Higher Levels of SARS-CoV-2 Genetic Variation in Immunocompromised Patients: A Retrospective Case-Control Study.

BACKGROUND: A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection lasts longer in immunocompromised hosts than in immunocompetent patients. Prolonged infection is associated with a higher probability of selection for novel SARS-CoV-2 mutations, particularly in the spike protein, a critical target for vaccines and therapeutics. METHODS: From December 2020 to September 2022, respiratory samples from 444 immunocompromised patients and 234 health care workers positive for SARS-CoV-2, diagnosed at 2 hospitals in Paris, France, were analyzed using whole-genome sequencing using Nanopore technology. Custom scripts were developed to assess the SARS-CoV-2 genetic diversity between the 2 groups and within the host. RESULTS: Most infections were SARS-CoV-2 Delta or Omicron lineages. Viral genetic diversity was significantly higher in infections of immunocompromised patients than those of controls. Minor mutations were identified in viruses sequenced from immunocompromised individuals, which became signature mutations for newer SARS-CoV-2 variants as the epidemic progressed. Two patients were coinfected with Delta and Omicron variants. The follow-up of immunocompromised patients revealed that the SARS-CoV-2 genome evolution differed in the upper and lower respiratory tracts. CONCLUSIONS: This study found that SARS-CoV-2 infection in immunocompromised patients is associated with higher genetic diversity, which could lead to the emergence of new SARS-CoV-2 variants with possible immune evasion or different virulence characteristics.

Epstein-Barr Virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.

Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies.

Association between humoral serological markers levels and risk of SARS-CoV-2 infection after the primary COVID-19 vaccine course among ANRS0001S COV-POPART cohort participants.

BACKGROUND: We assessed the prognostic value of serological humoral markers measured one month after the last dose of the primary COVID-19 vaccine course for predicting the risk of severe acute respiratory syndrome coronavirus 2 SARS-CoV-2 infection over the following six months in specific populations. METHODS: ANRS0001SCOV-POPART is a French nationwide multicenter prospective observational cohort study assessing the immune response to Covid-19 vaccines routinely administered to 11 subgroups of patients with chronic disease and a control group. Participants from the ANRS0001S COV-POPART were included if they received at least two doses of Covid-19 vaccine for the primary vaccine course, had measurements of anti-Spike, anti-receptor binding domain (RBD) IgG-specific or neutralizing antibodies one month after the end of the primary vaccine course, without being infected by SARS-CoV-2 before the measurement. SARS-CoV-2 infections defined by a positive PCR/antigenic test or seroconversion to detectable anti nucleocapsid antibodies were evaluated until the first COVID-19 booster injection. Cox proportional hazards models taking into account interval-censored data were implemented to estimate the association between each antibody level and the risk of SARS-CoV-2 infection. Predictive performances were evaluated by the area under the receiving operating characteristic curve (AUROC). RESULTS: Two thousand five hundred seventy adults from a specific population and 1,123 from the control group were included. The cumulative probabilities of SARS-CoV-2 infections at five months after serological measurement were 6.0% 95% confidence interval: [5.0; 7.9] and 10.1% 95% confidence interval: [8.3; 11.9], respectively. Higher levels of anti-Spike IgG antibody were associated with a lower risk of SARS-CoV-2 infections in the control group, but not in the specific populations. Among the specific populations, AUROC were 74.5%, 74.9%, and 72.4% for anti-Spike IgG, anti-RBD IgG, and neutralizing antibodies, respectively. AUROC were superior in the specific populations, 82.0%, 81.2%, and 81.4% for anti-Spike IgG, anti-RBD IgG, and neutralizing antibodies, respectively. CONCLUSIONS: Vaccine-induced antibody response after the primary course of Covid-19 infection only moderately discriminated between participants developing a SARS-CoV-2 infection during the Omicron wave. TRIAL REGISTRATION: NCT04824651 (first posted: 2021-04-01).

Initial experience, feasibility, and technical development with an electromagnetic navigation assistance in percutaneous pelvic bone cementoplasty: retrospective analysis.

OBJECTIVES: To assess the feasibility and technical outcomes of pelvic bone cementoplasty using an electromagnetic navigation system (EMNS) in standard practice. MATERIALS AND METHODS: Monocentric retrospective study of all consecutive patients treated with cementoplasty or reinforced cementoplasty of the pelvic bone with EMNS-assisted procedures. The endpoints were periprocedural adverse events, needle repositioning rates, procedure duration, and radiation exposure. RESULTS: A detailed description of the technical steps is provided. Thirty-three patients (68 years ± 10) were treated between February 2016 and February 2020. Needle repositioning was required for 1/33 patients (3%). The main minor technical adverse event was soft tissue PMMA cement leaks. No major adverse event was noted. The median number of CT acquisitions throughout the procedures was 4 (range: 2 to 8). Radiation exposure and mean procedure duration are provided. CONCLUSION: Electromagnetic navigation system-assisted percutaneous interventions for the pelvic bone are feasible and lead to low rates of minor technical adverse events and needle repositioning. Procedure duration and radiation exposure were low. KEY POINTS: • Initial experience for 33 patients treated with an electromagnetic navigation assistance for pelvic cementoplasty shows feasibility and safety. • The use of an electromagnetic navigation system does not expose to high procedure duration or radiation exposure. • The system is efficient in assisting the radiologist for extra-axial planes in challenging approaches.

FOLFIRI in advanced platinum-resistant/refractory small-cell lung cancer: a retrospective study.

BACKGROUND: Small-cell lung cancer (SCLC) accounts for approximately 15% of lung cancer and is associated with poor prognosis. In platinum-refractory or -resistant SCLC patients, few treatment options are available. Topotecan is one of the standards of care for these patients, however, due to its high toxicity, several different approaches are employed. FOLFIRI (folinate, 5-fluorouracil and irinotecan) is a chemotherapy regimen used in digestive neuroendocrine carcinoma, which shares pathological similarities with SCLC. In this retrospective study, we evaluated the efficacy and safety of FOLFIRI in patients with platinum-resistant/refractory SCLC. METHODS: Medical records from all consecutive SCLC patients treated with FOLFIRI in a French University Hospital from 2013 to 2021 were analyzed retrospectively. The primary endpoint was the objective response rate according to RECIST v1.1 or EORTC criteria (ORR); secondary endpoints included duration of response, disease control rate, progression-free survival (PFS), overall survival (OS) and safety profile. RESULTS: Thirty-four patients with metastatic platinum-resistant (n = 14) or -refractory (n = 20) SCLC were included. Twenty-eight were evaluable for response, with a partial response observed in 5 patients for an overall ORR in the evaluable population of 17.9% (5/28) and 14.7% (5/34) in the overall population. The disease control rate was 50% (14/28) in the evaluable population. The median PFS and OS were 2.8 months (95%CI, 2.0-5.2 months) and 5.3 months (95%CI, 3.5-8.9 months), respectively. All patients were included in the safety analysis. Grade 3 or 4 adverse events occurred in 13 (38.2%) patients. The most common grade 3 or 4 adverse events were asthenia, neutropenia, thrombopenia and diarrhea. There was no adverse event leading to discontinuation or death. CONCLUSION: FOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response and had an acceptable safety profile. However, caution is needed in interpreting this result. FOLFIRI could represent a potential new treatment for platinum-resistant/refractory SCLC patients. Further prospective studies are needed to assess the benefits of this chemotherapy regimen.HIGHLIGHTSFOLFIRI showed some activity for platinum-resistant/refractory SCLC in terms of overall response.FOLFIRI was well-tolerated in platinum resistant/refractory SLCL patients.FOLFIRI could represent a potential new treatment for SCLC, prospective studies are needed.

Reinforced cementoplasty for pelvic tumour lesions and pelvic traumatic fractures: preliminary experience.

OBJECTIVES: Pelvic bone pathological lesions and traumatic fractures are a considerable source of pain and disability. In this study, we sought to evaluate the effectiveness of reinforced cementoplasty (RC) in painful and unstable lesions involving the pelvic bone in terms of pain relief and functional recovery. METHODS: All patients with neoplastic lesion or pelvic fracture for whom a pelvic bone RC was carried out between November 2013 and October 2017 were included in our study. All patients who failed the medical management, patients unsuitable for surgery, and patients with unstable osteolytic lesions were eligible to RC. Clinical outcome was evaluated with a 1-month and 6-month post-procedure follow-up. The primary endpoint was local pain relief measured by the visual analogue scale (VAS). RESULTS: Twenty-two patients (18 females, 4 males; mean age of 65.4 ± 13.3 years [range 38-80]) presenting with painful and unstable pelvic lesions were treated by RC during the study period. Among the 22 patients, 8 patients presented with unstable pelvic fractures (3 patients with iliac crest fracture, 3 with sacral fractures, and the remaining 2 with peri-acetabular fractures). No procedure-related complications were recorded. All patients had significant pain relief and functional improvement at 1 month. One patient (4.5%) had suffered a secondary fracture due to local tumour progression. CONCLUSIONS: Reinforced cementoplasty is an original minimally invasive technique that may help in providing pain relief and effective bone stability for neoplastic and traumatic lesions involving the pelvic bone. KEY POINTS: • Reinforced cementoplasty is feasible in both traumatic fractures and tumoural bone lesions of the pelvis. • Reinforced cementoplasty for pelvic bone lesions provides pain relief and functional recovery. • Recurrence of pelvic bone fracture was observed in 4.5% of the cases in our series.

New Kaposi's sarcoma-associated herpesvirus variant in men who have sex with men associated with severe pathologies.

BACKGROUND: Kaposi sarcoma (KS)-associated herpesvirus (KSHV) subtype depends mostly on patient origin. The current study aimed to assess KSHV diversity in a population of men who have sex with men (MSM) living in France. METHODS: The study included 264 patients. In 65 MSM, including 57 human immunodeficiency virus (HIV)-infected men with KS, multicentric Castleman disease, or primary effusion lymphoma and 8 HIV-uninfected men receiving HIV preexposure prophylaxis (PrEP), we performed KSHV typing with K1 open reading frame Sanger and KSHV whole-genome sequencing. In 199 other patients, we performed real-time polymerase chain reaction screening for the new variant. RESULTS: We found that 51% of KSHV-strains were subtype C (85% C3), and 33% were subtype A. Four patients with severe KSHV disease (2 with visceral KS, 1 with multicentric Castleman disease, and 1 with primary effusion lymphoma) and 1 asymptomatic PrEP user had a new variant resembling the Ugandan subtype F, but with different K1 open reading frame and KSHV whole-genome sequences and a different epidemiological context (MSM vs African population). Its prevalence was 4.5% in Caucasian MSM, and it was absent in other epidemiological groups. CONCLUSIONS: Subtype C predominated among MSM living in France. The new F variant was identified in Caucasian MSM and associated with severe KSHV disease, suggesting that subtype F could be split into F1 and F2 variants. Careful screening for this variant may be required in MSM, given the severe clinical presentation of associated diseases.

Recurrence and Occurrence of Kaposi's Sarcoma in Patients Living With Human Immunodeficiency Virus (HIV) and on Antiretroviral Therapy, Despite Suppressed HIV Viremia.

In 21 cutaneous and/or visceral Kaposi's sarcoma cases, occurring in patients living with human immunodeficiency virus (HIV) who were on antiretroviral therapy with suppressed HIV viremia and high CD4 T cell counts, the efficacy of conventional chemotherapies was limited due to cumulative toxicities, comedications, and a lack of immune improvement.

First-line carboplatin plus pemetrexed with pemetrexed maintenance in HIV-positive patients with advanced non-squamous non-small cell lung cancer: the phase II IFCT-1001 CHIVA trial.

HIV infection is an exclusion criterion in lung cancer trials. This multicentre phase II trial aimed to assess feasibility, efficacy and safety of first-line carboplatin plus pemetrexed (CaP) followed by pemetrexed (P) maintenance in people living with HIV (PLHIV) with advanced non-squamous non-small cell lung cancer (NS-NSCLC).Four cycles of CaP were followed by P-maintenance therapy in patients with Eastern Cooperative Oncology Group performance status ≤2. The primary objective was a disease control rate (DCR) ≥30% after 12 weeks.Of the 61 PLHIV enrolled, 49 (80%) had a performance status of 0-1, and 19 (31%) had brain metastases. Median CD4 lymphocyte count was 418 cells·µL-1 (range 18-1230), median CD4 lymphocyte nadir was 169.5 cells·µL-1 (1-822); 48 (80%) patients were virologically controlled. Four-cycle inductions were achieved by 38 (62%) patients, and 31 (51%) started P-maintenance (median of 4.1 cycles (range 1-19)). The 12-week DCR was 50.8% (95% CI 38.3-63.4) and partial response rate 21.3%. Median progression-free survival and overall survival were 3.5 (95% CI 2.7-4.4) and 7.6 months (5.7-12.8), respectively. Patients with a performance status of 0-1 had the longest median progression-free survival (4.3 months, 95% CI 3.1-5.2) and overall survival (11.9 months, 95% CI 6.4-14.3). During induction, CaP doublet was well tolerated apart from grade 3-4 haematological toxicities (neutropenia 53.8%; thrombocytopenia 35.0%; anaemia 30.0%). Two fatal treatment-related sepses were reported. No opportunistic infections were experienced.In PLHIV with advanced NS-NSCLC, first-line four-cycle CaP induction followed by P-maintenance was effective and reasonably well-tolerated. Further studies should evaluate combination strategies of CaP with immunotherapy in PLHIV.

Safety and effectiveness of cervical vertebroplasty: report of a large cohort and systematic review.

PURPOSE: To evaluate retrospectively safety and effectiveness of cervical vertebroplasty (cVP) based on a single-center large cohort. MATERIALS AND METHODS: All cVP performed at a single center from January 2001 to October 2014 were included and reviewed. Procedure-related complications (minor and major) were systematically recorded. Effectiveness in terms of analgesia was evaluated using a semi-quantitative grading scale at 1-month follow-up. Risk factors for the occurrence of a procedure-related complication or cement leakage, as well as factors influencing pain relief at 1-month follow-up, were evaluated using a multivariate analysis. RESULTS: One hundred and forty cVP procedures (176 vertebrae) were performed in 130 consecutive patients (88 female, 42 male; mean age = 56 years) during the inclusion period. Among the treated lesions, 80% were bone metastases (mostly from breast cancer), 8% were related to hematological malignancies, and 12% were non-malignant lesions. One fatal complication (0.7%) was related to cement migration in the vertebrobasilar system. Three cervical hematomas were recorded, one of them requiring prolonged oral intubation. The overall rate of major complications was 1.5%. At 1 month, pain reduction was observed in 76% of the cases. Additional surgical fixation was required in 6.1% of the cases. cVP of more than one vertebra during the same session was an independent risk factor for procedure-related complications. CONCLUSION: Cervical vertebroplasty is a safe technique with an acceptable major complication rate. Its effectiveness in terms of pain relief is good at mid-term follow-up. KEY POINTS: • Cervical vertebroplasty (cVP) is a safe procedure with a low rate of major complications (1.5%). • cVP provides pain relief in 76% of the cases. • Additional fixation surgery is rarely required after cVP (6.1% of the cases).

Brain Metastases and Place of Antiangiogenic Therapies in Alveolar Soft Part Sarcoma: A Retrospective Analysis of the French Sarcoma Group.

BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare sarcoma characterized by a slow evolution, brain metastasis (BM), and resistance to doxorubicin. Antiangiogenic therapies (AAT) have shown clinical activity, but little is known about the optimal therapeutic strategy, specifically considering BM. SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective analysis of all patients with ASPS treated in three referral centers of the French Sarcoma Group. We aimed to describe factors associated with overall survival (OS) and the impact of BM on outcome of patients treated by AAT. RESULTS: We identified 75 patients between 1971 and 2012 (median age = 23, range: 5-96 years). Median follow-up was 74 months. Patients with localized (n = 44, 59%) and metastatic (n = 31, 41%) diseases had a 10-year OS of 69% and 25%, respectively. Only surgical incomplete resection was associated with shorter OS in localized disease (hazard ratio [HR] = 5.2, 95% confidence interval [CI] 1.2-22.4, p = .02). Fifty-two (69%) patients developed lung metastasis (LM; baseline: n = 31, [41%]; de novo: n = 21, [28%]). Thirteen patients developed BM, all occurring after LM. Tumor size ≥5 cm was associated with poorer BM-free survival (HR = 8.4, 95% CI 2.1-33.9, p = .002). Median OS post-BM was 17 months (95% CI 15 to not assessable). Overall, 12 patients were treated with AAT (sunitinib n = 10): 5 patients had BM and achieved poor outcomes compared with patients without, with median progression-free-survivals of 2 versus 11 months, respectively. CONCLUSION: Baseline larger tumors were associated with increased risk of brain metastasis in patients with ASPS. Patients with BM seem to have little benefit from AAT, suggesting the need to develop antineoplastic agents with high central nervous system penetrance in this setting. IMPLICATIONS FOR PRACTICE: Alveolar soft part sarcoma (ASPS) is an extremely rare subtype of sarcoma that is particularly resistant to conventional therapies. Antiangiogenic therapies (AAT) have shown promising results. However, patients with ASPS still die of tumor evolution. This study highlights the prognostic shift induced by brain metastasis (BM), identifying this event as a major contributor to the death of patients with ASPS, and observes a striking lack of effectiveness of AAT in patients who had previously developed BM. This observation is of interest for the therapeutic development in ASPS, highlighting the need to develop strategies dedicated to BM, such as radiosurgery or high-central nervous system penetrance tyrosine kinase inhibitors.

Intracardiac cement embolism during percutaneous vertebroplasty: incidence, risk factors and clinical management.

OBJECTIVE: To evaluate the incidence and risk factors for ICE during a PV. MATERIALS AND METHODS: Single-center retrospective analysis of 1512 consecutive patients who underwent 1854 PV procedures for osteoporotic (34 %), malignant (39.9 %) or other cause (26.1 %) of vertebral compression fractures (VCFs)/spine tumor lesions. Only thoracic or lumbar PVs were included. PVs were performed with polymethylmethacrylate (PMMA) low-viscosity bone cement under fluoroscopic guidance. Chest imaging (X-ray or CT) was performed the same day after PV in patients with high clinical suspicion of ICE. All post-procedural chest-imaging examinations were reviewed, and all ICEs were agreed upon in consensus by two radiologists. RESULTS: ICEs were detected in 72 patients (92 cement embolisms). In 86.1 % of the cases, concomitant pulmonary artery cement leakage was detected. Symptomatic ICEs were observed in six cases (8.3% of all ICEs; 0.32% of all PV procedures). No ICE led to death or permanent sequelae. Multiple levels treated during the same PV session were associated with a higher ICE rate [OR: 3.59, 95% CI: (1.98-6.51); p < 0.001]; the use of flat panel technology with a lower ICE occurrence [OR: 0.51, 95% CI: (0.32-0.83); p = 0.007]. CONCLUSION: Intracardiac cement embolism after PV has a low incidence (3.9 % in our study). Symptomatic complications related to ICE are rare (0.3%); none was responsible for clinical sequelae in our series. KEY POINTS: • The incidence of intracardiac cement embolism (ICE) during PVP is low (3.9%). • Having a high number of treated vertebrae during the same session is a significant risk factor for ICE. • Symptomatic intracardiac cement embolisms have a low incidence (8.3% of patients with ICE).

Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs. METHODS: In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC025 is the lower end of the IC 95% credibility interval, and an IC025 value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540. FINDINGS: We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 [95% CI 9·36-13·43]; IC025 3·20), pericardial diseases (12 800 vs 95, 3·80 [3·08-4·62]; IC025 1·63), and vasculitis (33 289 vs 82, 1·56 [1·25-1·94]; IC025 0·03), including temporal arteritis (696 vs 18, 12·99 [8·12-20·77]; IC025 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 [3·13-8·40]; IC025 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma (χ2 test for overall subgroup comparison, p<0·0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ2 test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0·0001). INTERPRETATION: Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy). FUNDING: The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014-2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation.

Value of Contrast-Enhanced Ultrasound Quantification Criteria for Identifying Patients not Responding to Bevacizumab-Based Therapy for Colorectal Liver Metastases.

PURPOSE: To evaluate changes in tumor vascularization parameters based on contrast-enhanced ultrasound (CEUS) quantification criteria of at least one visible liver metastasis as an early predictor of non-response to chemotherapy, including bevacizumab for colorectal cancer (CRC) liver metastases. MATERIALS AND METHODS: This multicenter prospective study included patients who received first-line bevacizumab-based chemotherapy. Tumor enhancement measured using CEUS within one liver metastasis and in relation to the surrounding healthy liver was quantified within 8 days before the first infusion of bevacizumab (E0), 24 hours after the end of the first infusion of bevacizumab (E1), in the 24 hours before the 2nd and 3 rd infusion of bevacizumab on day 15 (E2) and day 30 (E3), respectively, and after 2 months of treatment (E4). Endpoints were tumor response using RECIST criteria at 2 months, progression-free survival (PFS) and overall survival (OS). RESULTS: Among the 137 patients included in this study, 109 were analyzed. Only CEUS parameters calculated in relation to healthy liver were significant. High wash-in and wash-out rates at baseline were significantly associated with a better tumor response. Increases over time E2-E0 and E3-E0 for peak enhancement were significantly associated with shorter progression-free survival. Increases over time E2-E0 and E3-E0 for peak enhancement and wash-in area under the curve were significantly associated with a shorter overall survival. CONCLUSION: This large study demonstrated that early dynamic changes in the vascularity of liver metastases evaluated by quantified CEUS are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic CRC.

Predictive factors of renal toxicities related to anti-VEGFR multikinase inhibitors in phase 1 trials.

Purpose Renal toxicities are common with angiogenesis multikinase inhibitors (AMKI), and can be limiting in phase I trials. Factors associated with such toxicities are poorly known. The aims of this exploratory study were to describe renovascular toxicities associated with AMKI, impact on drug development and to identify baseline parameters associated with the occurrence of renal toxicities in phase I trials. Methods Consecutive patients treated with AMKI in Gustave Roussy phase I unit between October 2005 and August 2013 were included. We retrospectively collected baseline characteristics and renovascular side effects. Associations were assessed in univariate and multivariate analyses. Results Overall, 168 patients were included: male 53.0 %, mean age 55.5 years old, history of hypertension 26.8 %, diabetes 6.0 %, atherosclerosis 13.6 %, stage 3 Chronic Kidney Disease (CKD, NKF-KDOQI) 17.2 %. Incidences of reno-vascular side effects were: hypertension 47.6 %, proteinuria 19.0 %, renal failure 11.9 % and thrombotic microangiopathy 10.1 %. Eighty percent of dose limiting toxicities (DLTs) were related to a renal toxicity. Multivariate analysis showed that onset of renal failure was associated with history of hypertension (p = 0.0003) and stage 3 CKD (p = 0.032). Conclusions A majority of the DLTs associated with AMKI in phase 1 trials are renal toxicities. Baseline hypertension and stage 3 CKD (NKF-KDOQI) might help to better identify patients at risk of AMKI-related renal toxicities.

Outcomes and Prognostic Factors in Radioiodine Refractory Differentiated Thyroid Carcinomas.

BACKGROUND: Outcomes vary among patients with radioiodine refractory (RR) differentiated thyroid cancer (DTC). The prognostic factors for survival are not well-known, resulting in difficulty in selecting patients for new targeted therapies. We assessed overall survival (OS) and cancer-specific survival (CSS) from RR-DTC to identify prognostic factors associated with survival. PATIENTS AND METHODS: The data on all cases of metastatic RR-DTC treated in our center from 1990 to 2011 were retrospectively reviewed. Survival was estimated using the Kaplan-Meier method; associated prognostic factors were assessed using Cox's model. RESULTS: Of 153 cases of metastatic DTC, 59% (n = 91) met a criterion for RR: that is, 60% (n = 55) had at least 1 metastasis without (131)I uptake; 21% (n = 19) had progressive disease (PD) despite (131)I; 19% (n = 17) had persistent disease despite a cumulative activity of (131)I of ≥600 mCi. After the diagnosis of RR, median OS was 8.9 years (95% confidence interval [CI]: 5.4-NR); median CSS was 9.6 years (95% CI: 6.01-NR). In multivariate analyses, PD despite (131)I as a criterion for RR disease and the time from initial diagnosis of DTC to diagnosis of RR <3 years were the only independent prognostic factors for poor OS and CSS. Thyroglobulin doubling time (Tg-DT) was assessed in 31 of 91 cases. Among the 11 patients with Tg-DT for <1 year or undetectable Tg, 6 deaths occurred, whereas only 3 died of 20 patients with Tg-DT >1 year or negative Tg-DT. CONCLUSION: The identification of prognostic factors for decreased survival in RR-DTC may improve the selection of patients for targeted agents. IMPLICATIONS FOR PRACTICE: This study shows a great heterogeneity in terms of prognosis in radioiodine refractory differentiated thyroid carcinoma. Poorer prognosis is observed in patients with tumor progression or with a diagnosis of radioiodine resistance within 3 years after the initial diagnosis of thyroid cancer. Those findings could lead to improvements in the selection of patients for targeted therapies.

Trends in survival after cancer diagnosis among HIV-infected individuals between 1992 and 2009. Results from the FHDH-ANRS CO4 cohort.

Although the decline in cancer mortality rates with the advent of combination antiretroviral therapy (cART) in HIV-infected individuals can be mostly explained by a decrease in cancers incidence, we looked here if improved survival after cancer diagnosis could also contribute to this decline. Survival trends were analyzed for most frequent cancers in the HIV-infected population followed in the French Hospital Database on HIV: 979 and 2,760 cases of visceral and non-visceral Kaposi's sarcoma (KS), 2,339 and 461 cases of non-Hodgkin lymphoma (NHL) and Hodgkin's lymphoma (HL), 446 lung, 312 liver and 257 anal cancers. Five-year Kaplan-Meier survival rates were estimated for four periods: 1992-1996, 1997-2000, 2001-2004 and 2005-2009. Cox proportional hazard models were used to compare survival across the periods, after adjustment for confounding factors. For 2001-2004, survival was compared to the general population after standardization on age and sex. Between the pre-cART (1992-1996) and early-cART (1997-2000) periods, survival improved after KS, NHL, HL and anal cancer and remained stable after lung and liver cancers. During the cART era, 5-year survival improved after visceral and non-visceral KS, NHL, HL and liver cancer, being 83, 92, 65, 87 and 19% in 2005-2009, respectively, and remained stable after lung and anal cancers, being 16 and 65%, respectively. Compared with the general population, survival in HIV-infected individuals in 2001-2004 was poorer for hematological malignancies and similar for solid tumors. For hematological malignancies, survival continues to improve after 2004, suggesting that the gap between the HIV-infected and general populations will close in the future.

Hereditary-like urothelial carcinomas of the upper urinary tract benefit more from adjuvant cisplatin-based chemotherapy after radical nephroureterectomy than do sporadic tumours.

OBJECTIVE: To evaluate the impact of 'hereditary-like' status in upper tract urothelial carcinoma (UTUC) on the survival of patients who have undergone radical nephroureterectomy (RNU) and adjuvant chemotherapy. PATIENTS AND METHODS: A multicentre retrospective study was performed on all patients with high-risk UTUC who underwent RNU and adjuvant cisplatin-based chemotherapy. Using a patient risk identification tool, we distinguished tumours suspected to be hereditary from sporadic tumours and compared survival rates. RESULTS: A total of 112 patients with a median age of 67 years were included. Hereditary-like tumour status was detected in 35 patients (31.3%), while 77 patients (68.7%) had sporadic tumours. The median age was significantly younger in the hereditary-like tumour group (56.0 vs 69.8 years, P < 0.001). Overall survival (OS) after chemotherapy was significantly better in the group with hereditary-like tumours than in the group with sporadic tumours (5-year OS: 48.2 vs 32%; P = 0.008). The cancer-specific survival (CSS) rate was significantly better in the group with 'hereditary-like' tumours than in the group with sporadic tumours (5-year CSS: 58 vs 35%; P = 0.006). Although there was a trend in favour of the hereditary-like tumours, we observed no significant difference regarding progression-free survival (PFS) between the two groups (5-year PFS: 71 vs 52%; P = 0.07). CONCLUSION: Adjuvant chemotherapy after RNU improves survival outcomes in patients with hereditary-like UTUC compared with those with sporadic tumours.

Rationale for the use of upfront whole brain irradiation in patients with brain metastases from breast cancer.

Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy.