Deep learning-assisted radiomics facilitates multimodal prognostication for personalized treatment strategies in low-grade glioma.

Determining the optimal course of treatment for low grade glioma (LGG) patients is challenging and frequently reliant on subjective judgment and limited scientific evidence. Our objective was to develop a comprehensive deep learning assisted radiomics model for assessing not only overall survival in LGG, but also the likelihood of future malignancy and glioma growth velocity. Thus, we retrospectively included 349 LGG patients to develop a prediction model using clinical, anatomical, and preoperative MRI data. Before performing radiomics analysis, a U2-model for glioma segmentation was utilized to prevent bias, yielding a mean whole tumor Dice score of 0.837. Overall survival and time to malignancy were estimated using Cox proportional hazard models. In a postoperative model, we derived a C-index of 0.82 (CI 0.79-0.86) for the training cohort over 10 years and 0.74 (Cl 0.64-0.84) for the test cohort. Preoperative models showed a C-index of 0.77 (Cl 0.73-0.82) for training and 0.67 (Cl 0.57-0.80) test sets. Our findings suggest that we can reliably predict the survival of a heterogeneous population of glioma patients in both preoperative and postoperative scenarios. Further, we demonstrate the utility of radiomics in predicting biological tumor activity, such as the time to malignancy and the LGG growth rate.

Long-term survival after head and neck cancer surgery with immediate free flap reconstruction.

BACKGROUND: Head and neck cancer is one of the most frequent cancers worldwide. A combination treatment including surgery is known to have a better survival rate than exclusive radiotherapy-chemotherapy. In extreme cases of non-metastatic patients who have voluminous tumor, or complex location, surgery with immediate reconstruction by free flap could be an option to improve long term survival. PURPOSE: To share experience of long-term survival of patients with head and neck cancer who underwent oncologic surgery with immediate free flap reconstruction, and to analyze influencing factors. METHODS: All consecutive patients treated with free flaps for reconstruction of extensive defects after resection of head and neck cancer in our center (Nancy, France) were retrieved from the hospital database. Data was recorded in a systematic way. Bivariate and multivariate Cox proportional hazards models were used for statistical analysis. RESULTS: Between 1997 and December 2007, 70 patients underwent surgical resection of head and neck tumor with free flap reconstruction. 11 patients were excluded because of missing data. Follow-up time was 7.4 years, IQR from 4.3 to 11.3. Overall survival was 53.8%, 95% CI [39.9%; 65.8%] at 5 years and 38.6% [24.8%; 52.3%] at 10 years. Age>60 years at the surgery HR 2,373 (1,143; 4,927) and TNM score 3-4 HR 2,524 (1,093; 5,828) were statistically associated to a lesser survival rate. CONCLUSION: The ability to successfully and safely perform free flaps increases treatment options for patients with advanced head and neck cancer in a selected population. it seems worthwhile to perform these microvascular reconstructions.

Partial pharyngolaryngectomy with infrahyoid flap: Our experience.

AIM: We evaluated a cohort of advanced hypopharyngeal squamous cell carcinoma, treated with conservative surgery, reconstruction with infrahyoid flap and radio-chemotherapy. METHODS: We used partial pharyngo-laryngectomy and radio-chemotherapy to treat fifty-seven patients with stage III-IV hypopharyngeal SCC from November 1994 to December 2011. Clinical examination and speech therapy evaluation were used for estimation of laryngeal function. RESULTS: All patients received a partial pharyngo-laryngectomy. All patients underwent neck dissection; 56 patients received bilateral neck dissection. Reconstruction was achieved by infra-hyoid flap. Five-year overall and disease-specific survival rates were 54.4% and 61.4%, respectively. Successful laryngeal function preservation with complete five-year remission was achieved in 44% of the patients. CONCLUSION: Selected even if advanced carcinomas of the hypopharynx maybe treated with partial pharyngo-laryngectomy with reconstruction with pedicled flap. Both oncological and functional results showed a good outcome.

Gender differences in the association between physical activity and cognitive function in individuals with bipolar disorder.

INTRODUCTION: Bipolar disorder (BD) is accompanied by a high number of comorbidities and associated with an overall increased mortality. Especially obesity, systemic inflammatory processes and cognitive deficits are highly prevalent and increase with the course of illness. Physical activity (PA) is associated with beneficial effects on somatic comorbidities such as obesity or cardiovascular disease in individuals without psychiatric disorder. Furthermore, PA might increase neurocognitive performance and reduce systemic inflammation. OBJECTIVE: The aim of the study was to investigate the association between PA and neurocognitive function in euthymic individuals suffering from BD. METHODS AND PARTICIPANTS: 120 individuals with BD, euthymic at test time, completed the self-reported International Physical Activity Questionnaire (IPAQ) assessing PA of the past seven days and were accordingly assigned to a specific activity category (low, moderate or vigorous). Furthermore, clinical parameters were gathered and cognitive tests analysing verbal-dependent intelligence, attention, executive functioning as well as memory were administered. RESULTS: Female individuals in the vigorous PA group performed significantly higher in most of the cognitive domains compared to females with moderate or low PA. In males, we only found a significant difference in one test for attention between moderate/vigorous and the low activity group. CONCLUSION: Differences between PA groups in cognitive performance in female individuals with BD were obvious in almost all cognitive domains. As cognitive deficits are strongly associated with a worse course of disease and outcome, PA might offer a concomitant therapy targeting not only somatic comorbidities such as obesity and cardiovascular disease, but also neurocognition.

Using one-step nucleic acid amplification (OSNA) for intraoperative detection of lymph node metastasis in breast cancer patients avoids second surgery and accelerates initiation of adjuvant therapy.

BACKGROUND: Sentinel lymph node (SLN) analysis is conventionally analyzed using immunohistochemistry and in the case of SLN involvement, justifies a second surgery for axillary lymph node (ALN) resection, thus delaying the initiation of adjuvant therapies. PATIENTS AND METHODS: Three hundred and eighty-one patients with early stage breast cancer (BC) were considered in this retrospective study. SLNs were detected using combined radioisotope and dye detection. SLN involvement was analyzed using routine intraoperative One-Step Nucleic Acid Amplification (OSNA) assay, in 100 patients and compared with the conventional histopathology carried out previously in 281 patients. RESULTS: Considering positive SLNs as '++' (CK19 mRNA copy number>5000), '+' (250 < CK19 mRNA copy number <5000) and positive by inhibition in the OSNA group and macro-, micrometastases and isolated tumor cells in the histopathology group, no difference in SLN involvement rate was found between the two groups with 29.0% and 29.9% of positive SLNs, respectively. Using OSNA intraoperatively, the mean time to process the SLN was 42 min allowing immediate ALN resection, reduced significantly (P < 0.01) the re-intervention rate (9% versus 39%) and significantly (P < 0.01) accelerated the initiation of adjuvant therapy (6.2 versus 8.4 weeks). CONCLUSIONS: Using OSNA for intraoperative SLN analysis avoids second surgery for ALN resection in most patients and accelerates initiation of adjuvant therapy.

Emergent complexity of the cytoskeleton: from single filaments to tissue.

Despite their overwhelming complexity, living cells display a high degree of internal mechanical and functional organization which can largely be attributed to the intracellular biopolymer scaffold, the cytoskeleton. Being a very complex system far from thermodynamic equilibrium, the cytoskeleton's ability to organize is at the same time challenging and fascinating. The extensive amounts of frequently interacting cellular building blocks and their inherent multifunctionality permits highly adaptive behavior and obstructs a purely reductionist approach. Nevertheless (and despite the field's relative novelty), the physics approach has already proved to be extremely successful in revealing very fundamental concepts of cytoskeleton organization and behavior. This review aims at introducing the physics of the cytoskeleton ranging from single biopolymer filaments to multicellular organisms. Throughout this wide range of phenomena, the focus is set on the intertwined nature of the different physical scales (levels of complexity) that give rise to numerous emergent properties by means of self-organization or self-assembly.

Addressing parenting concerns of bone marrow transplant patients: opening (and closing) Pandora's box.

Although a significant number of adults undergoing stem cell transplant (SCT) or bone marrow transplantation (BMT) care for dependent children, and these treatments pose significant challenges for families, research has virtually ignored the impact of parenting on patients' quality of life during BMT/SCT and children's responses to having a parent undergo these treatments. Physicians rarely inquire about parenting concerns related to the extended hospitalizations necessitated by these treatments, yet clinical experience suggests that addressing patient concerns about children's reactions to cancer and BMT/SCT can improve the experience of the patient and the patient's family, and help the medical team respond effectively to sources of patients' distress. Parents frequently want to know what reactions to expect from children, thus general developmental information is reviewed, and recommendations given for when professional help for children is warranted. A key way for parents to support their children is with open, honest communication; however, parents often find it extremely difficult to talk about cancer and BMT/SCT with their children. The medical team can assist patients' efforts to communicate with and support their children by asking about a patient's children, providing some targeted information, and discussing the potential impact of treatments on parenting capacity. Inquiring about and addressing parenting concerns may initially seem difficult, but can ultimately facilitate stronger doctor-patient alliances, and more compassionate care.

Surgery after concurrent chemoradiotherapy and brachytherapy for the treatment of advanced cervical cancer: morbidity and outcome: results of a multicenter study of the GCCLCC (Groupe des Chirurgiens de Centre de Lutte Contre le Cancer).

OBJECTIVES: To evaluate the morbidity and therapeutic value of surgery after concurrent chemoradiotherapy and brachytherapy in a multicentric series of patients with advanced cervical cancer. METHODS: Patients with stage IB2 to IVA cervical cancer treated with concurrent chemoradiotherapy and pelvic radiotherapy followed by brachytherapy and surgery from seven participating French comprehensive cancer centers were enrolled. The surgical treatment consisted of a hysterectomy, which ranged from radical hysterectomy to anterior pelvic exenteration, and lymph node resection. Acute toxicity, pathological response, overall, and disease-free survival were assessed for each pathological response to therapy. RESULTS: One hundred seventy-five patients were enrolled from September 1987 to June 2002. The median age was 44 years [27;75]. Patients distribution according to clinical classification was as follows: 41 stage IB2, 18 IIA, 77 IIB, 12 IIIA, 14 IIIB, and 13 IVA. Forty-six patients experienced 51 postoperative complications. Thirty-three patients experienced grade 2 morbidity (18.9%, 33/175), among whom 19 experienced urinary complications (57.5%, 19/175). No post treatment mortality was observed. Grade 3 toxicity rate was 6.9% (12/175). Pathological complete response rate was 38% (67/175). After a median follow-up of 36 months, overall survival and disease-free survival were significantly better in patients who had a pathological complete response to therapy than those who achieved a partial pathological response (P < 0.0001). CONCLUSION: Surgery after concurrent chemoradiotherapy and brachytherapy for advanced cervical cancer leads to an acceptable morbidity. Furthermore, surgery allows evaluation of the pathological response to therapy and improves local control in the case of partial pathological response.

Telerobotic-assisted laparoscopic hysterectomy for benign and oncologic pathologies: initial clinical experience with 30 patients.

BACKGROUND: Telerobotic-assisted laparoscopic attempts to provide technological solutions to the inherent limitations of traditional laparoscopic surgery. The aim of this study is to report the first experience of two teams concerning telerobotic-assisted laparoscopic hysterectomy for benign and malignant pathologies. METHODS: This study included 14 patients at the University Hospital Saint Pierre of Brussels (Belgium) and 16 patients at the Cancer Center of Nancy (France) from September 1999 to July 2003. RESULTS: The indications for surgery were uterine malignant diseases in 12 cases (stade I) (41%), and benign pathologies of the uterus in 18 cases (59%). Five postoperative complications (17%) occurred, none related to the robotic system. CONCLUSION: Robotic surgery can be safely performed in gynecologic and gynecologic-oncologic surgery with no increase in complication rates. A significant advance is represented by the surgeon's ergonomic improvement.

Biliary lesions during radiofrequency ablation in liver. Study on the pig.

BACKGROUND: Radiofrequency (RF) is a method of in situ destruction of liver tumor. Biliary complications are bile ducts stenosis or biliary abcess. The aim of this work was to study consequences of liver RF on bile ducts. METHODS: A porcine model of biliary lesions was created using radiofrequency ablation liver. Twenty-two pigs were used for the study. The RF RITA 1500 generator (RITA Medical Systems, Mountain View, Calif., USA) was used for all experiments. The needle was positioned under sonographic control in liver parenchyma beside bile ducts. Two lesions were performed in left liver. Four groups of 5 pigs were treated. The pigs were sacrificed 1 or 3 weeks after the procedure. Pringle maneuver was utilized in half of the RF procedures. An ex vivo cholangiogram was obtained by direct injection into the main bile duct. Samples of RF lesions of liver parenchyma near and at a distance from the RF lesions were taken for pathological studies. RESULTS: Radiological lesions were biliary stenosis, with or without upstream bile duct dilatation, or complete interruption of the bile duct, or extravasation of the radiological contrast agent. Histological lesions of bile ducts were observed near RF lesions and at distance of the RF lesions when a Pringle maneuver was used or when the liver was removed after 3 weeks. CONCLUSIONS: RF ablation in contact of the intrahepatic bile duct induced biliary lesions. Therefore, it is required to stay away from the bile duct or to protect it when performing RF ablation.

The G2/M regulator 14-3-3sigma prevents apoptosis through sequestration of Bax.

In response to DNA damage and genotoxic stress, the p53 tumor suppressor triggers either cell cycle arrest or apoptosis. The G(2) arrest after damage is, in part, mediated by the p53 target, 14-3-3final sigma (final sigma). Colorectal tumor cells lacking final sigma are exquisitely sensitive to DNA damage. Here we analyzed the mechanism of this sensitivity in final sigma(-/-) as compared with final sigma(+/+) human colorectal tumor cells. Exposure to adriamycin resulted in rapid apoptosis only in final sigma(-/-) cells. This was further characterized by caspase-3 activation, p21(CIP1) cleavage, and CDK2 activation. Moreover, Bax was rapidly translocated out of the cytoplasm, and cytochrome c was released in final sigma(-/-) cells. Transient adenovirus-mediated reconstitution of final sigma in the final sigma(-/-) cells led to effective rescue of this phenotype and protected cells against apoptosis. The association of final sigma, Bax, and CDK1 in protein complexes may be the basis for this antiapoptotic mechanism. In conclusion, final sigma not only enforces the p53-dependent G(2) arrest but also delays the apoptotic signal transduction.

Multivariate curve resolution of wavelet and Fourier compressed spectra.

The multivariate curve resolution method SIMPLe to use Interactive Self-Modeling Mixture Analysis (SIMPLISMA) was applied to Fourier and wavelet compressed ion-mobility spectra. The spectra obtained from the SIMPLISMA model were transformed back to their original representation, that is, uncompressed format. SIMPULSMA was able to model the same pure variables for the partial wavelet transform, although for the Fourier and complete wavelet transforms, satisfactory pure variables and models were not obtained. Data were acquired from two samples and two different ion mobility spectrometry (IMS) sensors. The first sample was thermally desorbed sodium gamma-hydroxybutyrate (GHB), and the second sample was a liquid mixture of dicyclohexylamine (DCHA) and diethylmethylphosphonate (DEMP). The spectra were compressed to 6.3% of their original size. SIMPLISMA was applied to the compressed data in the Fourier and wavelet domains. An alternative method of normalizing SIMPLISMA spectra was devised that removes variation in scale between SIMPLISMA results obtained from uncompressed and compressed data. SIMPLISMA was able to accurately extract the spectral features and concentration profiles directly from daublet compressed IMS data at a compression ratio of 93.7% with root-mean-square errors of reconstruction < 3%. The daublet wavelet filters were selected, because they worked well when compared to coiflet and symmlet. The effects of the daublet filter width and compression ratio were evaluated with respect to reconstruction errors of the data sets and SIMPLISMA spectra. For these experiments, the daublet 14 filter performed well for the two data sets.

Factors affecting local control and survival after treatment of carcinoma of the rectum by endocavitary radiation: a retrospective study of 97 cases.

PURPOSE: Endocavitary radiation therapy constitutes an alternative to surgical therapy for some early rectal carcinomas. We studied the prognostic factors for locoregional or metastatic relapse after endocavitary radiation, and their impact for therapeutic strategy. METHODS AND MATERIALS: Our study reports the outcome of 97 patients with adenocarcinomas of the rectum treated from 1978 to 1998 by endocavitary irradiation (100 Gy), exclusive or combined with an interstitial brachytherapy boost of 20 Gy. The indications consisted mostly of polypoid, mobile tumors, less than 4 cm in diameter, and well differentiated. But the indications were extended to elderly patients, who presented with a high surgical risk or who refused mutilating surgery. RESULTS: The mean follow-up was 82 months. One patient presented with an isolated distant metastatic relapse, and 27 patients presented with locoregional recurrence, surgically salvaged in 16 cases. Disease-free survival was 71% at 5 years and 68% at 10 years. Multifactorial analysis suggests that clinical stage T1A, well-differentiated tumors, and early and complete response are favorable prognostic factors for disease-free survival. Response to therapy is the most powerful prognostic factor for relapse. CONCLUSION: This retrospective study confirms the efficacy of endocavitary radiotherapy combined with brachytherapy as a safe conservative treatment in well-selected patients.

Cutting edge: resistance to apoptosis and continuous proliferation of dendritic cells deficient for TNF receptor-1.

The individual roles of the two TNFRs on dendritic cells (DC) are poorly understood. Investigating bone marrow-derived DC from TNFR-deficient mice, we found that cultures from TNFR1(-/-) mice continue to form proliferating clusters for 6-9 mo. In contrast, DC derived from wild-type, TNFR2(-/-), or TNFR1/2(-/-) mice survived for only 3-4 wk. DC obtained from these TNFR1(-/-) long term cultures (LTC) mice show an unusual mixed immature/mature phenotype. The continuous proliferation of the LTC is GM-CSF dependent and correlates with decreased protein levels of the cyclin-dependent kinase inhibitors p27(KIP1) and p21(CIP1). Prolonged survival of TNFR1(-/-) DC appears to be independent from NF-kappaB and Bcl-2 pathways and is rather enabled by the down-regulation of CD95, resulting in the resistance to CD95 ligand-induced apoptosis. These data point to proapoptotic signals mediated via TNFR1 and antiapoptotic signals mediated via TNFR2 in DC.

Characterization of subclones of the epithelial cell line from Chironomus tentans resistant to the insecticide RH 5992, a non-steroidal moulting hormone agonist.

Selection of hormone resistant subclones in the continuous presence of the insecticide and ecdysteroid mimick RH 5992 (tefubenozide) resulted preferentially in clones with defects in ecdysteroid receptor function. RH 5992 is already degraded to polar products in wild-type cells; no increase in metabolism of tefubenozide is observed in resistant clones. According to Western blots, ecdysteroid receptor (EcR) and its heterodimerization partner ultraspiracle (USP) are present in all resistant clones. The concentrations are comparable to wild-type cells, but in three clones the extent of phosphorylation of USP is diminished. With regard to hormone binding several types of hormone resistance are distinguished: (1) The same two high-affinity hormone recognition sites are present as in wild-type cells (K(D1)=0.31+/-0.28 nM, K(D2)=6.5+/-2.4 nM) but the number of binding sites is reduced. (2) The binding site with the lower affinity (K(D2)) is missing. (3) The binding site with the higher affinity (K(D1)) is missing. (4) No specific binding is observed. Ponasterone A binding can be rescued by addition of EcR but not by USP. (5) Ligand specificity is altered. RH 5992 can not compete [(3)H]-ponasterone A as efficient as in wild-type cells.

Functional characterization of two Ultraspiracle forms (CtUSP-1 and CtUSP-2) from Chironomus tentans.

Two forms, CtUSP-1 and CtUSP-2, of the Chironomus tentans homolog of Ultraspiracle (new nomenclature: Chironomus NR2B4) were described and verified as components of the functional ecdysteroid receptor. The two forms differed from each other in the most N-terminal regions of the A/B domain and were tested for several properties. Both forms showed the ability to heterodimerize with CtEcR and interact with a variety of direct repeat and palindromic EcREs, and both conferred specific ligand binding when heterodimerized with EcR. CtUSP-2 showed a twofold higher ponasterone-binding potential than CtUSP-1. Both USP forms demonstrated the ability to activate ecdysteroid-inducible transcription in HeLa cells and the variations in the A/B domain of these forms were not associated with detectable differences in transcriptional activation. Thus, the two forms function similarly. Among species for which USP forms have been reported, Chironomus is the most closely related one evolutionarily to Drosophila. Despite this proximity, a variety of structural differences were noted in both the A/B and E domains of USP between the two species. The Chironomus USP forms lack many of the amino acid residues associated with the ligand-dependent AF2 transactivation function found in all other RXRs and USPs reported so far.

DNA-binding properties of the ecdysteroid receptor-complex (EcR/USP) of the epithelial cell line from Chironomus tentans.

DNA-binding features of EcR and USP were investigated using a 0.4 M NaCl extract of the epithelial cell line of Chironomus tentans by means of electrophoretic mobility shift assays (EMSAs). It is shown that the DNA-binding is enhanced by hormone administration and that in the hormone dependent shift, both EcR and USP, are present. Furthermore, we demonstrate that under these conditions, EcR/USP form a unique complex on inverted repeat elements (PAL1 and hsp27-EcRE), while on direct repeat elements (DR1-5), a second complex with higher mobility is formed. In this second complex, neither EcR nor USP are present. Thus, an additional difference between PAL1 and DR-elements is the competition of other factors for DR-elements, modulating its function as an EcRE. A competition EMSA, using PAL1 as radiolabeled probe, reveals the following order of binding strength: PAL1>DR4/5>DR1>DR2/3/hsp27. Surprisingly, using DR1 as radiolabeled probe, shows a different order of binding strength: DR1>DR2>DR3/4/5/PAL1>hsp27. This indicates that the complexes formed on PAL1 are not identical to the ones formed on DR1 and that both are not easily convertible. Furthermore, the affinity of the EcR/USP complex may be altered under various conditions or by interaction with cofactors. Upon hormone administration, DNA binding of the receptor complex is enhanced, but the difference to hormone-free binding reactions decreases in course of time, indicating an additional hormone independent activation. Arch.