in the clinical indices calculated by the two algorithms was < 10% for dose to organs at risk, < 5% for target volume coverage (V90, V95, and V100), and < 4 cc for dose to normal breast tissue (V150 and V200). No discernable difference was seen in the non conformance case.ConclusionsWe found that on average over our patient population CCC calculated (<10%) lower doses than TG-43. These results should inform clinicians as they prepare for the transition to heterogeneous dose calculation algorithms and determine if clinical tolerance limits warrant modification.

Teaser

We conducted a retrospective analysis of 50 brachytherapy accelerated partial breast irradiation patient plans comparing the dose distributions calculated by TG-43 and the collapsed cone convolution (CCC) algorithms. We found that the planning target volume coverage (V90, V95, and V100) differed < 5%, dose to organs at risk differed < 10%, and volume of highly-dosed normal tissue (V150,V200) differed < 4cc between algorithms. On average, the CCC algorithm calculated lower doses than the TG-43 algorithm.


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IDEAL-CRT: A phase I/II trial of isotoxic dose-escalated radiotherapy and concurrent chemotherapy in patients with stage II/III non-small cell lung cancer

Publication date: Available online 28 March 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): David B. Landau, Laura Hughes, Angela Baker, Andrew T. Bates, Michael C. Bayne, Nicholas Counsell, Ange Garcia-Alonso, Susan V. Harden, Jonathan D. Hicks, Simon R. Hughes, Marianne C. Illsley, Iftekhar Khan, Virginia Laurence, Zafar Malik, Helen Mayles, William PM. Mayles, Elizabeth Miles, Nazia Mohammed, Yenting Ngai, Emma Parsons, James Spicer, Paula Wells, Dean Wilkinson, John D. Fenwick
Backgroundand Purpose: Toxicity and early efficacy data are presented for IDEAL-CRT, a trial of an escalated, concurrent chemoradiotherapy schedule for advanced stage non-small cell lung cancer (NSCLC). Tumor dose-per-fraction-escalation was used in IDEAL-CRT to achieve therapy intensification without prolongation, and tumor doses were prescribed isotoxically to maximum levels consistent with normal tissue dose constraints.Patients and MethodsPatients received tumor doses of 63-73Gy in 30 once-daily fractions over 6 weeks with two concurrent cycles of cisplatin and vinorelbine. They were assigned to one of two groups according to esophageal dose. In Group 1, tumor doses were determined by an experimental constraint on maximum esophageal dose which was escalated following a 6+6 design from 65Gy through 68Gy to 71Gy, allowing an esophageal maximum tolerated dose (MTD) to be determined from early and late toxicities. Tumor doses for Group 2 patients were determined by other tissue constraints, often lung. Overall survival (OS), progression-free survival (PFS), tumor response and toxicity were evaluated for both groups combined.ResultsEight centres recruited 84 patients: 13, 12 and 10 in the 65Gy, 68Gy and 71Gy cohorts of Group 1, and 49 in Group 2. The mean prescribed tumor dose was 67.6Gy. Five grade 3 esophagitis and three grade 3 pneumonitis events were observed across both groups. Following one fatal esophageal perforation in the 71Gy cohort, 68Gy was declared the esophageal MTD. With a median follow-up of 35 months, median OS was 36.9 months, and OS and PFS were 87.8% and 72.0% at 1 year and 68.0% and 48.5% at 2 years.ConclusionsIDEAL-CRT achieved significant treatment intensification with acceptable toxicity and promising survival. The isotoxic design allowed the esophageal MTD to be identified from relatively few patients.

Teaser

Eighty-four patients (6 IIB, 57 IIIA, 21 IIIB) were recruited to IDEAL-CRT, an early phase trial of dose-per-fraction-escalated concurrent chemoradiation for NSCLC. Tumor doses of 63-73Gy (mean 67.6Gy) were isotoxically prescribed to the ICRU reference-point and delivered in 30 fractions over 40 days. Toxicity was acceptable. At 35 months median follow-up, median OS was 36.9 months, 1 year OS and PFS were 87.8% and 72.0%, and 2 year OS and PFS were 68.0% and 48.5%.


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Ubiquitin-Conjugating Enzyme E2T is an Independent Prognostic Factor and Promotes Gastric Cancer Progression

Abstract

Ubiquitin-conjugating enzyme E2T (UBE2T) is a member of the E2 family that mediates the ubiquitin-proteasome system and regulates gene expression. It is a major oncogene in several cancers such as lung cancer and breast cancer, while the potential functions of UBE2T in gastric cancer (GC) remains largely unknown. Here, we identified the roles of UBE2T in GC progression and its potential to act as a prognostic marker of GC. Our data demonstrated that UBE2T was significantly upregulated in gastric cancer tissues, and the high expression of UBE2T was significantly correlated with poor differentiation, high T classification, and poor prognosis. In vitro experiments indicated that UBE2T promoted cell proliferation and inhibited cell cycle arrest. In addition, we observed that UBE2T modulated cell mobility by inducing epithelial-mesenchymal transition. Collectively, these findings suggest that UBE2T plays an important role in the tumorigenesis of gastric cancer and could act as a potential independent prognostic factor for cancer therapy.

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The long non-coding RNA NEAT1 regulates epithelial to mesenchymal transition and radioresistance in through miR-204/ZEB1 axis in nasopharyngeal carcinoma

Abstract

Long non-coding RNAs (lncRNAs) play a critical role in cancer progression, including in nasopharyngeal carcinoma (NPC). However, it is still poorly understood whether lncRNA regulates epithelial to mesenchymal transition (EMT) and radioresistance of NPC cells. We found that lncRNA NEAT1 was significantly upregulated in NPC cell lines and tissues. Knockdown of NEAT1 could sensitize NPC cells to radiation in vitro. Further investigation found that NEAT1 regulated radioresistance by modulating EMT phenotype. Furthermore, we found that there was reciprocal repression between NEAT1 and miR-204. ZEB1 was identified as a downstream target of miR-204 and NEAT1 upregulated ZEB1 expression by negatively regulating miR-204 expression. Taking together, we proposed that NEAT1 regulated EMT phenotype and radioresistance by modulating the miR-204/ZEB1 axis in NPC.

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Discoidin domain receptor 1 (DDR1), a promising biomarker, induces epithelial to mesenchymal transition in renal cancer cells

Abstract

Discoidin domain receptor I (DDR1) is confirmed as a receptor tyrosine kinase (RTK), which plays a consequential role in a variety of cancers. Nevertheless, the influence of DDR1 expression and development in renal clear cell carcinoma (RCCC) are still not well corroborated. In our research, we firstly discovered that the expression level of DDR1 was remarkable related to TNM stage (p = 0.032), depth of tumor invasion (p = 0.047), and lymph node metastasis (p = 0.034) in 119 RCCC tissue samples using tissue microarray. The function of DDR1 was then evaluated in vitro using collagen I and DDR1 small interfering RNA (siRNA) to regulate the expression of DDR1 in OS-RC-2 and ACHN renal cancer cells (RCC). DDR1 expression correlated with increased RCC cell migration, invasion, and angiogenesis. Further study revealed that high expression of DDR1 can result in epithelial to mesenchymal transition (EMT) activation. Western blot assay showed that the N-cadherin protein and vimentin were induced while E-cadherin was reduced after DDR1 over expression. Our results suggest that DDR1 is both a prognostic marker for RCCC and a potential functional target for therapy.

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Autophagy inhibition sensitizes WYE-354-induced anti-colon cancer activity in vitro and in vivo

Abstract

Mammalian target of rapamycin (mTOR) complex 1 (mTORC1) and mTORC2 are frequently dysregulated in human colon cancers. In the present study, we evaluated the potential anti-colon cancer cell activity by a novel mTORC1/2 dual inhibitor WYE-354. We showed that WYE-354 was anti-survival and anti-proliferative when adding to primary (patient-derived) and established (HCT-116, HT-29, Caco-2, LoVo, and DLD-1 lines) colon cancer cells. In addition, WYE-354 treatment activated caspase-dependent apoptosis in the colon cancer cells. Mechanistically, WYE-354 blocked mTORC1 and mTORC2 activation. Meanwhile, it also induced autophagy activation in the colon cancer cells. Autophagy inhibitors (bafilomycin A1 and 3-methyladenine), or shRNA-mediated knockdown of autophagy elements (Beclin-1 and ATG-5), remarkably sensitized WYE-354-mediated anti-colon cancer cell activity in vitro. Further studies showed that WYE-354 administration inhibited HT-29 xenograft growth in severe combined immunodeficient (SCID) mice. Importantly, its activity in vivo was further potentiated with co-administration of the autophagy inhibitor 3-MA. Phosphorylations of Akt (Ser-473) and S6 were also decreased in WYE-354-treated HT-29 xenografts. Together, these pre-clinical results demonstrate the potent anti-colon cancer cell activity by WYE-354, and its activity may be further augmented with autophagy inhibition.

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Multicenter cohort study on the survival time of cancer patients dying at home or in a hospital: Does place matter?

BACKGROUND

Although the place of death has a great influence on the quality of death and dying for cancer patients, whether the survival time differs according to the place of death is unclear. The primary aim of this study was to explore potential differences in the survival time of cancer patients dying at home or in a hospital.

METHODS

This multicenter, prospective cohort study was conducted in Japan from September 2012 through April 2014 and involved 58 specialist palliative care services.

RESULTS

Among the 2426 patients recruited, 2069 patients were analyzed for this study: 1582 receiving hospital-based palliative care and 487 receiving home-based palliative care. A total of 1607 patients actually died in a hospital, and 462 patients died at home. The survival of patients who died at home was significantly longer than the survival of patients who died in a hospital in the days' prognosis group (estimated median survival time, 13 days [95% confidence interval (CI), 10.3-15.7 days] vs 9 days [95% CI, 8.0-10.0 days]; P = .006) and in the weeks' prognosis group (36 days [95% CI, 29.9-42.1 days] vs 29 days [95% CI, 26.5-31.5 days]; P = .007) as defined by Prognosis in Palliative Care Study predictor model A. No significant difference was identified in the months' prognosis group. Cox proportional hazards analysis revealed that the place of death had a significant influence on the survival time in both unadjusted (hazard ratio [HR], 0.86; 95% CI, 0.78-0.96; P < .01) and adjusted models (HR, 0.87; 95% CI, 0.77-0.97; P = .01).

CONCLUSIONS

In comparison with cancer patients who died in a hospital, cancer patients who died at home had similar or longer survival. Cancer 2015. © 2015 American Cancer Society.

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Evans Syndrome at Childhood-Onset Systemic Lupus Erythematosus Diagnosis: A Large Multicenter Study

Background

Evans syndrome (ES) in childhood-onset systemic lupus erythematosus (cSLE) patients has been rarely reported and limited to small populations.

Procedures

A retrospective multicenter cohort study (Brazilian cSLE group) was performed in 10 Pediatric Rheumatology services including 850 patients with cSLE. ES was assessed at disease diagnosis and defined by the combination of immune thrombocytopenia and autoimmune hemolytic anemia.

Results

ES was observed in 11 of 850 (1.3%) cSLE patients. The majority of them had hemorrhagic manifestations (91%) and active disease (82%). All patients with ES were hospitalized and none died. Comparisons of cSLE patients with and without ES at diagnosis revealed similar frequencies of female gender, multiorgan involvement, autoantibodies profile, and low complement (P > 0.05). Patients with ES had a lower frequency of malar rash (9% vs. 53%, P = 0.003) and musculoskeletal involvement (18% vs. 69%, P = 0.001) than those without this complication. The frequencies of intravenous methylprednisolone (82% vs. 43%, P = 0.013) and intravenous immunoglobulin use (64% vs. 3%, P < 0.0001) were significantly higher in the ES group, with similar current prednisone dose between groups (1.1 [0.76–1.5] vs. 1.0 mg/kg/day [0–30], P = 0.195).

Conclusions

Our large multicenter study identified ES as a rare and severe initial manifestation of active cSLE with good outcome. Diagnosis is challenging due to the lack of typical signs and symptoms of lupus and the requirement to exclude infection and primary immunodeficiency.

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Metabonomic changes from pancreatic intraepithelial neoplasia to pancreatic ductal adenocarcinoma in tissues from rats

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors and the diagnosis in early phase is quite difficult. This study was aimed at obtaining the metabolic profiles and characteristic metabolites of pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues from Sprague-Dawley (SD) rats to establish metabonomic methods used in PDAC's early diagnosis. In the present study, the animal models were established by embedding 7, 12-dimethylbenzanthracene (DMBA) in pancreas of SD rats to obtain PanIN and PDAC tissues. After the preprocessing of tissues, ¹H nuclear magnetic resonance(NMR) spectroscopy combined with multivariate and univariate statistical analysis was applied to identify the potential metabolic signatures and the corresponding metabolic pathways. As results, pattern recognition models were successfully established and differential metabolites including glucose, amino acids, carboxylic acids and coenzymes were screened out. Compared with the control, the variation trends of several metabolites were similar in both PanIN and PDAC. Kynurenate and methionine levels were elevated in PanIN but decreased in PDAC, indicating to be specific metabolites distinguishing PanIN from PDAC. Our results suggested that the metabonomic strategy of NMR-based techniques combined with multivariate statistical analysis could distinguish the metabolic differences of PanIN, PDAC and normal, demonstrated to be a promising approach in physiopathologic metabolism investigations and early diagnoses of PDAC.

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Identification of anti-cancer chemical compounds using Xenopus embryos

Summary

Cancer tissues have biological characteristics similar to those observed in embryos during development. Many types of cancer cells acquire pro-invasive ability through epithelial-mesenchymal transition (EMT). Similar processes (gastrulation and migration of cranial neural crest cells (CNCCs)) are observed in the early stages of embryonic development in Xenopus during which cells that originate from epithelial sheets through EMT migrate to their final destinations. This study examined Xenopus embryonic tissues to identify anti-cancer compounds that prevent cancer invasion. From the initial test of known anti-cancer drugs, AMD3100 (an inhibitor of CXCR4) and Paclitaxel (a cytoskeletal drug targeting microtubules) effectively prevented migration during gastrulation or CNCCs development. Blind-screening of 100 synthesized chemical compounds was performed, and nine candidates that inhibited migration of these embryonic tissues without embryonic lethality were selected. Of these, C-157 (an analog of podophyllotoxin) and D-572 (which is an indole alkaroid) prevented cancer cell invasion through disruption of interphase microtubules. In addition, these compounds affected progression of mitotic phase and induced apoptosis of SAS oral cancer cells. SAS tumors were reduced in size after intratumoral injection of C-157, and peritoneal dissemination of melanoma cells and intracranial invasion of glioma cells were inhibited by C-157 and D-572. When the other analogues of these chemicals were compared, those with subtle effect on embryos were not tumor suppressive. These results suggest that a novel chemical-screening approach based on Xenopus embryos is an effective method for isolating anti-cancer drugs especially targeting cancer cell invasion and proliferation.

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Awareness of Undergraduate Dental and Medical Students Towards Oral Cancer

Abstract

Oral cancer is a common malignancy in Nepal and many other South East Asian countries, which is predisposed by a variety of potentially malignant oral diseases. Considering the importance of knowledge of health professionals and their role in early diagnosis and reduction of cancer statistics, this study aims to evaluate the awareness of undergraduate dental and medical students towards oral cancer. The study involved undergraduate dental and medical students of BP Koirala Institute of Health Sciences, Nepal. A self-administered questionnaire adapted from Carter to Ogden was distributed. One hundred forty-three dental and 311 medical students responded to the questionnaire. Significantly more dental (80.4 %) than medical students (36.0 %) were found to routinely examine the oral mucosa. Tobacco smoking and chewing were the most commonly recognized risk factors by both medical and dental students. Most of the students found ulcer as the common change associated with oral cancer. Only 30 out of the total students felt very well informed about oral cancer. This study has demonstrated a lack of awareness in some aspects of oral cancer among medical and dental students which highlights the need to frame new teaching methodologies. Similar studies from other health institutions would provide an insight regarding the same and could be a base for formulating a uniform curriculum in the implementation of knowledge regarding oral cancer.

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In Memoriam—Richard F. Bakemeier, MD, MSc

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[Financial stress: A prognostic factor for cancer survival!]

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[Financial stress: A prognostic factor for cancer survival!]

Bull Cancer. 2016 Mar 23;

Authors: Gonçalves A

PMID: 27017058 [PubMed - as supplied by publisher]

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[Prescription of high-cost medicines in French Hospitals: Regulation and procedures of reimbursement].

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[Prescription of high-cost medicines in French Hospitals: Regulation and procedures of reimbursement].

Bull Cancer. 2016 Mar 23;

Authors: Wilkowsky C, Lenain A, Benbekhaled K, Le Gall MJ, Vignot S

Abstract
The high cost of several drugs or medical devices involves specific reimbursement procedures in French hospitals. Specific prescription rules have been developed and a regular survey by regional health authorities is performed. These particular funding procedures allow patients to access to innovative drugs. Some questions have recently been raised in France about the list of cancer drugs that could be concerned by an additional funding by health insurance. In this setting, this article proposes to summarize the current modalities of reimbursement of high-cost medicines in French Hospitals to enlighten the current debate.

PMID: 27017057 [PubMed - as supplied by publisher]

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