Interleukin-13 Treatment of Living Lung Tissue Model Alters the Metabolome and Proteome-A Nano-DESI MS Metabolomics and Shotgun Proteomics Study.

Asthma is a chronic respiratory disease with one of the largest numbers of cases in the world; thus, constant investigation and technical development are needed to unravel the underlying biochemical mechanisms. In this study, we aimed to develop a nano-DESI MS method for the in vivo characterization of the cellular metabolome. Using air-liquid interface (ALI) cell layers, we studied the role of Interleukin-13 (IL-13) on differentiated lung epithelial cells acting as a lung tissue model. We demonstrate the feasibility of nano-DESI MS for the in vivo monitoring of basal-apical molecular transport, and the subsequent endogenous metabolic response, for the first time. Conserving the integrity of the ALI lung-cell layer enabled us to perform temporally resolved metabolomic characterization followed by "bottom-up" proteomics on the same population of cells. Metabolic remodeling was observed upon histamine and corticosteroid treatment of the IL-13-exposed lung cell monolayers, in correlation with alterations in the proteomic profile. This proof of principle study demonstrates the utility of in vivo nano-DESI MS for characterizing ALI tissue layers, and the new markers identified in our study provide a good starting point for future, larger-scale studies.

Droplet and fibril formation of the functional amyloid Orb2.

The functional amyloid Orb2 belongs to the cytoplasmic polyadenylation element binding (CPEB) protein family and plays an important role in long-term memory formation in Drosophila. The Orb2 domain structure combines RNA recognition motifs with low-complexity sequences similar to many RNA-binding proteins shown to form protein droplets via liquid-liquid phase separation (LLPS) in vivo and in vitro. This similarity suggests that Orb2 might also undergo LLPS. However, cellular Orb2 puncta have very little internal protein mobility, and Orb2 forms fibrils in Drosophila brains that are functionally active indicating that LLPS might not play a role for Orb2. In the present work, we reconcile these two views on Orb2 droplet formation. Using fluorescence microscopy, we show that soluble Orb2 can indeed phase separate into protein droplets. However, fluorescence recovery after photobleaching (FRAP) data shows that these droplets have either no or only an extremely short-lived liquid phase and appear maturated right after formation. Orb2 fragments that lack the C-terminal RNA-binding domain (RBD) form fibrils out of these droplets. Solid-state NMR shows that these fibrils have well-ordered static domains in addition to the Gln/His-rich fibril core. Further, we find that full-length Orb2B, which is by far the major component of Orb2 fibrils in vivo, does not transition into fibrils but remains in the droplet phase. Together, our data suggest that phase separation might play a role in initiating the formation of functional Orb2 fibrils.

Molecular Scissors for Tailor-Made Modification of Siloxane Scaffolds.

The controlled design of functional oligosiloxanes is an important topic in current research. A consecutive Si-O-Si bond cleavage/formation using siloxanes that are substituted with 1,2-diaminobenzene derivatives acting as molecular scissors is presented. The method allows to cut at certain positions of a siloxane scaffold forming a cyclic diaminosilane or -siloxane intermediate and then to introduce new functional siloxy units. The procedure could be extended to a direct one-step cleavage of chlorooligosiloxanes. Both siloxane formation and cleavage proceed with good to excellent yields, high regioselectivity, and great variability of the siloxy units. Control of the selectivity is achieved by the choice of the amino substituent. Insight into the mechanism was provided by low temperature NMR studies and the isolation of a lithiated intermediate.

Structural and Electronic Effects on Phosphine Chalcogenide Stabilized Silicon Centers in Four-Membered Heterocyclic Cations.

Understanding the interplay of structural and electronic parameters in the stabilization of Lewis acidic silicon centers is crucial for stereochemical questions and applications in bond activation and catalytic transformations. Phosphine chalcogenide functionalized (Ch = O, S, and Se) hydrosilanes having tert-butyl and 2,4,6-trimethoxyphenyl (TMP) substituents on the silicon atom were synthesized, and the ring-closing reactions to afford the heterocyclic four-membered CPChSi cations were investigated. Synthetic access was only achieved for the sulfur- and selenium-based cations. A thorough study by means of single-crystal X-ray structure determination, NMR spectroscopic data, and density functional theory (DFT) calculations provided insight into important electronic and structural parameters affecting the stability of the intramolecularly stabilized cations. Detailed structural considerations were made on the contributions to the ring strain (angular strain and steric repulsion). Thermochemical investigations showed that the substituents on the silicon and phosphorus atoms play an important role for the stability of the cationic heterocycles. In the absence of large steric repulsions through bulky substituents (methyl groups on silicon and tert-butyl groups on phosphorus), an intrinsic stability sequence of the intramolecular Ch-Si coordination depending on the chalcogen atom in the direction Se ≤ S < O can be observed. However, the order is reversed (O < S < Se) in the case of strong repulsions between sterically demanding substituents (tert-butyl groups on both silicon and phosphorus atoms). Natural bond orbital (NBO) analysis supported the explanations for the observed deshielding trends in 31P NMR spectroscopy and revealed that the O-Si bond is more ionic in nature compared to the S-Si and Se-Si bonds, with the latter exhibiting higher covalent character due to a more efficient charge transfer through a σ-type nCh → pSi interaction.

Successful Treatment of Severe Lamotrigine Intoxication with CytoSorb Hemoadsorption.

Severe intoxication with the anti-epileptic drug, lamotrigine can cause cardiovascular collapse, neurotoxicity - expressed as intractable seizures, and even death. As there is currently no known specific antidote, extracorporeal removal therapies such as CytoSorb hemoadsorption might represent a promising therapeutic option. We report on a deeply comatosed 60-year-old woman who was treated in our intensive care unit with severe lamotrigine intoxication. To support removal from the blood, combined treatment with continuous veno-venous hemodialysis and CytoSorb hemoadsorption was started. Pre- and post-adsorber drug level measurements showed the rapid elimination of lamotrigine accompanied by an impressive clinical improvement in the patient. Two days after treatment discontinuation, there were no more clinical signs of intoxication and the patient could be extubated, followed by transfer to the stroke unit in a stable condition the following day. In the absence of a viable antidote, for the efficient short-term removal of lamotrigine, hemoadsorption with the CytoSorb device could represent a feasible treatment option for patients with severe lamotrigine intoxication.

Structural Model of the Proline-Rich Domain of Huntingtin Exon-1 Fibrils.

Huntington's disease is a heritable neurodegenerative disease that is caused by a CAG expansion in the first exon of the huntingtin gene. This expansion results in an elongated polyglutamine domain that increases the propensity of huntingtin exon-1 to form cross-ß fibrils. Although the polyglutamine domain is important for fibril formation, the dynamic, C-terminal proline-rich domain (PRD) of huntingtin exon-1 makes up a large fraction of the fibril surface. Because potential fibril toxicity has to be mediated by interactions of the fibril surface with its cellular environment, we wanted to model the conformational space adopted by the PRD. We ran 800-ns long molecular dynamics simulations of the PRD using an explicit water model optimized for intrinsically disordered proteins. These simulations accurately predicted our previous solid-state NMR data and newly acquired electron paramagnetic resonance double electron-electron resonance distances, lending confidence in their accuracy. The simulations show that the PRD generally forms an imperfect polyproline (polyP) II helical conformation. The two polyP regions within the PRD stay in a polyP II helix for most of the simulation, whereas occasional kinks in the proline-rich linker region cause an overall bend in the PRD structure. The dihedral angles of the glycine at the end of the second polyP region are very variable, effectively decoupling the highly dynamic 12 C-terminal residues from the rest of the PRD.

GEC-ESTRO APBI classification as a decision-making tool for the management of 2nd ipsilateral breast tumor event.

AIM: Second ipsilateral breast tumor event (2ndIBTE) occurring after primary radio-surgical treatment can be treated by either salvage mastectomy or 2nd conservative treatment (2ndCT) including an accelerated partial breast re-irradiation (APBrI). We analyzed the impact of the GEC-ESTRO APBI classification (GAC) on the oncological outcome after APBrI. MATERIALS AND METHODS: Between 2000 and 2016, 159 patients (pts) underwent a 2ndCT. After lumpectomy, APBrI was performed using either low-dose (30-55 Gy reference isodose) or high-dose rate brachytherapy (28-34 Gy). Oncological outcome including 3rdIBTE, regional (RFS) or metastasis-free survival (MFS), specific (SS) and overall survival (OS) was analyzed according to GAC. Univariate (UVA) and multivariate analyses (MVA) were conducted to identify significant prognostic factors for 3rdIBTE. RESULTS: With a median follow-up of 71 months (range 62-85 months), 60 pts (42%), 61 pts (42.7%) and 22 pts (15.4%) were classified as low-risk (LR), intermediate-risk (IR) and high-risk (HR), respectively. For the whole cohort, 6-year 3rdIBTE-free survival, RFS, MFS, SS and OS rates were 97.4, 96.4, 90.3, 92.9 and 91.2%, respectively. Six-year 3rdIBTE-free survival rates for LR, IR and HR were 100, 95.8 and 92.9%, respectively (p = 0.003), while no significant differences were found between the three GAC groups for RFS, MFS, SS. In UVA, lympho-vascular invasion (p = 0.009), positive margins (p = 0.0001) and GAC high-risk group (p = 0.001) were considered as significant prognostic factors for 3rdIBTE, while, in MVA, high-risk group (p = 0.009) was the only prognostic factor. CONCLUSION: In case of 2ndIBTE, GAC could be used as a decision helping tool to discuss conservative or radical treatment options. Patient information remains crucial in order to accurately define the salvage therapy modalities.

Effects on α- and ß-cell function of sequentially adding empagliflozin and linagliptin to therapy in people with type 2 diabetes previously receiving metformin: An exploratory mechanistic study.

AIMS: To investigate the effect of sequential treatment escalation with empagliflozin and linagliptin on laboratory markers of α- and ß-cell function in people with type 2 diabetes mellitus (T2DM) insufficiently controlled on metformin monotherapy. RESEARCH DESIGN AND METHODS: A total of 44 people with T2DM received 25 mg empagliflozin for a duration of 1 month in an open-label fashion (treatment period 1 [TP1]). Thereafter, they were randomized to a double-blind add-on therapy with linagliptin 5 mg or placebo (treatment period 2 [TP2]) for 1 additional month. α- and ß-cell function was assessed using a standardized liquid meal test and an intravenous (i.v.) glucose challenge. Efficacy measures comprised the areas under the curve for glucose, insulin, proinsulin and glucagon after the liquid meal test and the assessment of fast and late-phase insulin release after an i.v. glucose load with a subsequent hyperglycaemic clamp. RESULTS: Empagliflozin reduced fasting and postprandial plasma glucose levels, associated with a significant reduction in postprandial insulin levels and an improvement in the conversion rate of proinsulin (TP1). The addition of linagliptin during TP2 further improved postprandial glucose levels, probably as a result of a marked reduction in postprandial glucagon concentrations (TP2). The insulin response to an i.v. glucose load increased during treatment with empagliflozin (TP1), and further improved after the addition of linagliptin (TP2). CONCLUSION: After metformin failure, sequential treatment escalation with empagliflozin and linagliptin is an attractive treatment option because of the additive effects on postprandial glucose control, probably mediated by complementary effects on α- and ß-cell function.

Multimodal Therapy of Squamous Cell Carcinoma of the Anus With Distant Metastasis: A Single-Institution Experience.

BACKGROUND: Because of the rarity of the condition, studies concerning the management of patients with squamous cell carcinoma of the anus with distant metastasis are scarce. The available studies indicate poor outcomes with exclusive chemotherapy. OBJECTIVE: Our aim was to evaluate the impact of multidisciplinary treatment on overall survival among patients presenting with metastatic squamous cell carcinoma of the anus. DESIGN: This was a retrospective study. SETTINGS: The study was conducted at a single French institution between 2000 and 2014. PATIENTS: Consecutive patients with histologically proven, newly diagnosed, or recurrent metastatic squamous cell carcinoma of the anus were included. INTERVENTIONS: Study interventions included multimodal therapy combining systemic chemotherapy and local ablative treatment to remove all metastases through surgery, radiofrequency ablation, or radiotherapy. MAIN OUTCOME MEASURES: The primary outcome measure was overall survival. RESULTS: Fifty patients (median age, 62 years; men/women: 8/42) fulfilled the inclusion criteria, and 39 were available for Response Evaluation Criteria in Solid Tumors. Forty had metastatic relapse after previous treatment of localized disease, and 10 presented with synchronous metastasis. P16 status was not available. Patients received at least 1 chemotherapy regimen, including 5-fluorouracil-mitomycin C (n = 22), cisplatin-5-fluorouracil (n = 20), or 5-fluorouracil alone (n = 3). Thirteen also had surgical metastasectomy, 11 had radiotherapy, and 6 had radiofrequency ablation. Median overall survival was 20.0 months (95% CI, 18.2-21.8 mo), and median time to failure of strategy was 6.0 months (95% CI, 2.9-9.1 mo). Overall response rate was 56% (95% CI, 40%-73%). Outcomes from the 5-fluorouracil-mitomycin C and cisplatin regimens did not statistically differ. Patients treated with multimodal therapy had a median overall survival of 22.0 months (95% CI, 15.3-28.6 mo) versus 13.0 months (95% CI, 9.5-16.5 mo; p = 0.002). Median time to failure of strategy was 10.0 months (95% CI, 4.2-15.7 mo) versus 5.0 months (95% CI, 2.8-7.2; p = 0.007). After 2 years, 40% of patients with multimodal treatment and 20% of those without ablative treatment were alive. LIMITATIONS: This study is limited by its retrospective design and modest sample size. CONCLUSIONS: Stage IV squamous cell carcinoma of the anus outcomes are poor, but first-line chemotherapy can enable good response rates. Other treatment modalities, including surgery, radiotherapy, and thermoablation, should be considered, because they may provide a survival advantage. See Video Abstract at http://links.lww.com/DCR/A336.

Radiotherapy for elderly patients and cetuximab, a monocentric study.

Concomitant radiotherapy and cetuximab association has shown superiority to exclusive radiotherapy for head and neck cancers. Data on this association are scarce for the elderly population despite its rising incidence. A retrospective monocentric data collection was performed in the Antoine Lacassagne Cancer Center in France. Inclusion criteria were: age >70 years at time of diagnosis, histologically proven head and neck epidermoid carcinoma, treated with radiotherapy combined with cetuximab. Thirty-five patients were included between 2008 and 2012. Median follow-up was 22 months. Median age was 74 years (70-86). Median performance status was 1 (0-2). Female/male sex ratio was 0.34. Tumor sites were: oropharynx (57.1 %), larynx (20 %), hypopharynx (14.3 %), oral cavity (2.9 %), nasopharynx (2.9 %), and lymph node with unknown primary (2.9 %). Using TNM classification, tumors were: T1 (5.9 %), T2 (35.3 %), T3 (35.3 %), T4 (22.9 %), N0 (28.6 %), N1 (8.6 %), N2 (48.6 %), and N3 (14.3 %). Median radiotherapy dose was 70 (60-70). RT was interrupted in 94 % of patients and the dose of cetuximab was reduced in 29 %. Median survivals were, respectively: 49 months for overall survival (standard error (SE) = 8) and 32 months for relapse-free survival (SE = 10). Two-year local-regional relapse and metastatic relapse-free survivals were, respectively, 59 % (SE = 10) and 74 % (SE = 10). Concomitant radiotherapy and cetuximab seem to be an effective therapy in the elderly population with encouraging results similar to the literature concerning its efficacy and toxicity. This treatment should be considered for patients >70 years.

Dynamic domains of amyloid fibrils can be site-specifically assigned with proton detected 3D NMR spectroscopy.

Several amyloid fibrils have cores framed by highly dynamic, intrinsically disordered, domains that can play important roles for function and toxicity. To study these domains in detail using solid-state NMR spectroscopy, site-specific resonance assignments are required. Although the rapid dynamics of these domains lead to considerable averaging of orientation-dependent NMR interactions and thereby line-narrowing, the proton linewidths observed in these samples is far larger than what is regularly observed in solution. Here, we show that it is nevertheless possible to record 3D HNCO, HNCA, and HNcoCA spectra on these intrinsically disordered domains and to obtain site-specific assignments.

PD-L1 expression in basaloid squamous cell lung carcinoma: Relationship to PD-1+ and CD8+ tumor-infiltrating T cells and outcome.

PD-1/PD-L1 inhibitors demonstrated durable clinical responses in patients with lung squamous cell carcinoma. However, the expression pattern of PD-L1 and the presence of CD8+ and PD-1+ tumor-infiltrating T cells in the basaloid variant of squamous cell carcinoma remain unknown. immunohistochemistry analysis of PD-L1 expression, with three recently validated monoclonal antibodies used in clinical trials (clones SP142, SP263, and 28-8), and detection of CD8+ and PD-1+ tumor-infiltrating T cells was performed on whole-tissue sections from 56 patients following surgery for basaloid squamous cell carcinoma. Data were correlated to clinicopathological parameters and outcome. Fair to poor concordance was observed between the SP142 vs SP263 clones, and SP142 vs 28-8 (κ range, 0.018-0.412), while the 28-8 and SP263 demonstrated a strong correlation in both the tumor cell and immune cell compartments (κ=0.883, and κ=0.721). Expression of PD-L1 correlated with a high content of CD8+ and PD-1+ tumor-infiltrating T cells when using SP142 (P=0.012; P=0.022), but not with SP263 or 28-8 (P=0.314; P=0.611). In the multivariate analysis, we found significantly better disease-free and overall survival rates for high PD-L1 expression with SP142, CD8+ and PD-1+ tumor-infiltrating T cells (P=0.003; P=0.007). No significant prognosis value was observed for SP263 and 28-8 clones, except a correlation between improved overall survival and SP263 in the univariate analysis (P=0.039), not confirmed in the multivariate model. In conclusion, we report that the expression of PD-L1 and the content of CD8+ and PD-1+ tumor-infiltrating T cells is an independent indicator of better outcome in basaloid squamous cell carcinoma patients, although the observed effect is dependent on the PD-L1 immunohistochemistry assay.

Translating Clinical Evidence-Based Medicine into the Real World: Single-Center Experience with Cabazitaxel in Metastatic Prostate Cancer Patients.

BACKGROUND: We studied the efficacy and safety of cabazitaxel in unselected real-life patients. PATIENTS AND METHODS: We retrospectively investigated all patients with metastatic prostate cancer (mPC) treated with cabazitaxel 25 mg/m2 i.v. every 3 weeks combined with oral prednisolone (10 mg once daily) after first-line docetaxel chemotherapy. Study issues were to report patient characteristics and cabazitaxel data in terms of tolerance and efficacy. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method. All data were compared with TROPIC results. RESULTS: From 2011 to 2014, 41 patients received cabazitaxel; 15 patients (37%) had a performance status (PS) ≥2 versus 7% (p < 0.0001) in TROPIC, and 38 patients (93%) presented a Gleason score ≥7 at baseline (vs. 60%; p < 0.0001). All patients had metastatic disease at baseline. Previous therapies were radiotherapy in 17 patients (41 vs. 61%; p = 0.01) and surgery in 24 patients (59 vs. 52%; p = 0.4). The median number of cabazitaxel cycles was 5 (1-10) versus 6 (3-10) in TROPIC. Five patients completed 10 cycles of cabazitaxel (12%) versus 28% in TROPIC (p = 0.03). Toxicities were anemia (12 patients, 29%), diarrhea (9 patients, 22%), nausea (7 patients, 17%), pain (6 patients, 15%), sepsis (4 patients, 10%), neutropenia (3 patients, 7%) and urinary tract infection (1 patient, 2%). The tumor response rate was 19.5 versus 14.4% in TROPIC (nonsignificant). PFS was 4.5 months (95% CI 3.3-6.4) in our analysis and 2.8 months (95% CI 2.4-3.0) in TROPIC. OS was 12.1 months (95% CI 9.2 to not reached) and 15.1 months (95% CI 14.1-16.3), respectively. CONCLUSION: In our unselected mPC patients with poorer baseline clinical conditions and aggressive disease, cabazitaxel seems efficient and not more toxic than in the TROPIC study.

Clinical Impact of Bevacizumab in Patients with Relapsed Glioblastoma: Focus on a Real-Life Monocentric SurVey (SV1 Study).

OBJECTIVES: Glioblastoma is one of the most frequent primitive brain tumors. Patients who experience tumor relapse after surgery and concomitant radiochemotherapy have a dismal prognosis. The objective of this study is to analyze efficacy data in terms of overall survival (OS) and progression- free survival (PFS) following combination therapy with bevacizumab (BVZ) and irinotecan among patients with relapsed glioblastoma. Safety data will also be reviewed and all results will be compared with data of the literature. METHODS: In this single-center retrospective study, all records of patients treated with BVZ and irinotecan for a relapsed glioblastoma were analyzed. Each chemotherapy cycle was repeated every 15 days until progression. Magnetic resonance imaging and neurologic examination were repeated every 6 weeks during treatment. RESULTS: Forty-five patients were analyzed. The median number of BVZ-irinotecan cycles was 8 (range 1-38). Median PFS was 26 weeks and median OS was 28 weeks. Eighteen of the 45 patients (40% of cases) had an objective response 6 months after initiation of treatment. Two patients had to discontinue treatment due to toxicity. CONCLUSIONS: The results of the SV1 study are consistent with those found in phase II studies evaluating the same treatment. The irinotecan-BVZ combination is effective in relapsed glioblastoma with acceptable toxicity. Biomarkers predictive of response to BVZ should help in the selection of patients who could benefit from treatment.

Chemotherapy Regimen in Nonagenarian Cancer Patients: A Bi-Institutional Experience.

BACKGROUND: The elderly population in Western countries is growing and constitutes a public health issue. Concomitantly, age-related diseases such as cancer increase. There are few data on the efficacy, tolerability and toxicity of specific anticancer therapy in the very elderly patients; therefore, their management is not standardized. METHODS: In this bi-institutional study, we reviewed medical records of patients who received or continued specific anticancer therapy beyond the age of 90 years. Geriatric assessment was not reported for our patients. Twelve patients were enrolled. Their general health condition was good, and half of them were living in elderly institutions. Ten patients had a solid tumor and 2 were treated for hematological malignancies. Most were diagnosed with a locally advanced or metastatic disease, and the goal of treatment was curative for only 1 patient. Six patients received chemotherapy as first-line treatment, 4 patients received targeted therapy and 2 received concomitant chemoradiation. Four patients received a second-line treatment. RESULTS: Despite a significant reduction in treatment posology in half of the patients, 8 acute grade 3/4 toxicities were reported and 2 patients died of treatment-related septic shock. Median duration of first-line treatment was 3.2 months, and progression-free survival ranged from 18 to 311 days. Overall survival ranged from 18 days to 11 years. CONCLUSION: Aging is a heterogeneous process, and management of elderly patients is a multidisciplinary approach. Geriatric assessment helps to identify older patients with a higher risk of morbidity/mortality and allows to assess the risks and benefits of specific anticancer therapy. The choice of treatment should be based primarily on the expected symptomatic benefit, and treatment should not compromise the quality of life.

Correlation of Physical Activities and Breast Cancer Characteristics: A Prospective Analysis with Special Focus on Triple Negative Breast Cancer.

OBJECTIVE: Several studies have demonstrated that daily physical activity (PA) prevents the development of breast cancer. Our objective was to examine the relationship between PA and clinical and biological tumor characteristics in breast cancer patients in order to determine the impact of energy expenditure (EE) on tumor prognosis. METHODS: We pooled data from two prospective studies, including a total of 121 breast cancer patients. The measure of PA was done using the self-completion Population Physical Activity Questionnaire, which was answered by each patient. RESULTS: Ten patients harbored triple negative (TN) tumors. The mean body mass index (BMI) in the general population and in patients with TN tumors was 24.3 and 25.6, respectively. The mean daily EE (DEE) was 10,266 kJ×24 h(-1) in the general population and 11,212 kJ×24 h(-1) in patients with TN tumors. In the whole population, there was an inverse statistical correlation between BMI and DEE, rest, low PA, and high PA (p=0.0002, p=0.003, p<0001, and p=0.03, respectively). There was a positive correlation between negative estrogen receptor status and intensive PA (p=0.041) and DEE (p=0.007). For TN tumors, there was no significant correlation between BMI and categories of EE. CONCLUSIONS: Lifestyle (weight regulation, PA) should be adapted and personalized according to biological, clinical, and epidemiological characteristics of the tumors.

Safety of spinal radiotherapy in metastatic cancer patients receiving bevacizumab therapy: a bi-institutional case series.

We retrospectively assessed the outcome of patients receiving emergency spinal radiation therapy (RT) concurrently with bevacizumab. Clinical records of 18 consecutive patients receiving emergency spinal RT for symptomatic vertebral metastases during the course of bevacizumab-based therapy were examined. Patients were receiving biweekly bevacizumab combined with paclitaxel (n=17) or with docetaxel/carboplatin (n=1) or as a single agent (n=1) for advanced metastatic carcinoma. RT was delivered at doses of 30 Gy in 10 fractions (n=8), 20 Gy in five fractions (n=9) or 18 Gy in nine fractions (n=1). In 10 patients (56%), irradiation field encompassed the thoracic vertebrae. The median time interval between the bevacizumab infusion and the RT course was 1.5 days (0-8 days). The median follow-up was 8.3 months (2 days-42 months). A clinical benefit of RT was reported in 13 patients (72%), including four patients with complete pain relief. Two of the three patients with neurological impairment at the time of RT experienced a partial improvement in their symptoms. No pain recrudescence was reported within the irradiated field after RT completion. All toxicities were mild to moderate, with no acute toxicity reported in 13 patients (72%). No RT disruption was necessary because of acute toxicity. No delayed toxicity was reported within RT fields among 11 patients with at least 6 months of follow-up. Spinal RT during the course of bevacizumab-based therapy was not associated with the occurrence of unexpected adverse effects. This suggests that emergency RT should not be contraindicated in these patients, provided that doses and treatment volumes are defined carefully.

Radiotherapy for head and neck cancer in nonagenarian patients: a possible cornerstone?

In the field of radiotherapy, there is very little scientific data on the management of nonagenarians, especially in patients aged 90 years or more and with head and neck cancer (HNC). We made one of the first retrospective study of the feasibility and safety of radiotherapy in this population with HNC. Records of radiotherapy coming from four health facilities were studied to include all nonagenarian patients with HNC in the last 10 years and who received radiation therapy. We analyzed patient characteristics and primary cancers, as well as objective of the treatment (curative or palliative), efficacy and toxicity. Twenty patients receiving radiotherapy were identified; mean age was 93.2 years (standard deviation 2.8). Treatment was given with curative and palliative intent in 40 and 60 % of cases, respectively. The most common primary tumors were tumors of the salivary glands (30 % of cases), oral cavity tumors (25 % of cases) and thyroid tumors (15 % of cases). Median total prescribed dose was 47.5 Gy (12-70 Gy). Median number of delivered fractions was 18.5 (2-35 fractions). All patients received intensive supportive care during radiotherapy. Toxicities were mild to moderate. Radiotherapy could not be completed for four patients (20 % of cases). One patient developed grade 1-2 delayed toxicities. At the last follow-up, only four patients (20 % of cases) were alive. Cancer was cause of death in most cases. Radiotherapy may be performed for the nonagenarians with HNC. The total dose and fractionation must be adjusted to optimize the tolerance. However, the prognosis remains very poor, cancer being the main cause of death. Research of geriatric vulnerabilities prior to any treatment, in the context of a comprehensive geriatric assessment, is still recommended to select patients for radiotherapy.

The Combination of 80 Years of Age and Metastatic Castration-Resistant Prostate Cancer Remain an Uphill Battle: A Case Report with Cabazitaxel as a Double-Edged Sword.

We report the case of an 80-year-old patient who presented with a progressive prostate metastatic cancer with poor performance status. The patient had already benefitted from docetaxel and abiraterone. A new line of chemotherapy by cabazitaxel was started with good response, and there was a dramatic improvement in general status and pain symptoms. Age and performance status alone should not be limiting decision factors for elderly cancer patients.

A human IgM enriched immunoglobulin preparation, Pentaglobin, reverses autoimmune diabetes without immune suppression in NOD mice.

The immune system of healthy individuals is capable of regulating autoimmunity through multiple mechanisms. In Type 1 Diabetes (T1D) we recently discovered natural IgM, although present at normal levels, is unable to perform its normal immunoregulatory function. Treating diabetic mice with IgM from healthy donors led to reversal of disease without immune depletion. To investigate the therapeutic potential of a human preparation of IgM, we administered an IgM-enriched preparation of immunoglobulin called Pentaglobin. Administration of Pentaglobin therapy reversed disease in diabetic NOD mice and boosted CD4 + Foxp3 + Tregs. Importantly, the impact of Pentaglobin on the immune system was limited to inhibiting beta cell destruction but was not immune depleting nor did it inhibit the immunization response to an irrelevant antigen. These findings indicate that inhibition of deleterious autoimmunity in T1D is possible while leaving protective immunity fully intact.