Salvage brachytherapy for second ipsilateral breast tumor event: Relating dosimetric analysis to late side effects.

PURPOSE: For second ipsilateral breast tumor event (2ndIBTE), conservative treatment (CT) involving wide local excision plus accelerated partial breast reirradiation (APBrI) is increasingly used as an alternative to mastectomy. This study investigates the impact of APBrI technique and multicatheter interstitial high dose-rate brachytherapy (MIB) dosimetry parameters on toxicity and survival in patients with 2ndIBTE. MATERIALS-METHODS: Data from patients with 2ndIBTE treated with CT, were analyzed. Inclusion criteria specified 2ndIBTE occurring at least one year after 1st CT for primary breast cancer. Treatment details and dosimetry parameters were recorded. Primary endpoint was late toxicity. Secondary endpoints were late toxicity prognostic factors analysis and oncological outcome. RESULTS: From 07/2005 and 07/2023, 201 patients (pts) received 2nd CT. With a median follow-up of 49.6 months (44.9-59.5), tumor size was less than 2 cm (88.1%), with estrogen receptor positive (92.7%). Patients were low (63.7%) or intermediate (29.8%) GEC-ESTRO APBI risk classification. Late toxicities were observed in 34.8% (G1 52.3%, G2 40.7%). Cutaneous fibrosis was the most common toxicity. Cosmetic outcomes were excellent in 64.1%. Dosimetry analysis revealed positive correlations between complications and absolute volumes of CTV, V100, V150, and V200. Volumes requiring higher needle number and lower DNR resulted in fewer complications. 5-year disease-free and overall survival were 88% and 95% respectively. CONCLUSION: Second CT for 2ndIBTE showed favorable oncological outcomes and survival rates. Complications were correlated with specific dosimetric parameters, emphasizing the importance of tailored treatment planning. This study provides valuable insights in risk stratification and MIB optimization for APBrI.

Workflow optimization of brachytherapy-based very accelerated partial breast irradiation.

PURPOSE: For low-risk breast cancer, accelerated partial breast irradiation (APBI) is a level 1 evidence procedure. Brachytherapy based very APBI (vAPBI) makes it possible to perform adjuvant irradiation in 4 to 1 fraction. However, vAPBI organization is critical. The aim of this technical note is to report on its optimization. METHODS AND MATERIALS: To offer to low-risk breast cancer patient an efficient, simple, rapid adjuvant irradiation with a reduced number of hospital visits, a new organization of vAPBI based on a single fraction was established, merging all the different steps (from first consultation to irradiation) into a 4-5-consecutive-hour period. This therapeutic program was developed in strong collaboration with radiation oncologists, medical physicists, radiation therapists, and the medical secretary. RESULTS: After the validation of adjuvant breast irradiation, the patient was offered a telemedicine consultation with the radiation oncologist. Then, the day of vAPBI, the patient arrived at the brachytherapy unit at 08:00 AM for an in-person consultation followed by a preimplant CT scan (defining catheter number and position). After breast local anesthesia, catheter placement was performed followed by a postimplant CT scan for planning purposes. A total dose of 16 Gy in 1 fraction was delivered before removing the catheters. The patient was discharged from the brachytherapy unit around 12:30 PM with an upcoming surveillance consultation date. CONCLUSIONS: VAPBI organization optimization makes it possible to propose a short 5-h procedure from medical consultation to treatment with only one round trip. Strict organization among staff is required.

Single fraction of HDR brachytherapy for prostate cancer: Results of the SiFEPI phase II prospective trial.

Purpose: To report the results of the Single Fraction Early Prostate Irradiation (SiFEPI) phase 2 prospective trial. Materials/Methods: The SiFEPI trial (NCT02104362) evaluated a single fraction of high-dose rate brachytherapy (HDB) for low- (LR) and favorable-intermediate (FIR) risk prostate cancers. After rectal spacer placement, a single fraction of 20 Gy was delivered to the prostate. Oncological outcome (biochemical (bRFS) and local (lRFS) relapses, disease-free (DFS) and overall (OS) survivals and toxicity (acute/late genito-urinary (GU), gastro-intestinal (GI) and sexual (S) toxicities were investigated. Results: From 03/2014 to 10/2017, 35 pts were enrolled, of whom 33 were evaluable. With a median age of 66 y [46-79], 25 (76 %) and 8 (24 %) pts were LR and FIR respectively. With a MFU of 72.8 months [64-86], 6y-bRFS, lRFS and mRFS were 62 % [45-85], 61 % [44-85] and 93 % [85-100] respectively while 6y-DFS, CSS and OS were 54 % [37-77], 100 % and 89 % [77-100] respectively. Late GU, GI and S toxicities were observed in 11 pts (33 %;18G1), 4 pts (12 %;4G1) and 7 pts (21 %;1G1,5G2,1G3) respectively. Biochemical relapse (BR) was observed in 11 pts (33 %;7LR,4FIR) with a median time interval between HDB and BR of 51 months [24-69]. Nine of these pts (82 %) presented a histologically proven isolated local recurrence. Conclusions: Long-term results of the SiFEPI trial show that a single fraction of 20 Gy leads to sub-optimal biochemical control for LR/FIR prostate cancers. The late GU and GI toxicity profile is encouraging, leading to consideration of HDB as a safe irradiation technique.

TRPM7 Modulates Human Pancreatic Stellate Cell Activation.

Pancreatic diseases, such as pancreatitis or pancreatic ductal adenocarcinoma, are characterized by the presence of activated pancreatic stellate cells (PSCs). These cells represent key actors in the tumor stroma, as they actively participate in disease development and progression: reprograming these PSCs into a quiescent phenotype has even been proposed as a promising strategy for restoring the hallmarks of a healthy pancreas. Since TRPM7 channels have been shown to regulate hepatic stellate cells proliferation and survival, we aimed to study the role of these magnesium channels in PSC activation and proliferation. PS-1 cells (isolated from a healthy pancreas) were used as a model of healthy PSCs: quiescence or activation were induced using all-trans retinoic acid or conditioned media of pancreatic cancer cells, respectively. The role of TRPM7 was studied by RNA silencing or by pharmacological inhibition. TRPM7 expression was found to be correlated with the activation status of PS-1 cells. TRPM7 expression was able to regulate proliferation through modulation of cell cycle regulators and most importantly p53, via the PI3K/Akt pathway, in a magnesium-dependent manner. Finally, the analysis of TCGA database showed the overexpression of TRPM7 in cancer-associated fibroblasts. Taken together, we provide strong evidences that TRPM7 can be considered as a marker of activated PSCs.

High-dose-rate brachytherapy boost for elderly patients with intermediate to high-risk prostate cancer: 5-year clinical outcome of the PROSTAGE cohort.

Purpose: To analyze the oncological outcome in elderly (>70 years) prostate cancer after high-dose rate brachytherapy (HDB) boost. Materials/methods: In this retrospective study, patients with intermediate (IR) and high-risk (HR) prostate cancer underwent external beam radiation therapy (EBRT) followed by HDB boost with/without androgen deprivation therapy (ADT). The impact of age (≤70y vs. > 70y) was investigated. Oncological outcome focused on biochemical relapse-free survival (bRFS), cause-specific (CSS) and overall survival (OS). Late genito-urinary (GU) and gastro-intestinal (GI) toxicities were investigated. Results: From 07/08 to 01/22, 518 pts received a HDB boost, and 380 were analyzed (≤70y:177pts [46.6%] vs. > 70y:203pts [53.4%]). Regarding NCCN classification, 98 pts (≤70y: 53pts; >70y: 45pts; p = 0.107) and 282 pts (≤70y: 124pts; >70y: 158pts; p = NS) were IR and HR pts respectively. Median EBRT dose was 46 Gy [37.5-46] in 23 fractions [14-25]. HDB boost delivered a single fraction of 14/15 Gy (79%). ADT was used in 302 pts (≤70y: 130pts; >70y: 172pts; p = 0.01). With MFU of 72.6 months [67-83] for the whole cohort, 5-y bRFS, 5-y CSS and 5-y OS were 88% [85-92], 99% [97-100] and 94% [92-97] respectively; there was no statistical difference between the two age groups except for 5-y CSS (p = 0.05). Late GU and GI toxicity rates were 32.4% (G ≥ 3 7.3%) and 10.1% (no G3) respectively. Conclusions: For IR and HR prostate cancers, HDB boost leads to high rates of disease control with few late G ≥ 3 GU/GI toxicities. For elderly pts, HDB boost remains warranted mainly in HR pts, while competing comorbidity factors influence OS.

The Pharmacological and Structural Basis of the AahII-NaV1.5 Interaction and Modulation by the Anti-AahII Nb10 Nanobody.

Scorpion α-toxins are neurotoxins that target the fast inactivation mechanism of voltage-gated sodium (NaV) channels leading to several neuro- and cardiotoxic effects in mammals. The toxin AahII is the most active α-toxin from the North African scorpion Androctonus australis Hector that slows the fast inactivation of NaV channels. To fight scorpion envenomation, an anti-AahII nanobody named NbAahII10 (Nb10) was developed. The efficiency of this nanobody has been evaluated in vivo on mice, but its mechanism of action at the cellular level remains unknown. Here we have shown that AahII toxin slows the fast inactivation of the adult cardiac NaV1.5 channels, expressed in HEK293 cells, in a dose-dependent manner, while current amplitude was not affected. The inactivation of NaV1.5 is slower by a factor of 4, 7, and 35 in the presence of [AahII] at 75, 150, and 300 nM, respectively. The washout partially reversed the toxin effect on inactivation from 8.3 ± 0.9 ms to 5.2 ± 1.2 ms at 75 nM. We have also demonstrated that the highly neutralizing Nb10 can fully reverse the effect of AahII toxin on the channel inactivation kinetics even at the 1:1 M ratio. However, the 1:0.5 M ratio is not able to neutralize completely the AahII effect. Therefore, the application of Nb10 promotes a partial abolishment of AahII action. Bioinformatic analysis and prediction of NaV1.5-driven docking with AahII show that Ala39 and Arg62 of AahII play a crucial role to establish a stable interaction through H-bound interactions with Gln1615 and Lys1616 (S3-S4 extracellular loop) and Asp1553 (S1-S2 loop) from the voltage-sensing domain IV (VSD4) of NaV1.5, respectively. From this, we notice that AahII shares the same contact surface with Nb10. This strongly suggests that Nb10 dynamically replaces AahII toxin from its binding site on the NaV1.5 channel. At the physiopathological level, Nb10 completely neutralized the enhancement of breast cancer cell invasion induced by AahII. In summary, for the first time, we made an electrophysiological and structural characterization of the neutralization potent of Nb10 against the α-scorpion toxin AahII in a cellular model overexpressing NaV1.5 channels.

The genetic history of Mayotte and Madagascar cattle breeds mirrors the complex pattern of human exchanges in Western Indian Ocean.

Despite their central economic and cultural role, the origin of cattle populations living in Indian Ocean islands still remains poorly documented. Here, we unravel the demographic and adaptive histories of the extant Zebus from the Mayotte and Madagascar islands using high-density SNP genotyping data. We found that these populations are very closely related and both display a predominant indicine ancestry. They diverged in the 16th century at the arrival of European people who transformed the trade network in the area. Their common ancestral cattle population originates from an admixture between an admixed African zebu population and an Indian zebu that occurred around the 12th century at the time of the earliest contacts between human African populations of the Swahili corridor and Austronesian people from Southeast Asia in Comoros and Madagascar. A steep increase in the estimated population sizes from the beginning of the 16th to the 17th century coincides with the expansion of the cattle trade. By carrying out genome scans for recent selection in the two cattle populations from Mayotte and Madagascar, we identified sets of candidate genes involved in biological functions (cancer, skin structure, and UV-protection, nervous system and behavior, organ development, metabolism, and immune response) broadly representative of the physiological adaptation to tropical conditions. Overall, the origin of the cattle populations from Western Indian Ocean islands mirrors the complex history of human migrations and trade in this area.

High-dose-rate brachytherapy boost for locally advanced cervical cancer: Oncological outcome and toxicity analysis of 4 fractionation schemes.

PURPOSE: Brachytherapy (BT) boost after radio-chemotherapy (RCT) is a standard of care in the management of locally advanced cervical cancer (LACC). As there is no consensus on high-dose-rate (HDR) BT fractionation schemes, our aim was to report the oncological outcome and toxicity profile of four different schemes using twice-a-day (BID) HDR-BT. PATIENTS AND METHODS: This was an observational, retrospective, single institution study for patients with LACC receiving a HDR-BT boost. The latter was performed with a single implant and single imaging done on day 1. The different fractionation schemes were: 7 Gy + 4x3.5 Gy (group 1); 7 Gy + 4x4.5 Gy (group 2); 3x7Gy (group 3) and 3x8Gy (group 4). Local (LFS), nodal (NFS) and metastatic (MFS) recurrence-free survival as well as progression-free survival (PFS) and overall survival (OS) were analyzed. Acute (≤6 months) and late toxicities (>6 months) were reported. RESULTS: From 2007 to 2018, 191 patients were included. Median follow-up was 57 months [45-132] and median EQD210D90CTVHR was 84, 82 and 90 Gy for groups 2, 3 and 4 respectively (dosimetric data missing for group 1). The 5-year LFS, NFS, MFS, PFS and OS were 85% [81-90], 83% [79-86], 70% [67-73], 61% [57-64] and 75% [69-78] respectively, with no significant difference between the groups. EQD210D90CTVHR < 85 Gy was a prognostic factor for local recurrence in univariate analysis (p = 0.045). The rates of acute/late grade ≥ 2 urinary, digestive and gynecological toxicities were 9%/15%, 3%/15% and 9%/25% respectively. CONCLUSION: Bi-fractionated HDR-BT boost seems feasible with good oncological outcome and slightly more toxicity after dose escalation.

Brachytherapy for oligometastatic prostate cancer to the penis.

The origin of penile metastases is in 70% of cases from primary pelvic cancers (genitourinary and recto-sigmoid primary tumors). The prognosis is poor and it is often associated with synchronous bone metastases at the time of diagnosis. We present the case of a 61-year-old patient who developed a penile induration 7 years after radical prostatectomy followed by adjuvant external beam radiation therapy for high-risk prostatic adenocarcinoma. Biopsies confirmed the metastatic localization and a detailed assessment failed to find any further remote lesions. Faced with this penile oligometastatic prostate cancer, we proposed an ablative treatment based on interstitial multi-catheter high-dose rate brachytherapy. At the six-month follow-up, clinical examination and 68Ga-PSMA-11-PET confirmed a complete response of the penile tumor without new lesion at a distance.

Orai1 Channel Regulates Human-Activated Pancreatic Stellate Cell Proliferation and TGFß1 Secretion through the AKT Signaling Pathway.

Activated pancreatic stellate cells (aPSCs), the crucial mediator of pancreatic desmoplasia, are characterized, among others, by high proliferative potential and abundant transforming growth factor ß1 (TGFß1) secretion. Over the past years, the involvement of Ca2+ channels in PSC pathophysiology has attracted great interest in pancreatic cancer research. We, thus, aimed to investigate the role of the Orai1 Ca2+ channel in these two PSC activation processes. Using the siRNA approach, we invalided Orai1 expression and assessed the channel functionality by Ca2+ imaging, the effect on aPSC proliferation, and TGFß1 secretion. We demonstrated the functional expression of the Orai1 channel in human aPSCs and its implication in the store-operated Ca2+ entry (SOCE). Orai1 silencing led to a decrease in aPSC proliferation, TGFß1 secretion, and AKT activation. Interestingly, TGFß1 induced a higher SOCE response by increasing Orai1 mRNAs and proteins and promoted both AKT phosphorylation and cell proliferation, abolished by Orai1 silencing. Together, our results highlight the role of Orai1-mediated Ca2+ entry in human aPSC pathophysiology by controlling cell proliferation and TGFß1 secretion through the AKT signaling pathway. Moreover, we showed a TGFß1-induced autocrine positive feedback loop by promoting the Orai1/AKT-dependent proliferation via the stimulation of Orai1 expression and function.

APBI Versus Ultra-APBI in the Elderly With Low-Risk Breast Cancer: A Comparative Analysis of Oncological Outcome and Late Toxicity.

PURPOSE: Accelerated partial breast irradiation (APBI) represents a validated technique for low-risk breast cancer. Recently, ultra-APBI (uAPBI) using fewer than 5 fractions was described in the literature. We compared clinical outcomes and late toxicity after APBI or uAPBI in older patients. METHODS AND MATERIALS: Two cohorts of older patients (aged ≥70 years) with low-risk breast cancer treated with APBI (interstitial brachytherapy) were analyzed retrospectively. A total dose of 34 Gy in10 fractions (APBI) or 16 Gy in 1 fraction (uAPBI) was delivered from 2004 to 2012 and from 2013 to 2018, respectively. Oncologic outcome analyzed the cumulative incidence of local relapse, regional relapse, and distant metastases with disease-free survival, cause-specific survival, and overall survival. Late toxicity and cosmetic results were investigated. RESULTS: One hundred fifty-seven patients (APBI, n = 109 patients; uAPBI, n = 48 patients) underwent APBI according to the same selection criteria. Apart from the median follow-up (97 vs 72 months for APBI and uAPBI; P < .002), no significant difference was noted between the 2 groups. Regarding 6-year oncologic outcome, no significant difference was observed between APBI and uAPBI for local recurrence (1.3% vs 0%; P = .4), regional recurrence (2.5% vs 2.3%; P = .9), distant metastases (4.3% vs. 2.4%; P = .6), disease-free survival (85.2% vs. 82.2%; P = .8), cause-specific survival (96.7% vs. 96.2%; P = .9), and overall survival (86.7% vs. 82.2%; P = .7). Regarding late toxicity, no significant difference was observed between APBI and uAPBI (total complication number, 45 vs 33%; P = .173) with only grade 1 (88.4% vs. 95%) and grade 2 (11.6% vs. 5%) late toxicities (P = .677). Similarly, no significant difference was observed for excellent/good cosmetic results between the 2 cohorts (P = .98). CONCLUSIONS: We report the first study comparing APBI versus uAPBI in a cohort of older patients with low-risk breast cancer. No significant difference was found between the 2 treatment groups regarding oncologic outcome, late toxicity, and cosmetic result. uAPBI based on a single fraction of brachytherapy represents an attractive option for therapeutic de-escalation in older patients with breast cancer.

High-dose rate brachytherapy in localized penile cancer: 5-Year clinical outcome analysis.

PURPOSE: To analyze the oncological outcome and toxicity profile after conservative treatment based on multicatheter interstitial high-dose rate brachytherapy (MHB) for patients presenting a localized penile cancer. MATERIALS AND METHODS: Patients with histologically proven, non-metastatic (T1-T2 N0-N2 M0) localized penile cancer were treated with MHB. Needles were placed under general anesthesia into the target volume using a dedicated template. Treatment planning was performed using a post-implant CT-scan to deliver 35 Gy or 39 Gy (9f, 5d) for adjuvant or definitive treatment respectively. Five-year oncological outcome was evaluated with local relapse-free (LRFS), regional relapse-free (RRFS), and metastasis-free survival (MFS), specific (SS) and overall survival (OS). In pre-treatment and follow-up consultations, skin, urinary and sexual toxicities were investigated using CTCAEv4.0 classification, International Prostate Symptom Score (IPSS) and International Index of Erectile Function 5-items (IIEF-5). Dosimetry data were also analyzed. RESULTS: From 03/2006 to 05/2020, with a median follow-up of 72.4 months [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], 29 pts, mainly T1 (75.9%) and N0 (89.7%), underwent MHB. Eleven (38%) and 18 pts (62%) received MHB as adjuvant or definitive treatment respectively. Five-year LRFS, RRFS, MFS, SS and OS were 82%, 82%, 89%, 88% and 73% respectively. Six patients (20.7%) experienced local relapse and underwent salvage penectomy leading to a penile preservation rate of 79.3%. Acute skin toxicity was reported 1 month after MHB, with 28% G1, 66% G2 and 6% G3. Late skin complications were telangiectasia for 5 pts (17%) and necrosis for 3 pts (10.3% requiring hyperbaric oxygen therapy). Comparing pre- and post-treatment status, no significant change was observed for skin appearance, IPSS and IIEF-5. CONCLUSION: MHB represents an efficient first line conservative treatment option for early penile cancers. Oncological outcome and late toxicity profile appear encouraging. However, larger-scale cohorts with longer follow-up are needed to more accurately precise the features of the best candidate to MHB.

Mg2+ Transporters in Digestive Cancers.

Despite magnesium (Mg2+) representing the second most abundant cation in the cell, its role in cellular physiology and pathology is far from being elucidated. Mg2+ homeostasis is regulated by Mg2+ transporters including Mitochondrial RNA Splicing Protein 2 (MRS2), Transient Receptor Potential Cation Channel Subfamily M, Member 6/7 (TRPM6/7), Magnesium Transporter 1 (MAGT1), Solute Carrier Family 41 Member 1 (SCL41A1), and Cyclin and CBS Domain Divalent Metal Cation Transport Mediator (CNNM) proteins. Recent data show that Mg2+ transporters may regulate several cancer cell hallmarks. In this review, we describe the expression of Mg2+ transporters in digestive cancers, the most common and deadliest malignancies worldwide. Moreover, Mg2+ transporters' expression, correlation and impact on patient overall and disease-free survival is analyzed using Genotype Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets. Finally, we discuss the role of these Mg2+ transporters in the regulation of cancer cell fates and oncogenic signaling pathways.

Accelerated partial breast irradiation in the elderly: 8-year oncological outcomes and prognostic factors.

PURPOSE: The purpose of the study is to evaluate long-term clinical outcomes and prognostic factors after accelerated partial breast irradiation (APBI) in the elderly using high-dose-rate interstitial multicatheter brachytherapy (HIBT). METHODS AND MATERIALS: Between 2005 and 2018, 109 patients underwent APBI using HIBT (34 Gy/10f/5d or 32 Gy/8f/4d). Based on a prospective database, outcomes were retrospectively analyzed (local relapse-free survival, metastatic-free survival, specific survival (SS), and overall survival (OS)). Prognostic factors were investigated. Late toxicity and cosmetic evaluation were reported. RESULTS: With a median followup of 97 months [7-159], median age was 81.7 years [58-89]. In accordance with the GEC-ESTRO APBI classification, 72.5%, 11.9%, and 15.6% were classified as low, intermediate, and high risk, respectively. The histological type was mainly invasive ductal carcinoma (87.1%). The median tumor size was 10 mm [range 1-35]. Eight-year local relapse-free survival, SS, and OS were 96.7% [95% confidence interval (CI) [0.923; 1]), 96.7% [95% CI [0.924; 1], and 72% [95% CI [0.616; 0.837], respectively. In univariate analysis, APBI classification was not considered as prognostic factor, whereas molecular classification was prognostic factor for OS (p < 0.0001), SS (p = 0.007), and metastatic-free survival (p = 0.009) but not for local recurrence (p = 0.586). No Grade ≥3 late toxicity was observed, whereas 61 patients (88.4%) and 8 patients (11.6%) presented Grade 1 and 2 toxicities, respectively. The cosmetic outcome was excellent/good for 96.4%. CONCLUSIONS: Long-term followup confirms that HIBT is safe and effective for elderly early breast cancer. Our results suggest that selected elderly women presenting with high-risk breast cancer could be also considered for APBI.

Unsupervised Hierarchical Clustering of Pancreatic Adenocarcinoma Dataset from TCGA Defines a Mucin Expression Profile that Impacts Overall Survival.

Mucins are commonly associated with pancreatic ductal adenocarcinoma (PDAC) that is a deadly disease because of the lack of early diagnosis and efficient therapies. There are 22 mucin genes encoding large O-glycoproteins divided into two major subgroups: membrane-bound and secreted mucins. We investigated mucin expression and their impact on patient survival in the PDAC dataset from The Cancer Genome Atlas (PAAD-TCGA). We observed a statistically significant increased messenger RNA (mRNA) relative level of most of the membrane-bound mucins (MUC1/3A/4/12/13/16/17/20), secreted mucins (MUC5AC/5B), and atypical mucins (MUC14/18) compared to normal pancreas. We show that MUC1/4/5B/14/17/20/21 mRNA levels are associated with poorer survival in the high-expression group compared to the low-expression group. Using unsupervised clustering analysis of mucin gene expression patterns, we identified two major clusters of patients. Cluster #1 harbors a higher expression of MUC15 and atypical MUC14/MUC18, whereas cluster #2 is characterized by a global overexpression of membrane-bound mucins (MUC1/4/16/17/20/21). Cluster #2 is associated with shorter overall survival. The patient stratification appears to be independent of usual clinical features (tumor stage, differentiation grade, lymph node invasion) suggesting that the pattern of membrane-bound mucin expression could be a new prognostic marker for PDAC patients.

TRPM7/RPSA Complex Regulates Pancreatic Cancer Cell Migration.

Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a very poor prognosis due to highly metastatic profile. Cell migration is an essential step of the metastatic cascade allowing cancer cells to spread toward target tissues. Recent studies strongly suggest that bioactive elastin peptides, also named elastokines or elastin-derived peptides (EDPs), are released in the extracellular microenvironment during tumoral remodeling of the stroma. EDPs stimulate cancer cell migration by interacting with their membrane receptor, ribosomal protein SA (RPSA). Others membrane proteins like ion channels are also involved in cancer cell migration. It has been recently shown that the transient receptor potential melastatin-related 7 (TRPM7) channel regulates PDAC cell migration and invasion. The objective of this work was to study the effect of EDPs on TRPM7 channel in human pancreatic cancer cells. We showed that EDPs promote MIA PaCa-2 cell migration using Boyden chamber assay. Cells transfected with a siRNA targeting TRPM7 were not able to migrate in response to EDPs indicating that TRPM7 regulated cell migration induced by these peptides. Moreover, EDPs were able to stimulate TRPM7 currents recorded by Patch-Clamp. Finally, we showed that TRPM7 channels and RPSA receptors are colocalized at the plasma membrane of human pancreatic cancer cells. Taken together, our data suggest that TRPM7/RPSA complex regulated human pancreatic cancer cell migration. This complex may be a promising therapeutic target in PDAC.

Cadmium exposure enhances cell migration and invasion through modulated TRPM7 channel expression.

Cadmium is a xenobiotic involved in neoplastic transformation. Cadmium enters the cells through divalent cation transporters including the Transient Receptor Potential Melastatin-related 7 (TRPM7) which is known to be involved in cancer cell fate. This work aimed to study the role of TRPM7 in neoplastic transformation induced by cadmium exposure in non-cancer epithelial cells. Non-cancer epithelial cells were chronically exposed to low-dose of cadmium. TRPM7 expression and function were studied by Western-Blot, Patch-Clamp and calcium and magnesium imaging. Finally, cell migration and invasion were studied by Boyden chamber assays. Chronic cadmium exposure induced TRPM7 overexpression and increased the membrane currents (P < 0.001). Cells exposed to cadmium had higher intracellular calcium and magnesium levels (P < 0.05). TRPM7 silencing restored calcium levels but strongly decreased intracellular magnesium concentration (P < 0.001). Moreover, cadmium exposure enhanced both cell migration and invasion, but TRPM7 silencing strongly decreased these features (P < 0.001). Furthermore, mammary epithelial cells exposed to cadmium became rounded and had less cell-to-cell junctions. Cadmium exposure decreased epithelial markers while the mesenchymal ones were increased. Importantly, TRPM7 silencing was able to reverse these phenotypic modifications (P < 0.05). To summarize, our data show that chronic cadmium exposure enhanced TRPM7 expression and activity in non-cancer epithelial cells. TRPM7 overexpression induced intracellular magnesium increase and stimulated cell migration and invasion. These neoplastic properties could be linked to a TRPM7-dependent epithelial-to-mesenchymal transition reprogramming in cell exposed to cadmium. These findings provide new insights into the regulation of cell fates by cadmium exposure.

Accelerated partial breast irradiation in the elderly: 5-Year results of the single fraction elderly breast irradiation (SiFEBI) phase I/II trial.

PURPOSE: To evaluate the clinical outcomes of a very-accelerated partial breast irradiation (vAPBI) in the elderly based on a single fraction of multicatheter interstitial high-dose rate brachytherapy (MIB). Mature results with a median follow-up of 5 years. METHODS AND MATERIALS: From November 2012 to September 2014, 26 patients (pts) (≥70) with early breast cancer were enrolled in a prospective phase II trial (NCT01727011). After lumpectomy, intraoperative catheter implant was performed for postoperative APBI (single fraction 16 Gy). Surveillance was performed twice a year after APBI. Oncologic outcome (local [LRFS], metastasis-free survival, cancer-specific survival, and overall survival [OS]) as well as late toxicity and cosmetic outcome were investigated. RESULTS: Median age was 77 years [69-89]. After a median follow-up of 63 months [60-68], 5-year LRFS, metastasis-free survival, cancer-specific survival, and overall survival rates were 100%, 95.5%, 100%, and 88.5%, respectively. Late toxicity was observed in 5 pts (19.2%) with a total of five events: 3 pts G1 (60%); and 2 pts G2 (40%). The observed late side effects were breast pain in 1 pt (G2 cytosteatonecrosis with occasional acetaminophen consumption), hypopigmentation (puncture site) in 2 pts (G1) and breast fibrosis in 2 pts (G1: 1 pt; G2: 1 pt). Cosmetic evaluation was excellent for 21 pts (81%) and good for 2 pts (19%). CONCLUSION: For elderly with early breast cancer, a vAPBI using a single fraction of postoperative MIB (16 Gy) provides excellent oncologic results, mainly in terms of local control and cancer death. Late toxicity and cosmetic profile are acceptable.

Coronary angiography in the setting of acute infective endocarditis requiring surgical treatment.

BACKGROUND: International guidelines recommend that preoperative coronary angiography is performed on patients at risk of coronary disease who have infective endocarditis requiring surgical treatment. However, the risks of contrast-induced nephropathy or vegetation embolization in case of aortic endocarditis should be considered. AIMS: To assess the safety, therapeutic implications and prognostic impact of coronary angiography in patients requiring surgical treatment for active infective endocarditis. METHODS: This retrospective monocentric study was conducted in patients referred to a tertiary care centre for active endocarditis management with a theoretical indication for surgery between January 2013 and February 2017. RESULTS: One hundred and ninety-three patients were included; 73.1% were men, the mean age was 61.9±16.3 years and the median EuroSCORE II was 5.8%. One hundred and nineteen patients (61.7%) had aortic endocarditis, which was associated with aortic vegetation in 74 cases (38.3%). Invasive coronary angiography was performed in 142 patients (73.6%) - 130 (91.6%) by radial approach - and 14 patients were evaluated by coronary multislice computed tomography (one patient had exploration with both techniques). Acute renal failure after coronary angiography was observed in 15 patients (10.6%), two patients (1.4%) presented a stroke within 24h after coronary angiography, but none had aortic endocarditis. Among the 178 patients (92.2%) who underwent surgery, 35 (19.7%) had significant coronary lesion(s) and 25 (14.0%) underwent an associated coronary artery bypass graft. CONCLUSIONS: Preoperative coronary angiography in patients affected by infective endocarditis provides relevant information in a significant proportion of patients and can be performed safely.