Tumor-Suppressive and Immunomodulating Activity of miR-30a-3p and miR-30e-3p in HNSCC Cells and Tumoroids.

Head and neck squamous cell carcinomas (HNSCCs) are heterogeneous tumors, well known for their frequent relapsing nature. To counter recurrence, biomarkers for early diagnosis, prognosis, or treatment response prediction are urgently needed. miRNAs can profoundly impact normal physiology and enhance oncogenesis. Among all of the miRNAs, the miR-30 family is frequently downregulated in HNSCC. Here, we determined how levels of the 3p passenger strands of miR-30a and miR-30e affect tumor behavior and clarified their functional role in LA-HNSCC. In a retrospective study, levels of miR-30a-3p and miR-30e-3p were determined in 110 patients and correlated to overall survival, locoregional relapse, and distant metastasis. miR-30a/e-3p were expressed in HNSCC cell lines and HNSCC patient-derived tumoroids (PDTs) to investigate their effect on tumor cells and their microenvironment. Both miRNAs were found to have a prognosis value since low miR-30a/e-3p expression correlates to adverse prognosis and reduces overall survival. Low expression of miR-30a/e-3p is associated with a shorter time until locoregional relapse and a shorter time until metastasis, respectively. miR-30a/e-3p expression downregulates both TGF-ßR1 and BMPR2 and attenuates the survival and motility of HNSCC. Results were confirmed in PDTs. Finally, secretomes of miR-30a/e-3p-transfected HNSCC activate M1-type macrophages, which exert stronger phagocytic activities toward tumor cells. miR-30a/e-3p expression can discriminate subgroups of LA-HNSCC patients with different prognosis, making them good candidates as prognostic biomarkers. Furthermore, by targeting members of the TGF-ß family and generating an immune-permissive microenvironment, they may emerge as an alternative to anti-TGF-ß drugs to use in combination with immune checkpoint inhibitors.

Ellipsoid calculations versus manual tumor delineations for glioblastoma tumor volume evaluation.

In glioblastoma, the response to treatment assessment is essentially based on the 2D tumor size evolution but remains disputable. Volumetric approaches were evaluated for a more accurate estimation of tumor size. This study included 57 patients and compared two volume measurement methods to determine the size of different glioblastoma regions of interest: the contrast-enhancing area, the necrotic area, the gross target volume and the volume of the edema area. The two methods, the ellipsoid formula (the calculated method) and the manual delineation (the measured method) showed a high correlation to determine glioblastoma volume and a high agreement to classify patients assessment response to treatment according to RANO criteria. This study revealed that calculated and measured methods could be used in clinical practice to estimate glioblastoma volume size and to evaluate tumor size evolution.

Weekly Paclitaxel, Carboplatin, and Cetuximab as First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma for Patients Ineligible to Cisplatin-Based Chemotherapy: A Retrospective Monocentric Study in 60 Patients.

OBJECTIVE: For most patients suffering from recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC), chemotherapy is the main option after considering surgery and reirradiation. Cetuximab combined with a platinum-fluorouracil regimen (EXTREME) has been the standard of care for over a decade. Nevertheless, a significant number of patients remain unfit for this regimen because of age, severe comorbidities, or poor performance status. The aim of this study is to investigate an alternative regimen with sufficient efficacy and safety. METHODS: We reviewed retrospectively the medical charts of all patients treated with paclitaxel, carboplatin, and cetuximab (PCC) at our institution. Eligibility criteria were as follows: first-line R/M-HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx not suitable for local therapy, cisplatin, and/or 5-FU ineligibility, ECOG-PS: 0-2. PCC consisted of paclitaxel 80 mg/m2, carboplatin AUC 2, and cetuximab at an initial dose of 400 mg/m2 then 250 mg/m2, for 16 weekly administrations followed by cetuximab maintenance for patients for whom a disease control was obtained. The primary endpoint was overall survival (OS), and secondary endpoints were overall response rate (ORR), progression free survival (PFS), and safety. RESULTS: We identified 60 consecutive patients treated with PCC between 2010 and 2016 at our institution. Thirty-one patients (52%) were ECOG-PS 2. Fifty-five patients (92%) were cisplatin ineligible. ORR was 43.3% (95% CI, 30.8-55.8), and disease control rate was 65% (95% CI, 52.9-77.1). With a median follow-up of 35.7 months (IQR 28.6-48.8), median PFS was 5.8 months (95% CI, 4.5-7.2), and median OS was 11.7 months (95% CI, 7.5-14.8). For ECOG-PS 0-1 patients, median OS was 14.8 months (95% CI, 12.2-21.7) while it was only 7.5 months (95%CI: 5.5-12.7) for ECOG-PS 2 patients (p < 0.04). Grades III-IV toxicities occurred in 30 patients (50%). Most toxicities were hematologic. Six patients (10%) had febrile neutropenia. Nonhematologic toxicities were reported such as cutaneous toxicities, neuropathy, infusion-related reactions, or electrolyte disorders. CONCLUSION: The weekly PCC regimen seems to be an interesting option in cisplatin-unfit patients. This study shows favorable PFS and OS when compared with what is achieved with the EXTREME regimen and a high controlled disease rate with predictable and manageable toxicities even in the more fragile population.

Cav1/EREG/YAP Axis in the Treatment Resistance of Cav1-Expressing Head and Neck Squamous Cell Carcinoma.

The EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy is the only targeted therapy that has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Recurrence arises in 50% of patients with HNSCC in the years following treatment. In clinicopathological practice, it is difficult to assign patients to classes of risk because no reliable biomarkers are available to predict the outcome of HPV-unrelated HNSCC. In the present study, we investigated the role of Caveolin-1 (Cav1) in the sensitivity of HNSCC cell lines to CTX-radiotherapy that might predict HNSCC relapse. Ctrl- and Cav-1-overexpressing HNSCC cell lines were exposed to solvent, CTX, or irradiation, or exposed to CTX before irradiation. Growth, clonogenicity, cell cycle progression, apoptosis, metabolism and signaling pathways were analyzed. Cav1 expression was analyzed in 173 tumor samples and correlated to locoregional recurrence and overall survival. We showed that Cav1-overexpressing cells demonstrate better survival capacities and remain proliferative and motile when exposed to CTX-radiotherapy. Resistance is mediated by the Cav1/EREG/YAP axis. Patients whose tumors overexpressed Cav1 experienced regional recurrence a few years after adjuvant radiotherapy ± chemotherapy. Together, our observations suggest that a high expression of Cav1 might be predictive of locoregional relapse of LA-HNSCC.

Role of hippocampal location and radiation dose in glioblastoma patients with hippocampal atrophy.

BACKGROUND: The hippocampus is a critical organ for irradiation. Thus, we explored changes in hippocampal volume according to the dose delivered and the location relative to the glioblastoma. METHODS: All patients were treated for glioblastoma with surgery, concomitant radiotherapy and temozolomide, and adjuvant temozolomide. Hippocampi were retrospectively delineated on three MRIs, performed at baseline, at the time of relapse, and on the last MRI available at the end of follow-up. A total of 98, 96, and 82 hippocampi were measured in the 49 patients included in the study, respectively. The patients were stratified into three subgroups according to the dose delivered to 40% of the hippocampus. In the group 1 (n = 6), the hippocampal D40% was < 7.4 Gy, in the group 2 (n = 13), only the Hcontra D40% was < 7.4 Gy, and in the group 3 (n = 30), the D40% for both hippocampi was > 7.4 Gy. RESULTS: Regardless of the time of measurement, homolateral hippocampal volumes were significantly lower than those contralateral to the tumor. Regardless of the side, the volumes at the last MRI were significantly lower than those measured at baseline. There was a significant correlation among the decrease in hippocampal volume regardless of its side, and Dmax (p = 0.001), D98% (p = 0.028) and D40% (p = 0.0002). After adjustment for the time of MRI, these correlations remained significant. According to the D40% and volume at MRIlast, the hippocampi decreased by 4 mm3/Gy overall. CONCLUSIONS: There was a significant relationship between the radiotherapy dose and decrease in hippocampal volume. However, at the lowest doses, the hippocampi seem to exhibit an adaptive increase in their volume, which could indicate a plasticity effect. Consequently, shielding at least one hippocampus by delivering the lowest possible dose is recommended so that cognitive function can be preserved. Trial registration Retrospectively registered.

Pseudoprogression versus true progression in glioblastoma patients: A multiapproach literature review: Part 1 - Molecular, morphological and clinical features.

With new therapeutic protocols, more patients treated for glioblastoma have experienced a suspicious radiologic image of progression (pseudoprogression) during follow-up. Pseudoprogression should be differentiated from true progression because the disease management is completely different. In the case of pseudoprogression, the follow-up continues, and the patient is considered stable. In the case of true progression, a treatment adjustment is necessary. Presently, a pseudoprogression diagnosis certainly needs to be pathologically confirmed. Some important efforts in the radiological, histopathological, and genomic fields have been made to differentiate pseudoprogression from true progression, and the assessment of response criteria exists but remains limited. The aim of this paper is to highlight clinical and pathological markers to differentiate pseudoprogression from true progression through a literature review.

Effects of a metallic implant on radiotherapy planning treatment-experience on a human cadaver.

BACKGROUND: Metallic implants (MIs) complicate radiotherapy planning. Several studies have worked on tissue-equivalent phantoms as experimental models to estimate dose distributions in this context. The application of these results to clinical practice remains disputable because the inhomogeneity of human tissue densities is a difficult factor to integrate into dose calculation software. In this work, we evaluate the impact of human tissue inhomogeneities by assessing the discrepancies between treatment planning system (TPS) dose calculations and measured delivered doses on a human cadaver with hip prostheses. METHODS: A total of 143 alanine dosimeters were positioned in contact with the prostheses (bones group), soft tissues (soft tissues group), skin surfaces (skin group) and natural cavities (cavities group) of a human cadaver. The planning target volume (PTV) corresponded to a standard endometrial cancer treatment. The irradiation was performed with 6 MV X-ray tomotherapy at the one fraction-dose of 10 Gy. RESULTS: A total of 140 dosimeters were analyzed. After applying a temperature correction coefficient to the measured doses, the global analysis of all dosimeters showed a significant difference between the calculated doses and the measured doses (P<0.001). For dosimeters of the bones, soft tissues, skin and cavities groups, this difference was also significant (P<0.001 for each group). The mean measured doses were 21.9% lower than the mean calculated doses in the global analysis and 17.0%, 21.2%, 33.0% and 19.0% lower for the bones, soft tissues, skin and cavities groups, respectively. CONCLUSIONS: This study showed that the received doses were significantly lower than the calculated doses and suggested the need to improve the understanding of this discrepancy.

[Supportive day care at a cancer center: A comparative study of 2008 versus 2016 activity]. / Hôpital de jour de soins de support dans un Centre de Lutte contre le cancer : étude comparative de l'activité entre 2008 et 2016.

The Paul Strauss Center day-care accompaniment department ("SSAJ") is an oncologic supportive day-care, also an alternative to conventional hospitalization. In order to follow the SSAJ department's activity, in the "ambulatory turnover" context, we compared the 2008 and 2016 four first months activity. In 2016, there was an average of 4.96 patients per day versus 5.62 in 2008 (P<0.001); average day incoming of 653€ per stay in 2016 versus 775€ in 2008 (P<0.001). In 2016, there was an average 63.9 % of imagery done versus 27.7 % in 2008 (P<0.001). The 2016 average patient following period was of 84.7 days versus 67.6 days in 2008 (P=0.019). Average time between first day-care visit and death was 161.7 days in 2016 versus 133.5 days in 2008 (P=0.0033). Average day activity is lower in 2016 than 2008, nonetheless number of total stays and inpatients has increased on the four months period. The SSAJ intervenes more precociously in 2016 than 2008. Hospital technical platform is better used, but average per-stay incoming has statistically lowered. The SSAJ limits and prepares complete hospitalizations. Inpatient close reevaluation after a "shorter-willing" stay, home issues anticipation and identification with the home-care team, and worsening prevention gives this activity all its meaning.

Efficacy and Tolerance of Intensity Modulated Radiation Therapy for Skull Base Meningioma.

PURPOSE: The purpose of this study was to evaluate the efficacy and tolerance of normofractionated stereotactic radiation therapy (RT) and intensity modulated RT with helical tomotherapy for skull base meningioma. METHODS AND MATERIALS: Between January 2009 and 2014, 46 patients with skull base meningioma were treated with normofractionated intensity modulated RT in stereotactic conditions (50%) or with helical tomotherapy (50%). Most of the lesions were localized in the cavernous sinus (59%). The mean planning target volume was 47.2 mL (range, 1.1-223 mL). RESULTS: After treatment, 5 lesions exhibited a partial response radiologically and 39 lesions were stable. At the time of treatment, 35 patients were symptomatic with a mean of 2 symptoms per patient. The most frequent symptoms were visual impairment (41%), cranial nerve dysfunction (20%), and headache (16%). The median follow-up time was 42 months (range, 10-76 months). After RT, 71% of patients exhibited an improvement of at least 1 symptom with a median interval of 15.6 months (range, 5.3-30.5 months). The most frequent improved symptoms were cranial nerve deficits (47%), visual impairment (45%), and headache (42%).The clinical response was correlated with the clinical target volume (CTV) margin (P = .06), extended clinical follow-up time (P = .004), and larger planning target volume (P = .05) by univariate analysis. Taking in account correlation factors, in the multivariate analysis, only CTV was a favorable significant factor of clinical improvement (P = .049; hazard ratio: 5 95%; confidence interval, 1.1-28). We observed 3 cases of trigeminal nerve dysfunction at 4.2, 5.7, and 24.6 months; 2 cases of visual disturbance at 10.1 and 24 months; 2 cases of neurocognitive disorders at 12.9 and 35.2 months; and 1 case of stroke at 20.3 months. CONCLUSIONS: RT for skull base meningiomas is an effective and safe treatment, leading in most cases to clinical improvement. The addition of a CTV margin to meningioma volume improved the symptoms of patients.

Hemodialysis without anticoagulation: Less clotting in conventional hemodialysis than in predilution hemodiafiltration.

INTRODUCTION: Hemodialysis patients with contraindication to systemic anticoagulation require a heparin-free hemodialysis technique. Among several alternatives to heparin, predilution hemodiafiltration (HDF) is often used, albeit without any confirmation of its effectiveness. METHODS: Patients hospitalized in a nephrology ICU and hemodialysed for stage 5 CKD or AKI and with contraindication to systemic anticoagulation were randomized to either standard HD with a polysulfone membrane, or to predilution HDF with the same membrane. Coagulation activation was evaluated clinically by the need for premature termination and by the measurement of D-dimers. FINDINGS: Two hundred dialysis sessions were performed in 155 patients. Survival curves showed better circuit survival in HD (P = 0.046). In HD, 12% of sessions were interrupted for coagulation versus 23% in predilution HDF (P = 0.04). DISCUSSION: Predilution HDF was associated with more premature clotting than conventional HD without improvement in dialysis duration or performance epuration indices. When aiming for a 4-hour duration session, conventional heparin-free hemodialysis can be safely proposed in most patients with high bleeding risk.

Survival advantage of planned haemodialysis over peritoneal dialysis: a cohort study.

Background: Previous studies comparing the outcomes in haemodialysis (HD) with those in peritoneal dialysis (PD) have yielded conflicting results. Methods: The aim of the study was to compare the survival of planned HD versus PD patients in a cohort of adult incident patients who started renal replacement therapy (RRT) between 2006 and 2008 in the nationwide REIN registry (Réseau Epidémiologie et Information en Néphrologie). Patients who started RRT in emergency or stopped RRT within 2 months were excluded. Adjusted Cox models, propensity score matching and marginal structural models (MSMs) were used to compensate for the lack of randomization and provide causal inference from longitudinal data with time-dependent treatments and confounders including transplant censorship, modality change over time and time-varying covariates. Results: Among a total of 13 767 dialysis patients, 13% were on PD at initiation of RRT and 87% were on HD. The median survival times were 53.5 months or 4.45 years and 38.6 months or 3.21 years for patients starting on HD and PD, respectively. Regardless of the model used, there was a consistent advantage in terms of survival for HD patients: hazard ratio (HR) 0.76 [95% confidence interval (95% CI) 0.69-0.84] with the Cox model using propensity score; HR 0.67 (95% CI 0.62-0.73) in the Cox model with censorship for each treatment change; and HR 0.82 (95% CI 0.69-0.97) with MSMs. However, MSMs tended to reduce the survival gap between PD and HD patients. Conclusion: This large cohort study using various statistical methods to minimize the bias appears to demonstrate a better survival in planned HD than in PD.

Treatments, Outcomes, and Validity of Prognostic Scores in Patients With Sarcomatoid Renal Cell Carcinoma: A 20-Year Single-Institution Experience.

INTRODUCTION: Metastatic renal cell carcinoma (RCC) with a sarcomatoid component is a rare disease associated with a poor prognosis. We report the outcomes of 47 patients with metastatic sarcomatoid RCC (SRCC) treated with different modalities including chemotherapy, tyrosine kinase inhibitors, or immunotherapy over 2 decades in a French cancer center. Furthermore, we assessed the validity of prognostic scores in this subset of RCC. PATIENTS AND METHODS: Patients were retrospectively identified from the database of the pathology department of the University Hospital of Strasbourg. We enrolled all patients with RCC with a sarcomatoid component diagnosed between 1995 and 2016. Patients with nonmetastatic RCC were excluded. Recorded variables included: clinical stage, metastatic sites, pathologic stage, type of treatments, prognostic group, and survival data. The primary end point was overall survival. The institutional ethical committee approved the study protocol. RESULTS: Of 104 patients with SRCC, 47 patients with metastatic SRCC were included. The median age was 60 years (range, 41-77 years). Median length of follow-up was 34 months (range, 1-180 months). Fifty-five percent of patients had known metastases at diagnosis. Lung represented the first metastatic site (70%) followed by glandular (28%), bone (23%), liver (21%), and brain (6%). Fifteen percent of patients received immunotherapy including cytokine-based therapy (n = 7), or checkpoint inhibitors (n = 2). Moreover, 7 patients received chemotherapy. Five patients received no systemic treatment because of their poor performance status. Of 42 treated patients, 2 patients achieved complete response and 9 partial response (24%). Median overall survival was 13.3 months. International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups were valid in this subset of SRCC patients. A sarcomatoid percentage cutoff of 30% had the strongest influence on overall survival. CONCLUSION: Despite the arrival of tyrosine kinase inhibitors 10 years ago, metastatic SRCC remains a disease of poor prognosis and difficult to treat. Chemotherapy regimen and targeted therapies showed little activity in SRCC. IMDC score is a relevant prognostic factor in SRCC patients. Additionally, the MSKCC score, the sarcomatoid percentage, the necrotic fraction, and the vascular invasion could prove useful in identifying patients with a more favorable prognosis. These findings could help toward better patient stratification in clinical trials. Prospective trials assessing new drugs including immune checkpoint inhibitors are currently ongoing to improve SRCC survival.

Proposal of a new preliminary scoring tool for early identification of significant blunt bowel and mesenteric injuries in patients at risk after road traffic crashes.

PURPOSE: Blunt bowel and mesenteric injuries (BBMI) are regularly missed by abdominal computed tomography (CT) scans. The aim of this study was to develop a risk assessment tool for BBMI to help clinicians in decision-making for blunt trauma after road traffic crashes (RTCs). METHODS: Single-center retrospective study of trauma patients from January 2010 to April 2015. All patients admitted to our hospital after blunt trauma following RTCs and CT scan at admission were assessed. RESULTS: Of the 394 patients included, 78 (19.8%) required surgical exploration and 34 (43.6%) of these had a significant BBMI. A univariate and multivariate analysis were performed comparing patients with BBMI (n = 34) and patients without BBMI (n = 360). A score with a range from 0 to 13 was created. Scores from 8 to 9 were associated with 5-25% BBMI risk. The power of this new score ≥ 8 to predict a surgically significant BBMI had a sensitivity of 96%, specificity of 86.4%, positive predictive value (PPV) of 48% and negative predictive value (NPV) of 99.4%. CONCLUSION: This score could be a valuable tool for the management of blunt trauma patients after RTA without a clear indication for laparotomy but at risk for BBMI. The outcome of this study suggests selective diagnostic laparoscopy for a score ≥ 8 in obtunded patients and ≥ 10 in all other. To assess the value and accuracy of this new score, a prospective validation of these retrospective findings is due.

Interest to consider re-challenging by cetuximab and platinum containing regimen in recurrent Head and Neck Cancer.

BACKGROUND: The EXTREME protocol is the standard of care for recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) in first line. Beyond the first-line except immunotherapy, poor efficacy was reported by second-line chemotherapy. Re-challenge strategies based on a repetition of the first line with platinum and cetuximab regimens might have been an option to consider. METHODS: We performed a retrospective study in order to assess the efficacy of the cetuximab plus platinum doublet-based chemotherapy regimen in patients with R/M HNSCC progressing after at least 3 months of cetuximab maintenance (EXTREME protocol). We complete a retrospective review of all medical records from R/M HNSCC patients treated after 16 weeks with the EXTREME regimen and treated with a re-challenge strategy between January 2010 and December 2014 in our institution (Centre Paul Strauss, Strasbourg, France). RESULTS: 33 patients were identified. The re-challenged strategy provided an ORR in 33.3% of cases and a DCR of 69.6% of cases. The median OS and PFS observed from the second line were 11.2 months and 6.5 months for the subset re-challenged by EXTREME or PCC regimens respectively. The response rate between patients with a platin free interval within 3 and 6 months and greater than 6 months were equal. Drugs dose intensity were better with the PCC protocol than the EXTREME regimen used as a rechallenge. CONCLUSIONS: This study suggest re-challenging strategy by these regimens could be considered beyond the first line as an option when the platin free interval is greater than 3 months.

Psychotropic Drug Use in Recreational Scuba Divers and its Effect on Severe Narcosis.

Recreational scuba diving is no longer reserved for young healthy individuals, and as a result, medical drug consumption is on the rise in the diving population. Due to the possible potentiation of nitrogen narcosis by psychotropic drugs, the latter are hence discouraged and are subject to contraindications for practice. However, there are no available experimental data to support this theoretical assumption. The objective of this study is to investigate whether psychotropic drug users are more at risk of severe narcosis. An online survey was sent to the licensed divers from the East of France registered with the French Underwater Federation. Divers were surveyed regarding their consumption of psychotropic drugs, the occurrence of nitrogen narcosis as well as their respective diver's curriculum vitae.1 608 divers responded to the survey of which 15.2% confirmed having used psychotropic drugs and 7.8% since they became divers. Overall, 40.0% and 5.5% experienced severe and critical narcosis. In multivariate analysis, neither severe nor critical narcosis was associated with psychotropic drug use (OR 0.97 [0.59-1.57] and 0.76 [0.29-2.00], respectively).In conclusion, despite the recommendations, a significant proportion of divers use psychotropic drugs but do not seem to be more prone to severe narcosis.

Excess cervical cancer screening smears: Any benefit? A retrospective cohort in Alsace, France.

Objectives Although cervical cancer screening guidelines in France recommend a smear test every three years, many physicians order more regular screening. We aimed to assess the benefits or harms of shorter intervals between screenings, both for women and public health. Methods For a retrospective cohort of women aged 25-65 who had two normal smears and at least one additional smear, data were sourced from a regionally organized cervical cancer screening programme in France, with follow-up for nine years. Based on the interval between the second and third smear, two groups were formed; the first comprised overscreened women (interval <24 months), and the second of 'correctly' screened women (interval between 24 and 42 months). The primary outcome was cervical intraepithelial neoplasia 2 or worse (CIN2+); secondary outcomes were cervical cancers and CIN1 lesions. Results Among 63,821 women, CIN2+ incidence rate per 10,000 women per year was 14.5 for 40,350 overscreened women, and 11.5 for 23,471 correctly screened women. Age-adjusted relative risk was 1.22[1.02; 1.46]. We found no significant difference for cancer (RR = 1.39; 95%CI = [0.60; 3.61]), but did find additional CIN1 in the overscreened group (RR = 2.09; 95%CI = [1.76; 2.51]). Conclusions A shorter interval between smears has a low benefit for CIN2+ lesion detection, which may not help avoid cancer. The excess number of CIN1 detected by overscreening may cause needless risk and excess costs due to overtreatment.