Pentavalent technetium-99m dimercaptosuccinic acid [<Superscript>99m</Superscript>Tc-(V)DMSA] brain scintitomography—a plausible non-invasive depicter of glioblastoma proliferation and therapy response

The biological behavior and prognosis of gliomas depend largely on cellular proliferation, resistance to chemotherapy, and metastatic potential. Proliferative propensity has significant implications on patient management but its assessment requires tissue sampling; the non-invasive estimation of brain tumor proliferation represents therefore a major goal. Pentavalent technetium-99 m dimercapto-succinic acid [^99mTc-(V)DMSA] is a tumor-seeking radiotracer displaying affinity for gliomas; its intracellular accumulation is directly linked to cell proliferation. We performed a tomographic ^99mTc-(V)DMSA brain scan in a 35-year-old male baring a recurrent glioblastoma multiforme, to depict its proliferative disposition. The patient had been diagnosed 14 months earlier and had been submitted to surgery, followed by adjuvant radiotherapy and temozolomide-based chemotherapy. On clinical suspicion of recurrence 5 months later, magnetic resonance imaging (MRI) revealed a lesion at the site of preceded surgery, which was treated by imatinib mesylate. No improvement was ascertained the following months and radiographic assessment verified tumor progression. Scintitomography revealed avid radiotracer uptake in the entirety of the lesion (the distribution of radioactivity closely conforming to the morphological tumor boundaries), an indication that the neoplasm demonstrated no substantial proliferation decline in response to imatinib. The patient deceased a few weeks later. Mounting in vivo and in vitro evidence indicates that ^99mTc-(V)DMSA is a credible non-invasive proliferation depicter, its cellular accumulation linked closely to phosphate uptake and kinase pathway activation. A potential role in patient management, prognosis estimation, and therapy response monitoring could occur for this tracer.     

Sstr2A immunohistochemical expression in human meningiomas: is there a correlation with the histological grade, proliferation or microvessel density?

Somatostatin anti-proliferative and anti-angiogenic activities, together with the expression of somatostatin receptors (sstrs), account for the use of somatostatin analogues in the treatment of human tumours. In the present study, sstr2A immunohistochemical expression was analyzed in grade II and III meningiomas and was compared with that revealed in grade I meningiomas. Thirty-five formalin-fixed paraffin-embedded meningiomas, comprising 13 grade I, 19 grade II and 3 grade III tumours, according to the WHO 2007 classification, were submitted to immunohistochemical assays for sstr2A. Moreover, in the same cohort of tumours, the immunoexpression of CD105, a specific marker for neo-angiogenesis, as well as the Ki-67 labelling index (LI), reflecting the proliferative activity of the meningiomas, were recorded. Sstr2A immunoreaction was evidenced in 26/35 cases and was localized at the cytoplasm and the plasma membrane in 12 and in 14 cases, respectively. Specifically, a positive staining was found in 7/13 grade I, in 16/19 grade II and in 3/3 grade III tumours, thus demonstrating that sstr2A is frequently expressed in high grade meningiomas. A significantly higher microvessel density (MVD), assessed by CD105 immunostaining and Ki-67 LI were evidenced in high grade meningiomas. A significant correlation was recorded between sstr2A expression and a high MVD of the meningiomas. The existence of a correlation between sstr2A expression and the entity of neo-angiogenesis provides the basis for the use of somatostatin analogue-based therapies in the treatment of meningiomas.     

Association of TNFα<Superscript>−308</Superscript>, IFNγ<Superscript>+874</Superscript>, and IL10<Superscript>−1082</Superscript> gene polymorphisms and the risk of non-small cell lung cancer in the population of the South Indian state of Telangana

Background

Cytokine-mediated inflammation is important in the pathogenesis of non-small cell lung cancer (NSCLC). Genetic polymorphisms in cytokine genes and their association with lung cancer in the Indian population have not been reported.

Methods

For the first time, we analyzed genetic polymorphisms of TNFα ^?308, IFNγ ⁺⁸⁷⁴, and IL10 ^?1082 genes in 246 NSCLC patients and 250 healthy controls in the South Indian population from Telangana using ARMS PCR.

Results

IFNγ⁺⁸⁷⁴ A/T and IL10^?1082 G/G gene polymorphisms were found to be significantly associated with NSCLC with 1.56- and 1.68-fold disease risk, respectively. There was no association between the risk of NSCLC and TNFα^?308 polymorphism. Gene polymorphisms stratified according to smoking revealed that IFNγ⁺⁸⁷⁴ A/T polymorphisms in smokers increased the disease risk by 2.91 fold. IL10^?1082 G/G polymorphisms showed 2-fold increased risk among patients who were smokers when compared to the controls. However, there was no association between TNFα^?308, IFNγ⁺⁸⁷⁴, and IL10^?1082 gene polymorphism and the stage of the NSCLC patients. The overall risk associated with the combination of these polymorphisms indicated that the TNFα^?308 G/A + IFNγ⁺⁸⁷⁴ A/T + IL10^?1082 G/G genotype increased the risk by 1.5 fold.

Conclusions

The results of our study indicate an association between cytokine gene polymorphisms and the risk of NSCLC in an Indian population.

     

A study on the CD<Subscript>4</Subscript><Superscript>+</Superscript> CD<Subscript>25</Subscript><Superscript>+</Superscript> regulatory T cells in patients with gastrointestinal malignancies

Objectives Regulatory T cells play an active role in the maintenance of the immune system’s tolerance of both foreign and self antigens. Particularly, CD₄ ⁺ CD₂₅ ⁺ regulatory T cells participate in tumor immunity. The study provided further evidence on the involvement of CD₄ ⁺ CD₂₅ ⁺ regulatory T cells in immune system impairment in patients with gastrointestinal malignancies. Methods Using flow cytometry, CD₄ ⁺ CD₂₅ ⁺ regulatory T cells were analyzed in peripheral blood from 114 patients with gastrointestinal malignancies and 15 healthy controls. Results The prevalence of the CD₂₅ ⁺ subset in CD₄ ⁺ T cells was increased in patients with colorectal carcinoma compared with healthy controls. The phenotic characteristics of the CD₄ ⁺ CD₂₅ ⁺ T cells in patient with malignancies were low expression of CD₄₅ RA and no expression of CD₆₉. Our results indicated that when compared with healthy control, the proportions of CD₄ ⁺ CD₂₅ ⁺ T cells in the peripheral blood of patients with colorectal, gastric, and esophageal carcinoma were significantly higher (P < 0.05) in colorectal carcinoma (22.11 ± 9.65%), gastric carcinoma (17.74 ± 4.24%), and esophageal carcinoma (24.37 ± 4.82)%, respectively. Further analysis on the proportion of CD₄ ⁺ CD₂₅ ⁺ T cells revealed that those patients with gastrointestinal malignancies in stages IV were higher than those of in stage I–III, though no significant difference was observed (P > 0.05). However, the proportion of CD₄ ⁺ CD₂₅ ⁺ T cells in the patients with relapse gastric carcinoma (23.32 ± 4.98%) was significantly higher than that of patients with primary gastric carcinoma (P < 0.01). Conclusions The increased CD₄ ⁺ CD₂₅ ⁺ T cells in patients with gastrointestinal malignancies may be related to immunosuppression and tumor progression. This suggests that elimination or reduction of CD₄ ⁺ CD₂₅ ⁺ regulatory T cells can improve effective tumor immunity for immunotherapy.     

Efficacy and safety of nab-paclitaxel 125 mg/m<Superscript>2</Superscript> and nab-paclitaxel 150 mg/m<Superscript>2</Superscript> compared to paclitaxel in early high-risk breast cancer. Results from the neoadjuvant randomized GeparSepto study (GBG 69)

Purpose

The GeparSepto study demonstrated that the use of nab-paclitaxel instead of paclitaxel prior to anthracycline-based chemotherapy could lead to a significantly increased pCR rate, especially in the triple negative subpopulation. We report efficacy and safety for patients treated with two different doses of nab-paclitaxel in comparison to weekly solvent-formulated paclitaxel.

Methods

Patients were treated for 12 weeks with either intravenous nab-paclitaxel 150 mg/m² (nP150) weekly, after study amendment 125 mg/m² (nP125) weekly or solvent-based paclitaxel 80 mg/m² (P80) weekly followed by epirubicin 90 mg/m² and cyclophosphamide 600 mg/m² on day 1 for four 3-week cycles.

Results

229 patients received nP150, 377 nP125. Baseline characteristics were fairly balanced between these two sequential cohorts as well as compared to 601 patients receiving P80 except for hormone receptor status, HER2 status, and Ki67. Taxane treatment was discontinued in 26.8% (nP150), 16.6% (nP125), and 13.3% of (P80) patients, respectively. Median relative total dose intensity (mRTDI) based on 125 mg/m² for nP was 103% with nP150, 95% with nP125, 99% with P80 before and 98% with P80 after the amendment. PSN grade 3–4 was observed in 14.5% of patients with nP150, 8.1% of patients with nP125 (p = 0.018), and 2.7% of patients with P80. Overall pCR before the amendment was 33.6% after nP150 and 23.5% after P80 (OR 1.65 [95% CI 1.10–2.50]; p = 0.022); pCR after the amendment was 41.4% after nP125, and 32.4% after P80 (1.48 [95% CI 1.10–1.99]; p = 0.013).

Conclusions

Nab-paclitaxel 125 mg/m² was associated with a better safety profile and compliance without compromising the efficacy compared to nab-paclitaxel 150 mg/m².

     

Retrospective audit of 957 consecutive <Superscript>18</Superscript>F-FDG PET–CT scans compared to CT and MRI in 493 patients with different histological subtypes of bone and soft tissue sarcoma

Background

The use of ¹⁸F-FDG PET–CT (PET–CT) is widespread in many cancer types compared to sarcoma. We report a large retrospective audit of PET–CT in bone and soft tissue sarcoma with varied grade in a single multi-disciplinary centre. We also sought to answer three questions. Firstly, the correlation between sarcoma sub-type and grade with ¹⁸FDG SUVmax, secondly, the practical uses of PET–CT in the clinical setting of staging (during initial diagnosis), restaging (new baseline prior to definitive intervention) and treatment response. Finally, we also attempted to evaluate the potential additional benefit of PET–CT over concurrent conventional CT and MRI.

Methods

A total of 957 consecutive PET–CT scans were performed in a single supra-regional centre in 493 sarcoma patients (excluding GIST) between 2007 and 2014. We compared, PET–CT SUVmax values in relation to histology and FNCCC grading. We compared PET–CT findings relative to concurrent conventional imaging (MRI and CT) in staging, restaging and treatment responses.

Results

High-grade (II/III) bone and soft tissue sarcoma correlated with high SUVmax, especially undifferentiated pleomorphic sarcoma, leiomyosarcoma, translocation induced sarcomas (Ewing, synovial, alveolar rhabdomyosarcoma), de-differentiated liposarcoma and osteosarcoma. Lower SUVmax values were observed in sarcomas of low histological grade (grade I), and in rare subtypes of intermediate grade soft tissue sarcoma (e.g. alveolar soft part sarcoma and solitary fibrous tumour). SUVmax variation was noted in malignant peripheral nerve sheath tumours, compared to the histologically benign plexiform neurofibroma, whereas PET–CT could clearly differentiate low from high-grade chondrosarcoma. We identified added utility of PET–CT in addition to MRI and CT in high-grade sarcoma of bone and soft tissues. An estimated 21% overall potential benefit was observed for PET–CT over CT/MRI, and in particular, in ‘upstaging’ of high-grade disease (from M0 to M1) where an additional 12% of cases were deemed M1 following PET–CT.

Conclusions

PET–CT in high-grade bone and soft tissue sarcoma can add significant benefit to routine CT/MRI staging. Further prospective and multi-centre evaluation of PET–CT is warranted to determine the actual predictive value and cost-effectiveness of PET–CT in directing clinical management of clinically complex and heterogeneous high-grade sarcomas.

     

Phase II study of S-1 plus oxaliplatin 130 mg/m<Superscript>2</Superscript> in Japanese patients with advanced gastric cancer

Purpose

Although oxaliplatin 130 mg/m² every 3 weeks was approved for advanced gastric cancer in Japan, data regarding S-1 plus oxaliplatin 130 mg/m² (SOX130) are limited in Japanese patients with advanced gastric cancer. We investigated the feasibility and safety of SOX130 in Japanese patients with advanced gastric cancer.

Methods

Patients with unresectable or recurrent gastric adenocarcinoma, no previous chemotherapy, and Eastern Cooperative Oncology Group Performance Status of 0–1 were treated with SOX130. The primary endpoint was the 3-cycle completion rate, defined as the proportion of patients who completed the first three cycles with ≥?80% relative dose intensity of oxaliplatin.

Results

Twenty-five patients were enrolled from April 2015 to 2016. The 3-cycle completion rate was 72.0% (90% confidence interval: 53.8–86.1), which was higher than the predetermined threshold rate of 50%. With the median number of cycles being 6 (range, 1–19+), grade 3 or 4 adverse events occurred in 10 patients (40%). Major grade 3 adverse events were anorexia (24%), thrombocytopenia (16%), and neutropenia (12%). No febrile neutropenia or treatment-related deaths occurred. Among 12 patients with measurable lesions, the overall response rate was 58.3%. Median progression-free and overall survival were 5.7 months (95% confidence interval 2.9–8.5) and 13.1 months (95% confidence interval 7.4–19.0), respectively.

Conclusion

Results indicated that SOX130 was feasible in Japanese patients with advanced gastric cancer.

     

Metalloprotease-dependent activation of EGFR modulates CD44<Superscript>+</Superscript>/CD24<Superscript>−</Superscript> populations in triple negative breast cancer cells through the MEK/ERK pathway

Purpose

Objective cosmetic analysis is important to evaluate the cosmetic outcome after breast surgery or breast radiotherapy. For this purpose, we aimed to improve our recently developed objective scoring software, the Breast Analyzing Tool (BAT^®).

Methods

A questionnaire about important factors for breast symmetry was handed out to ten experts (surgeons) and eight non-experts (students). Using these factors, the first-generation BAT^® software formula has been modified and the breast symmetry index (BSI) from 129 women after breast surgery has been calculated by the first author with this new BAT^® formula. The resulting BSI values of these 129 breast cancer patients were then correlated with subjective symmetry scores from the 18 observers using the Harris scale. The BSI of ten images was also calculated from five observers different from the first author to calculate inter-rater reliability. In a second phase, the new BAT^® formula was validated and correlated with subjective scores of additional 50 women after breast surgery.

Results

The inter-rater reliability analysis of the objective evaluation by the BAT^® from five individuals showed an ICC of 0.992 with almost no difference between different observers. All subjective scores of 50 patients correlated with the modified BSI score with a high Pearson correlation coefficient of 0.909 (p < .001) which was better compared to the old software (r = 0.769; p < .001).

Conclusions

The modified BAT^® software improves the correlation between subjective and objective BSI values, and may be a new standard for trials evaluating breast symmetry.

     

Increase of α-SMA<Superscript>+</Superscript> and CK<Superscript>+</Superscript> Cells as an Early Sign of Epithelial-Mesenchymal Transition during Colorectal Carcinogenesis

Our aim was to examine cell transition events by detecting the frequency of intrapithelial α-smooth muscle actin (SMA)⁺/cytokeratin (CK)⁺ cells during colorectal adenoma–carcinoma sequence, in relation to E-cadherin expression. Our further aim was to determine the proliferative activity of intraepithelial α-SMA⁺ cells. Histologically healthy, adenoma, and colorectal cancer (CRC) biopsy samples were taken during routine colonoscopy and were included into tissue microarrays (TMAs). Slides immunostained for Ki-67, α-SMA, E-cadherin and pan-cytokeratin were digitalized and analyzed by using a digital microscope software. The proportion of α-SMA⁺/CK⁺ cells was significantly higher in CRC samples (3.34 ± 1.01%) compared to healthy (1.94 ± 0.69%) or adenoma (1.62 ± 0.78%) samples (p < 0.01). E-cadherin expression negatively correlated with the number of α-SMA⁺ cells. The majority of intraepithelial α-SMA⁺ cells were in the proliferative phase. During tumor progression, the appearance of dot-like α-SMA staining in CK positive cells may indicate the initial phase of the epithelial-to-mesenchymal transition (EMT). The high proportion of intraepithelial α-SMA⁺ proliferating cells may refer to their increased plasticity compared to differentiated cells. The negative correlation between E-cadherin and intraepithelial α-SMA expression suggests that EMT is facilitated by a loss of epithelial cell contact.     

Diagnostic accuracy of <Superscript>18</Superscript>F–FDG PET/CT and MR imaging in patients with adenoid cystic carcinoma

Background

The aim of this study was to evaluate the value of 18F–FDG PET/CT (PET/CT) and MRI for local and/or whole-body restaging of adenoid cystic carcinoma of the head and neck (ACC).

Methods

Thirty-six patients with ACC underwent conventional MRI of the head and neck and a whole-body PET/CT and were analysed with regards to detection of a local tumor recurrence, lymph node or distant metastases. A consensus interpretation of all available imaging data was used as reference standard. Sensitivity, specificity, diagnostic accuracy, positive and negative predictive values were calculated for MRI and PET/CT.

Results

The sensitivity of PET/CT and MRI was 96% (89%), specificity 89% (89%), PPV 96% (96%), NPV 89% (73%) and accuracy 94% (89%) for detection of local tumors. Additionally, PET/CT revealed lymph node metastases in one patient and distant metastases in 9/36 patients. In three patients secondary primaries were found.

Conclusions

Whole-body PET/CT in addition to MRI of the head and neck improves detection of local tumour and metastastic spread in ACC.

     

Evaluation of the sonographic visibility and sonographic appearance of the breast biopsy marker (UltraClip<Superscript>®</Superscript>) placed in phantoms and patients

Purpose

To evaluate the usefulness of the UltraClip^® dual trigger breast tissue marker (UltraClip) for sonographic localization, we investigate the sonographic visibility and sonographic appearance of the UltraClip placed in phantoms and patients.

Materials and methods

Ten UltraClips were placed in the target lesions in the phantoms. After the ultrasound examination of the UltraClip, the ultrasound images were compared to the real appearance of the UltraClip obtained by cutting the phantoms. In the patient, the UltraClip markers were placed after biopsy of a suspicious breast lesion or before or during neoadjuvant chemotherapy. The patients consented to return 1–3 weeks after the procedure for ultrasound imaging of the UltraClip.

Results

The UltraClip placed in the phantom appeared as a hyperechoic structure with a mean maximum diameter of 5.5 mm, which was found to correspond to the metallic clip in 90% (9/10) of the cases, and as a hyperechoic tubular structure with a maximum diameter of 9.0 mm corresponded to the expanded polyvinyl alcohol polymer in the remaining 10% (1/10) of cases. On the other hand, the UltraClip was detected as a hyperechoic structure measuring 3.5 mm in size only in 9 of the 15 (60%) patients. The sonographic visibility of the UltraClip was not affected depending on whether the target lesion or post-biopsy scar was sonographically detectable or not [60% (6/10) vs. 60% (3/5)].

Conclusions

While sonographic localization by targeting the UltraClip may be useful in 60% of the patients, another localization technique will be needed in the remaining patients.

     

<Superscript>18</Superscript>F-FDOPA PET and MRI characteristics correlate with degree of malignancy and predict survival in treatment-naïve gliomas: a cross-sectional study

Introduction

To report the potential value of pre-operative ¹⁸F-FDOPA PET and anatomic MRI in diagnosis and prognosis of glioma patients.

Methods

Forty-five patients with a pathological diagnosis of glioma with pre-operative ¹⁸F-FDOPA PET and anatomic MRI were retrospectively examined. The volume of contrast enhancement and T2 hyperintensity on MRI images along with the ratio of maximum ¹⁸F-FDOPA SUV in tumor to normal tissue (T/N SUV_max) were measured and used to predict tumor grade, molecular status, and overall survival (OS).

Results

A significant correlation was observed between WHO grade and: the volume of contrast enhancement (r?=?0.67), volume of T2 hyperintensity (r?=?0.42), and ¹⁸F-FDOPA uptake (r?=?0.60) (P?<?0.01 for each correlation). The volume of contrast enhancement and ¹⁸F-FDOPA T/N SUV_max were significantly higher in glioblastoma (WHO IV) compared with lower grade gliomas (WHO I–III), as well as for high-grade gliomas (WHO III–IV) compared with low-grade gliomas (WHO I–II). Receiver-operator characteristic (ROC) analyses confirmed the volume of contrast enhancement and ¹⁸F-FDOPA T/N SUV_max could each differentiate patient groups. No significant differences in ¹⁸F-FDOPA uptake were observed by IDH or MGMT status. Multivariable Cox regression suggested age (HR 1.16, P?=?0.0001) and continuous measures of ¹⁸F-FDOPA PET T/N SUV_max (HR 4.43, P?=?0.016) were significant prognostic factors for OS in WHO I–IV gliomas.

Conclusions

Current findings suggest a potential role for the use of pre-operative ¹⁸F-FDOPA PET in suspected glioma. Increased ¹⁸F-FDOPA uptake may not only predict higher glioma grade, but also worse OS.

     

Prolonged and severe thrombocytopenia with pancytopenia induced by radiation-combined temozolomide therapy in a patient with newly diagnosed glioblastoma—analysis of <Emphasis Type="Italic">O</Emphasis><Superscript>6</Superscript>-methylguanine-DNA methyltransferase status

BACKGROUND: We reviewed the risk of second tumor (ST), both malignant and benign, in germinoma survivors followed at the Johns Hopkins Hospital (JHH). METHODS: Between 1977 and 2002, 27 patients with intracranial germinoma were treated with radiation therapy (RT). In the presence of competing events, a cumulative incidence function of ST was estimated using the minimal time interval from the date of diagnosis to the date of ST, date of death, or date of last follow-up. RESULTS: Five patients (18%) developed a ST of which 4 (15%) were malignant. One developed a benign falcine meningioma. The cumulative incidence of ST was 9% at 11 years (95% CI, 0-22%). CONCLUSIONS: The relative contributions of RT and patient susceptibility to a ST cannot be determined but suggests the need for long-term surveillance, including testicular self-exams in male germinoma survivors. Current trials of chemotherapy and reduced RT dose and volume offer the prospect of a lower risk of treatment-induced ST.     

Differential kinetics of α-[<Superscript>11</Superscript>C]methyl-<Emphasis Type="SmallCaps">l</Emphasis>-tryptophan on PET in low-grade brain tumors

Increased tryptophan metabolism via the kynurenine pathway is a major mechanism of tumor immuno-resistance. α-[¹¹C]Methyl-l-tryptophan (AMT) is a positron emission tomography (PET) tracer for tryptophan catabolism, and increased AMT uptake has been demonstrated in brain tumors. In this study we evaluated the use of AMT PET for detection of low-grade gliomas and glioneuronal tumors, and determined if kinetic parameters of AMT uptake can differentiate among tumor types. AMT PET images were obtained in 23 patients with newly diagnosed low-grade brain tumors (WHO grade II gliomas and WHO grade I dysembryoplastic neuroepithelial tumors [DNETs]). Kinetic variables, including the unidirectional uptake rate (K-complex) and volume of distribution (VD; which characterizes tracer transport), were measured using a graphical approach from tumor dynamic PET and blood-input data, and metabolic rates (k^￠₃ k^{\prime}_{3} ) were also calculated. These values as well as tumor/cortex ratios were compared across tumor types. AMT PET showed increased tumor/cortex K-complex (n = 16) and/or VD ratios (n = 15) in 21/23 patients (91%), including 11/13 tumors with no gadolinium enhancement on MRI. No increases in AMT were seen in an oligodendroglioma and a DNET. Astrocytomas and oligoastrocytomas showed higher k^￠₃ k^{\prime}_{3} tumor/cortex ratios (1.66 ± 0.46) than oligodendrogliomas (0.96 ± 0.21; P = 0.001) and DNETs (0.75 ± 0.39; P < 0.001). These results demonstrate that AMT PET identifies most low-grade gliomas and DNETs by high uptake, even if these tumors are not contrast-enhancing on MRI. Kinetic analysis of AMT uptake shows significantly higher tumor/cortex tryptophan metabolic ratios in astrocytomas and oligoastrocytomas in comparison with oligodendrogliomas and DNETs.     

15-Deoxy-Δ<Superscript>12,14</Superscript>-prostaglandin J<Subscript>2</Subscript> inhibits G<Subscript>2</Subscript>-M phase progression in human breast cancer cells via the down-regulation of cyclin B1 and survivin expression

The cyclopentenone prostaglandin 15-deoxy-Δ^12,14-prostaglandin J₂ (15d-PGJ₂) exerts a growth inhibitory effect on cancer cells, and this effect is linked to the induction of apoptosis or cell cycle arrest. Induction of apoptosis by 15d-PGJ₂ is associated with the down-regulation of anti-apoptotic proteins. G₀-G₁→S phase progression is inhibited by 15d-PGJ₂ via the degradation of cyclin D1. In this study, we further investigated the mechanism by which 15d-PGJ₂ inhibits cancer cell growth by using the breast cancer cell lines MCF-7 and T-47D. Treatment with 20 μM 15d-PGJ₂ for 72 h completely blocked the growth in both cell lines. However, the proportions of apoptotic MCF-7 and T-47D cells were 21.1% and 40.9%, respectively, indicating that the induction of apoptosis did not appear to fully account for growth inhibition by 15d-PGJ₂. Cell cycle analysis using cells synchronized at the G₀-G₁ or S phase revealed that 15d-PGJ₂ blocked not only G₀-G₁→S phase progression but also G₂-M phase progression. The expression of both cyclins D1 and B1 was decreased by 15d-PGJ₂. Furthermore, 15d-PGJ₂ inhibited aurora-B kinase activity, which coincided with the down-regulation of survivin. Thus, 15d-PGJ₂ induced cell cycle arrest at the G₂-M phase via inhibition of cyclin B1 expression and aurora-B kinase activity. We conclude that survivin may be an important target for 15d-PGJ₂, and its down-regulation may lead to a decrease in aurora-B kinase activity. Naoki Tsuji substantially contributed to this work and should also be considered a first author.     

Activated CD4<Superscript>+</Superscript>T cells enhance radiation effect through the cooperation of interferon-γ and TNF-α

Background  

Approaches that enhance radiation effect may lead to improved clinical outcome and decrease toxicity. Here we investigated whether activated CD4+ T cells (aCD4) can serve as an effective radiosensitizer.     

<Emphasis Type="Italic">NRAS</Emphasis><Superscript><Emphasis Type="Italic">Q61K</Emphasis></Superscript> mutated diffuse leptomeningeal melanomatosis in an adult patient with a brief review of the so-called “forme fruste” of neurocutaneous melanosis

Primary melanocytic tumors of central nervous system represent rare tumors arising from melanocytes of the leptomeninges. These neoplasms include focal forms like melanocytoma and primary malignant melanoma and diffuse forms like leptomeningeal melanocytosis and primary leptomeningeal melanomatosis. The clinical diagnosis remains challenging, with clinical and radiologic features overlapping with other more common diseases. Here we present a case of a 38 years old male with primary diffuse leptomeningeal melanomatosis with presence of a NRAS^Q61K mutation without features of neurocutaneous melanosis.     

Flap adhesion and effect on postoperative complication rates using Tissuglu<Superscript>®</Superscript> in mastectomy patients

Introduction

Post-mastectomy seroma and related complications are common problems in modern oncological surgery. Occurrence rates of up to 59 % have been reported in literature. High-risk patients, that is, those who have undergone previous surgeries, present with a high body mass index, have had radiation or chemotherapy, present a particular challenge. Noninvasive measures such as fibrin-based sealants have thus far not been able to effectively reduce complications associated with fluid accumulation. A recent study using a lysine-derived urethane adhesive named TissuGlu^® however, showed promising results in patients after abdominoplasty.

Methods

32 consecutively recruited patients received a mastectomy using a gold standard mastectomy technique as well as TissuGlu^® flap fixation. A control group of 173 patients, having received a gold standard mastectomy-only, was analyzed retrospectively, totaling 205 patients. Primary endpoints were post-discharge seroma formation and revision surgery/re-hospitalization. Secondary endpoints were initial seroma volume, postoperative pain, hematoma formation and day of drain removal.

Results

No significant difference in seroma formation was demonstrated. The revision surgery/re-hospitalization rate was reduced from 6.9 to 0 %, though this did not reach significance. Significant improvement could be shown in the TissuGlu^® group regarding time to drain removal (17 % decrease), and hematoma formation (14 % decrease). No difference was shown in postoperative pain.

Conclusion

Although patient numbers are still small, advantages in revision surgery/re-hospitalization rate, hematoma formation as well as time to drain removal was shown for the TissuGlu^® group.

Clinical question/level of evidence

Therapeutic, IV.

     

The impact of <Superscript>60</Superscript>Co γ-ray on apoptosis to Hep-2 human laryngeal cancer cell in the condition of reoxygenation after hypoxia

Objective  

The aim of the study was to establish models of Hep-2 laryngeal cancer cell line of different oxygen supplying, trying to investigate the impact of normoxia, hypoxia, reoxygenation after hypoxia on apoptosis and expression of proteins HIF-1α and p53 to Hep-2 human laryngeal cancer cell line induced by ⁶⁰Co γ-ray.