Harmonization of programmed death-ligand 1 immunohistochemistry and mRNA expression scoring in metastatic melanoma: a multicentre analysis.

AIMS: The aim of this multicentre study was to harmonize programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and melanoma scoring. To provide a reference for PD-L1 expression independently of the IHC protocol, PD-L1 mRNA expression was compared with IHC. METHODS AND RESULTS: Standardized PD-L1 assays (22C3, 28-8, SP142, SP263) and laboratory-developed tests (QR1, 22C3) were evaluated on three IHC platforms with a training set (seven cases). mRNA expression was determined by RNAscope (CD274/PD-L1 probe) and analysed with image analysis. PD-L1 IHC findings were scored by seven blinded pathologists using the tumour proportion score (TPS), the combined positive score (CPS), and the MELscore. This method was validated by three blinded pathologists on 40 metastatic melanomas. Concordances among various antibody/platforms were high across antibodies [intraclass correlation coefficient (ICC) >0.80 for the CPS], except for SP142. Two levels of immunostaining intensity were observed: high (QR1 and SP263) and low (28-8, 22C3, and SP142). Reproducibilities across pathologists were higher for QR1 and SP263 (ICC ≥0.87 and ICC ≥0.85 for the TPS and the CPS, respectively). QR1, SP263 and 28-8 showed the highest concordance with mRNA expression. We developed a standardized method for PD-L1 immunodetection and scoring, tested on 40 metastatic melanomas. Concordances among antibodies were excellent for all criteria, and concordances among pathologists were better for the MELscore than for other scores. CONCLUSION: Harmonization of PD-L1 staining and scoring in melanomas with good concordance is achievable with the PD-L1 IHC protocols applied to other cancers; this reproducible approach can simplify daily practice.

Functional and oncological outcomes of salvage transoral robotic surgery: a comparative study.

PURPOSE: Transoral robotic surgery (TORS) as a first-line therapy has been well-documented but evidence is missing regarding salvage therapy. The aim of this study is to compare the oncological and functional outcomes of TORS as a primary and salvage therapy. METHODS: This retrospective monocentric study included 74 patients operated by a single surgeon and sorted out into two groups: primary treatment (PT) or Salvage treatment (ST) in case of previous history of radiation therapy. Patients were further stratified by tumour location: larynx and pharynx (lST vs lPT and pST vs pPT). RESULTS: Forty-eight patients were included in PT group (64.9%) and 26 in ST group (35.1%). ST patients had more frequent cTis/T1 tumours (57.7% vs 29.2%, p = 0.0164) and no clinical lymph disease (3.8% vs 37.5%, p = 0.0016). Tracheostomy was more often performed in the ST group (57.7% vs 16.7%, p = 0.0003) and the lST subgroup (88.9% vs 9.1%, p < 0.0001). Gastric feeding tube placement was more frequent in the ST group (76.9% vs 33.3%, p = 0.0003), the pST subgroup (64.7% vs 15.4%, p = 0.0009) and the lST subgroup (100% vs 54.5%, p = 0.0297). We observed a trend for more postoperative complications in the ST group (69.2% vs 47.9%, p = 0.0783). The overall survival was lower in the ST group (p = 0.0004), and in the pST subgroup (p < 0.0001). The disease-free survival rate was lower in the ST group (p = 0.0001), the pST subgroup (p = 0.0002) and the lST subgroup (p = 0.0328). CONCLUSION: This study confirms that survival and functional outcomes after salvage TORS are worse than in first line surgery.

PD-L1 expression and pattern of immune cells in pre-treatment specimens are associated with disease-free survival for HR-NMIBC undergoing BCG treatment.

PURPOSE: To assess the association between PD-L1 expression and disease-free survival (DFS) in High-Risk Non-Muscle Invasive Bladder Cancer (HR-NMIBC) patients treated with intravesical Bacillus Calmette-Guerin (BCG) instillations (IBI). METHODS: Retrospective study in five French centres between 2001 and 2015. Participants were 140 patients with histologically confirmed HR-NMIBC. All patients received induction and maintenance IBI. Pathological stage/grade, concomitant carcinoma in situ, lesion number and tumour size were recorded. CD3, CD8 and PD-L1 expression in tumour cells and in T cells in the tumour microenvironment (TME) was determined immunohistochemically. Median follow-up was 54.2 months. The primary outcome measure was DFS. Univariable and multivariable analyses were performed using the log rank test and Cox proportional hazards model. RESULTS: Of the 140 NMIBC, 52 (37.1%) were Ta, 88 (62.9%) were T1 and 100% were high grade. Median number of maintenance IBI was six (range 1-30). Twenty-five (17.9%) patients had recurrence/progression. In multivariable analysis, age (HR 1.07 [95% CI 1.02-1.13], p = 0.009), PD-L1 expression in tumour cells (HR per 10 units = 1.96 [95% CI 1.28-3.00], p = 0.02) and CD3/CD8 ratio (HR per 10 units = 3.38 [95% CI 1.61-7.11], p = 0.01) were significantly associated with DFS. However, using the cut-off corresponding for each PD-L1 antibodies, PD-L1 + status was not associated with DFS. CONCLUSION: Despite an association between PD-L1 expression and BCG failure in HR-NMIBC, the PD-L1 + status was not a prognostic factor in the response of BCG. Moreover, we confirmed the key role played by the IC within the microenvironment in BCG treatment. These findings highlighted the rationale to combine BCG and PD-L1/PD-1 antibodies in early bladder cancer.

Oncologic and Functional Outcomes of Pelvic Perineal Reconstruction by Perineal Colostomy and Malone Procedure After Abdominoperineal Resection.

BACKGROUND: Abdominoperineal resection is the standard curative surgical technique for locally advanced adenocarcinoma of the lower rectum and squamous cell carcinoma of the anal canal after chemoradiotherapy. However, it requires a definitive abdominal colostomy that modifies the body appearance. OBJECTIVE: The study aim was to evaluate the combination of abdominoperineal resection with perineal colostomy reconstruction and Malone antegrade continence enema. DESIGN: This was a retrospective study. SETTINGS: The study was conducted at the Toulouse Hospital Digestive Surgery Department. PATIENTS: All of the patients with advanced adenocarcinoma or squamous cell carcinoma who underwent abdominoperineal resection with perineal colostomy reconstruction and Malone antegrade continence enema (n = 80) between December 1999 and December 2016 were included. MAIN OUTCOME MEASURES: The main outcome was the 5-year overall survival rate. RESULTS: The 5-year overall survival was 74.89% (95% CI, 62.91%-83.50%), and the median recurrence-free survival was 107.6 months (95% CI, 65.1-198.1 mo). The median follow-up was 91.0 months (95% CI, 70.4-116.6 mo). R0 resection was obtained in 64 patients (80.0%). The median Cleveland Clinic Incontinence Score (to assess the functional outcomes) was 9.0 (interquartile range, 1.0-18.0), and it was lower in patients with advanced adenocarcinoma than with squamous cell carcinoma (7.0 (interquartile range, 2.0-18.0) vs 11.0 (interquartile range, 1.0-17.0); p = 0.01). Eleven patients (13.8%) reported perineal stains during the night, and 19 patients (23.8%) needed drugs to reduce colon motility. The rate of severe complications (Clavien-Dindo >II) was 11.7% (n = 9). Definitive colostomy was performed in 15 patients (18.8%). LIMITATIONS: This retrospective study included a small number of patients from a single center. Moreover, the functional outcome was tested with self-report questionnaires (risk of response bias). CONCLUSIONS: This study suggests that abdominoperineal resection associated with perineal reconstruction by perineal colostomy and Malone antegrade continence enema is safe and may improve patient quality of life. See Video Abstract at http://links.lww.com/DCR/B629. RESULTADOS ONCOLGICOS Y FUNCIONALES DE LA RECONSTRUCCIN PLVIPERINEAL MEDIANTE COLOSTOMA PERINEAL Y PROCEDIMIENTO DE MALONE DESPUS DE LA RESECCIN ABDOMINOPERINEAL: ANTECEDENTES:La resección abdominoperineal es la técnica quirúrgica curativa estándar para el tratamiento del adenocarcinoma localmente avanzado del recto inferior y el carcinoma a células escamosas del canal anal, después de radio-quimioterapia. Sin embargo, requiere una colostomía abdominal definitiva que modifica la apariencia corporal.OBJETIVO:El propósito del presente estudio fue el evaluar la combinación de la resección abdominoperineal con la confección de una colostomía perineal asociada a enemas de continencia anterógrada según Malone.DISEÑO:Estudio retrospectivo.AJUSTES:Servicio de Cirugía Digestiva del Hospital de Toulouse, Francia.PACIENTES:Se incluyeron todos los pacientes con adenocarcinoma avanzado o carcinoma de células escamosas que se sometieron a resección abdominoperineal con la confección de una colostomía perineal asociada a enemas de continencia anterógrada según Malone (n = 80) entre diciembre de 1999 y diciembre de 2016.PRINCIPALES MEDIDAS DE RESULTADO:El principal resultado fue la tasa de sobrevida global a 5 años.RESULTADOS:La sobrevida global a 5 años fue de 74,89% (IC del 95%, 62,91 a 83,50) y la mediana de supervivencia libre de recurrencia fue de 107,6 meses (IC del 95%, 65,1 a 198,1). La mediana de seguimiento fue de 91,0 meses (IC del 95%, 70,4-116,6). La resección R0 se obtuvo en 64 pacientes (80,0%). La mediana de puntuación de la escala de incontinencia de la Cleveland Clinic (para evaluar los resultados funcionales) fue de 9,0 [1,0; 18,0], y fue menor en pacientes con adenocarcinoma avanzado que con carcinoma de células escamosas (7,0 [2,0; 18,0] versus 11,0 [1,0; 17,0]; p = 0,01). Once pacientes (13,8%) refirieron manchado perineal nocurno y 19 pacientes (23,8%) necesitaron fármacos para reducir la motilidad del colon. La tasa de complicaciones graves (Clavien-Dindo > II) fue del 11,7% (n = 9). Se realizó colostomía definitiva en 15 (18,8%) pacientes.LIMITACIONES:Este estudio retrospectivo incluyó un pequeño número de pacientes y de un solo centro. Además, el resultado funcional se probó con cuestionarios de autoinforme (riesgo de sesgo de respuesta).CONCLUSIONES:Este estudio sugiere que la resección abdominoperineal asociada con la confección de una colostomía perineal asociada a enemas de continencia anterógrada según Malone es segura y puede mejorar la calidad de vida de los pacientes. Consulte Video Resumen en http://links.lww.com/DCR/B629.

Multicentre evaluation of the interest in planned surgery for mandibular reconstruction with fibula free flap: a retrospective cohort study.

PURPOSE: The aim of this study was to determine the impact and cost-effectiveness of virtual surgical planning during fibula free flap mandibular reconstruction on peri- and postoperative data. METHODS: We conducted a retrospective cohort study from January 2012 to December 2016 in four French university centres. RESULTS: Three hundred fibula free flaps for mandibular reconstruction were performed in 294 patients. Surgeries were planned in 29.7% of cases (n = 89). There was no significant difference in the rate of negative-margins excision, median length of hospital stay, operative time, and early complications between planned and non-planned surgeries. Morphological analysis revealed a higher rate of centred occlusion in planned patients (satisfactory alignment of interincisal points: Planned 65.5% vs Non-Planned 33.3%, p = 0.006). CONCLUSION: In mandibular reconstruction by fibula free flap, the additional cost generated by virtual surgical planning does not seem to be balanced by savings resulting from a shorter operative course, a reduced hospital stay, or a reduction in postoperative complications. However, virtual surgical planning may provide a higher rate of centred occlusion. Long-term benefits should be assessed by further studies.

Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor.

Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3ß,5α,6ß-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3ß,5α-diol (OCDO) by 11ß-hydroxysteroid-dehydrogenase-type-2 (11ßHSD2). 11ßHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11ßHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11ßHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11ßHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.

Adipocytes promote breast cancer resistance to chemotherapy, a process amplified by obesity: role of the major vault protein (MVP).

INTRODUCTION: Clinical studies suggest that obesity, in addition to promoting breast cancer aggressiveness, is associated with a decrease in chemotherapy efficacy, although the mechanisms involved remain elusive. As chemotherapy is one of the main treatments for aggressive or metastatic breast cancer, we investigated whether adipocytes can mediate resistance to doxorubicin (DOX), one of the main drugs used to treat breast cancer, and the mechanisms associated. METHODS: We used a coculture system to grow breast cancer cells with in vitro differentiated adipocytes as well as primary mammary adipocytes isolated from lean and obese patients. Drug cellular accumulation, distribution, and efflux were studied by immunofluorescence, flow cytometry, and analysis of extracellular vesicles. Results were validated by immunohistochemistry in a series of lean and obese patients with cancer. RESULTS: Adipocytes differentiated in vitro promote DOX resistance (with cross-resistance to paclitaxel and 5-fluorouracil) in a large panel of human and murine breast cancer cell lines independently of their subtype. Subcellular distribution of DOX was altered in cocultivated cells with decreased nuclear accumulation of the drug associated with a localized accumulation in cytoplasmic vesicles, which then are expelled into the extracellular medium. The transport-associated major vault protein (MVP), whose expression was upregulated by adipocytes, mediated both processes. Coculture with human mammary adipocytes also induced chemoresistance in breast cancer cells (as well as the related MVP-induced DOX efflux) and their effect was amplified by obesity. Finally, in a series of human breast tumors, we observed a gradient of MVP expression, which was higher at the invasive front, where tumor cells are at close proximity to adipocytes, than in the tumor center, highlighting the clinical relevance of our results. High expression of MVP in these tumor cells is of particular interest since they are more likely to disseminate to give rise to chemoresistant metastases. CONCLUSIONS: Collectively, our study shows that adipocytes induce an MVP-related multidrug-resistant phenotype in breast cancer cells, which could contribute to obesity-related chemoresistance.

PIK3CA mutations early persistence in cell-free tumor DNA as a negative prognostic factor in metastatic breast cancer patients treated with hormonal therapy.

PURPOSE: The identification of biomarkers of hormonal therapy (HT) failure would allow tailored monitoring in metastatic breast cancer (mBC) patients. PIK3CA gene mutation is one of the most frequent events in mBC and is associated with HT resistance. We evaluated the early prognostic value of cell-free DNA (cfDNA) PIK3CA detection in first-line HT-treated mBC patients. METHODS: Between June 2012 and January 2014, 39 patients were prospectively included in a dedicated clinical trial (NCT01612871). Blood sampling was performed before (M0) and 4 weeks (M1), 3 months (M3) and 6 months (M6) after HT initiation, and at tumor progression. Patients were followed until progression or until the end of the study (2 years). Mutation detection was performed using droplet-based digital PCR (ddPCR). Progression-free survival (PFS) was used as primary endpoint. RESULTS: Median age at inclusion was 63 years (range 40-86). Most patients (34/39) received an aromatase inhibitor and presented a non-measurable disease (71.8%). PIK3CA mutations were reported in 10 (27.8%) and 5 (14.3%) cases at M0 and M1, respectively. The persistence of a detectable circulating mutation at M1 was highly correlated with a worse progression-free survival (PFS), rate at 1 year: 40% versus 76.7%; p = 0.0053). CONCLUSIONS: Four-week persistence of cfDNA PIK3CA mutation appears highly correlated with PFS. TRIAL REGISTRATION: NCT01612871, registered on June 6th, 2012; https://clinicaltrials.gov/ct2/show/NCT01612871 .

Evaluation of 2 diuretic 18fluorine-fluorodeoxyglucose positron emission tomography/computed tomography imaging protocols for intrapelvic cancer.

BACKGROUND: 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) plays an important part in the oncological evaluation of the abdomen and pelvis, but the interpretation and quantification is often hampered by intense physiological urinary activity. We evaluate 2 different diuretic imaging protocols by comparing intensity of urinary activity and we look at the impact of multiple variables on the final urinary activity. METHODS: Comparative analysis of 102 patients (median age: 64) having intrapelvic carcinoma. After full body acquisition, 58 patients were administered 20 mg of furosemide 90 min post injection of FDG (P90). For 44 patients, 20 mg of furosemide was administered 30 min post injection of FDG (P30). Comparisons between groups were performed using the Mann-Whitney Test and χ2. The BMI, creatinine, clearance, age, injected activity, diuretic protocol, gender and glycemia were evaluated with multivariate analysis for their impact on the final urinary activity. RESULTS: Concerning the comparison of the urinary activity we observe a significant difference (P=0.0029) between P90 and P30 for the SUVmax (median 4.3 [range 1.6: 17.7] vs. 6.0 [range 2.9: 15.1]), and for the SUVmean (P<0.001) (median 2.4 [range 1.1; 9.9] vs. 3.8 [range 2.0; 10.1]). For 2 patients of P30, the acquisition was interrupted because the patient needed to void. Multivariate analysis shows that creatinine and creatinine clearance do not have a significant independent impact on the final bladder activity. CONCLUSIONS: By comparing the 2 diuretic imaging protocols, we found a significant lower urinary activity for the P90 protocol and the regression decision tree shows that the P90 protocol is mostly superior. The P30 protocol, which seems to be less well tolerated, is adequate in the group of patients with an injected activity of less than 240 MBq and older than 65 years, if P90 is not feasible. For most patients with injected activity ≥240 MBq or BMI of ≥25 and a glycemia >120 mg/dL, a significant amount of residual urinary activity remains for both protocols.

Predictive risk factors of acute kidney injury after cytoreductive surgery and cisplatin-based hyperthermic intra-peritoneal chemotherapy for ovarian peritoneal carcinomatosis.

OBJECTIVE: The aim of our study was to assess the incidence and identify the predictive risk factors of acute kidney injury after cytoreductive surgery and cisplatin-based hyperthermic intra-peritoneal chemotherapy. METHODS: This is a retrospective study from two centers evaluating patients with advanced or recurrent ovarian cancer who underwent cytoreductive surgery followed by cisplatin-based hyperthermic intra-peritoneal chemotherapy from January 2007 to December 2013. Patients were classified into two groups according to the occurrence of acute kidney injury, defined as a glomerular filtration rate at post-operative day 7 25% lower than at day 0. We also evaluated acute kidney injury following Risk, Injury, Failure, Lost and End-stage kidney function criteria. Univariate and multivariate analyses were conducted in order to assess the association between different variables and the occurrence of acute kidney injury. RESULTS: Sixty-six patients were included: 29 (44%) underwent first-line treatment and 37 (56%) were treated for recurrent disease. The incidence of post-operative acute kidney injury was 48%. After multivariate analysis, hypertension (OR 18.6; 95% CI 1.9 to 182.3; p=0.012) and low intra-operative diuresis (OR 0.5; 95% CI 0.4 to 0.8; p=0.001) were associated with acute kidney injury. CONCLUSION: The incidence of acute kidney injury after cytoreductive surgery and cisplatin-based hyperthermic intra-peritoneal chemotherapy was high. Hypertension and low intra-operative diuresis were independent risk factors for this complication. Adequate peri-operative hydration, in order to maintain correct diuresis, could decrease the occurrence of acute kidney injury in patients undergoing cytoreductive surgery plus hyperthermic intra-peritoneal chemotherapy.

Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy.

BACKGROUND: Prescribing anti-programmed death-1 (PD-1) immunotherapy for advanced melanoma is currently not restricted by any biomarker assessment. Determination of programmed death-ligand-1 (PD-L1)-expression status is technically challenging and is not mandatory, because negative tumours also achieve therapeutic responses. However, reproducible biomarkers predictive of a response to anti-PD-1 therapy could contribute to improving therapeutic decision-making. METHODS: This retrospective study on 70 metastatic melanoma patients was undertaken to evaluate the relationships between clinical, histological, immunohistochemical and/or molecular criteria, and the 6-month objective response rate. RESULTS: Better objective response rates were associated with metachronous metastases (P = 0.04), PD-L1 tumour- and/or immune-cell status (P = 0.01), CD163+ histiocytes at advancing edges (P = 0.009) of primary melanomas and NRAS mutation (P = 0.019). Moreover, CD163+ histiocytes at advancing edges (P = 0.04) were associated with longer progression-free survival (PFS), and metachronous metastases with longer overall survival (P = 0.02) and PFS (P = 0.049). CONCLUSIONS: Combining these reproducible biomarkers could help improve therapeutic decision-making for patients with progressive disease.

Do perfusion and diffusion MRI predict glioblastoma relapse sites following chemoradiation?

To assess the value of T2* dynamic-susceptibility contrast MRI (DSC-MRI) and diffusion-weighted imaging (DWI) to predict the glioblastoma relapse sites after chemoradiation. From a cohort of 44 patients, primarily treated with radiotherapy (60 Gy) and concomitant temozolomide for glioblastoma, who were included in the reference arm of a prospective clinical trial (NCT01507506), 15 patients relapsed and their imaging data were analyzed. All patients underwent anatomical MRI, DSC-MRI and DWI before radiotherapy and every 2 months thereafter until relapse. Voxels within the sites of relapse were correlated with their perfusion and/or diffusion abnormality (PDA) pretreatment status after rigid co-registration. The relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were used as biomarkers. Several PDA areas were thresholded: hyperperfused voxels using a 1.75 fixed rCBV threshold (HPt); hypoperfused (hPg) and hyperperfused (HPg) voxels using a histogram-based Gaussian method; diffusion-restricted voxels (DRg); and HPg voxels with diffusion restriction (HPg&DRg). Two sets of voxels (2,459,483 and 2,073,880) were analyzed according to these thresholding methods. Positive predictive values (PPV) of PDA voxels were low (between 9.5 and 31.9 %). The best PPV was obtained with HPg&DRg voxels within the FLAIR hyperintensity, as 18.3 % of voxels without initial PDA were within relapse sites, versus 31.9 % with initial PDA (p < 0.0001). This prospective study suggests that DSC and/or DWI-MRI do not predict the glioblastoma relapse sites. However, further investigations with new methodological approaches are needed to better understand the role of these modalities in the prediction of glioblastoma relapse sites.

Oncologic safety of autologous fat grafting in primary breast reconstruction after mastectomy for cancer.

INTRODUCTION: Autologous fat transfer (AFT) is widely used to improve results of breast reconstructive surgery, but its safety is controversial. Our objective was to evaluate the oncologic safety of AFT in a homogeneous population of patients who underwent a total mastectomy with immediate reconstruction for breast cancer. METHODS: We performed a retrospective cohort study by identifying all patients who underwent immediate breast reconstruction after mastectomy for breast cancer from 2007 to 2015 in our center. A patient group with AFT performed in the 24 months after mastectomy was compared to a control group. RESULTS: Five hundred fifty cases were included, of whom 136 (24.7%) underwent at least one fat graft transfer. Median age was 51 years. Reconstruction was performed in 465 (84.5%) with an implant reconstruction. The median time from mastectomy to AFT was 13.8 months. The median follow up was 55.2 months. A total of 53 events were observed, including 10 (7.4%) in the AFT group and 43 (10.4%) in the control group. There was no difference in 5-year recurrence-free survival (RFS) between the groups. In the subgroup analysis, only lymph node involvement in patients who underwent AFT in the first 24 months after oncologic surgery appeared as a risk factor of recurrence. Among the 104 patients with lymph node involvement, 5-year RFS was 69.2% in patients with lipofilling vs 92.5% in patients without it (p = 0 0.0351). CONCLUSION: Performing early lipofilling in primary breast reconstruction after mastectomy for cancer seems to be oncologically safe. Lymph node involvement increases the risk of recurrence in this population.

Insertion of synthetic lesions on patient data: a method for evaluating clinical performance differences between PET systems.

BACKGROUND: Performance assessment of positron emission tomography (PET) scanners is crucial to guide clinical practice with efficiency. We have already introduced and experimentally evaluated a simulation method allowing the creation of a controlled ground truth for system performance assessment. In the current study, the goal was to validate the method using patient data and demonstrate its relevance to assess PET performances accuracy in clinical conditions. METHODS: Twenty-four patients were recruited and sorted into two groups according to their body mass index (BMI). They were administered with a single dose of 2 MBq/kg 18F-FDG and scanned using clinical protocols consecutively on two PET systems: the Discovery-IQ (DIQ) and the Discovery-MI (DMI). For each BMI group, sixty synthetic lesions were dispatched in three subgroups and inserted at relevant anatomical locations. Insertion of synthetic lesions (ISL) was performed at the same location into the two consecutive exams. Two nuclear medicine physicians evaluated individually and blindly the images by qualitatively and semi-quantitatively reporting each detected lesion and agreed on a consensus. We assessed the inter-system detection rates of synthetic lesions and compared it to an initial estimate of at least 1.7 more targets detected on the DMI and the detection rates of natural lesions. We determined the inter-reader variability, evaluated according to the inter-observer agreement (IOA). Adequate inter-reader variability was found for IOA above 80%. Differences in standardized uptake value (SUV) metrics were also studied. RESULTS: In the BMI ≤ 25 group, the relative true positive rate (RTPR) for synthetic and natural lesions was 1.79 and 1.83, respectively. In the BMI > 25 group, the RTPR for synthetic and natural lesions was 2.03 and 2.27, respectively. For each BMI group, the detection rate using ISL was consistent to our estimate and with the detection rate measured on natural lesions. IOA above 80% was verified for any scenario. SUV metrics showed a good agreement between synthetic and natural lesions. CONCLUSIONS: ISL proved relevant to evaluate performance differences between PET scanners. Using these synthetically modified clinical images, we can produce a controlled ground truth in a realistic anatomical model and exploit the potential of PET scanner for clinical purposes.

Randomized phase III trial of metabolic imaging-guided dose escalation of radio-chemotherapy in patients with newly diagnosed glioblastoma (SPECTRO GLIO trial).

BACKGROUND: Glioblastoma (GBM) systematically recurs after a standard 60 Gy radio-chemotherapy regimen. Since magnetic resonance spectroscopic imaging (MRSI) has been shown to predict the site of relapse, we analyzed the effect of MRSI-guided dose escalation on overall survival (OS) of patients with newly diagnosed GBM. METHODS: In this multicentric prospective phase III trial, patients who had undergone biopsy or surgery for a GBM were randomly assigned to a standard dose (SD) of 60 Gy or a high dose (HD) of 60 Gy with an additional simultaneous integrated boost totaling 72 Gy to MRSI metabolic abnormalities, the tumor bed and residual contrast enhancements. Temozolomide was administered concomitantly and maintained for 6 months thereafter. RESULTS: One hundred and eighty patients were included in the study between March 2011 and March 2018. After a median follow-up of 43.9 months (95% CI [42.5; 45.5]), median OS was 22.6 months (95% CI [18.9; 25.4]) versus 22.2 months (95% CI [18.3; 27.8]) for HD, and median progression-free survival was 8.6 (95% CI [6.8; 10.8]) versus 7.8 months (95% CI [6.3; 8.6]), in SD versus HD, respectively. No increase in toxicity rate was observed in the study arm. The pseudoprogression rate was similar across the SD (14.4%) and HD (16.7%) groups. For O(6)-methylguanine-DNA methyltransferase (MGMT) methylated patients, the median OS was 38 months (95% CI [23.2; NR]) for HD patients versus 28.5 months (95% CI [21.1; 35.7]) for SD patients. CONCLUSION: The additional MRSI-guided irradiation dose totaling 72 Gy was well tolerated but did not improve OS in newly diagnosed GBM. TRIAL REGISTRATION: NCT01507506; registration date: December 20, 2011. https://clinicaltrials.gov/ct2/show/NCT01507506?cond=NCT01507506&rank=1.

5-fluorouracil with oxaliplatin and/or irinotecan for advanced sinonasal intestinal-type adenocarcinoma (ITAC).

INTRODUCTION: Sinonasal intestinal-type adenocarcinoma (ITAC) is a rare tumor, typically found in the ethmoid or upper nasal cavity. There is no standard systemic treatment for metastatic/locally advanced disease ineligible for upfront surgery or radiotherapy. METHODS: Patients treated between 2015 and 2021 in our institution with a fluoropyrimidine plus oxaliplatin and/or irinotecan for advanced ITAC were retrospectively assessed for overall survival (OS), progression-free survival (PFS) and tumoral responses. RESULTS: Six patients without meningeal involvement received chemotherapy (three FOLFOX, two FOLFIRI, one FOLFIRINOX). All achieved a response, including those with brain extension. Median PFS with FOLFOX and FOLFIRI was similar (6.0 months, 95%CI 5.8-NR; 5.8 months, 95%CI 5.8-NR respectively). Three patients had meningeal involvement with meningitis symptoms and received first-line therapy. All had rapid disease progression (median PFS 1.2 months, 95%CI 1.0-NR) DISCUSSION: FOLFOX, FOLFIRI or FOLFIRINOX appear to have anti-tumor efficacy for metastatic or locally advanced unresectable ITAC, except in cases of carcinomatous meningitis. These regimens require further evaluation.

Survival analysis and prognostic factors of retroperitoneal liposarcoma curative surgery in a single centre. Analysis of adjacent organ invasion between imaging and definitive histopathology.

INTRODUCTION: Retroperitoneal liposarcoma (RPL) is a rare primary mesenchymal tumour that develops in retroperitoneal adipose tissue. Unlike the majority of published series, this homogeneous cohort focuses on RPL. The main purpose of this study is to evaluate the overall and recurrence-free survival of RPLs who underwent excision surgery and the prognostic factors involved. PATIENTS AND METHODS: A total of 82 patients from a single centre, who underwent curative surgery for histologically confirmed retroperitoneal liposarcoma between 2008 and 2020, were analysed in the study. Compartmental surgical excision was advised as per the guidelines. The primary endpoints were 5 years of overall survival and recurrence-free survival. Predictable tumour invasion of adjacent organs, based on a pre-operative CT scan, was also investigated to test the correlation between pre-operative imaging and pathological data. RESULTS: Median follow-up was 61.6 months. Five year overall survival was 71.9% [95% CI: 59.8; 80.9] and 5 year recurrence-free survival was 49% [95% CI: 36.4; 60.5]. Following multivariable analysis, the factors influencing overall survival were tumour rupture and onset of severe complications (Dindo-Clavien grade ≥3). Factors influencing recurrence-free survival were neoadjuvant radiotherapy and tumour rupture. A significant correlation (p < 0.05) was found between predicted invasion based on a CT scan of the colon, spleen, adrenal gland, posterior abdominal wall and diaphragm, and pathological invasion. CONCLUSIONS: Curative compartmental surgery remains the gold standard treatment for RPL. This study, highlights the fact that the quality of the surgical excision is a crucial factor in patient prognosis.

Population pharmacokinetic analysis reveals no impact of aprepitant on the pharmacokinetics of ifosfamide, 2-dechloroifosfamide, and 3-dechloroifosfamide.

PURPOSE: Several case reports and retrospective series have clearly pointed to the role of aprepitant, an antiemetic drug, in the development of encephalopathy when used with ifosfamide. Described as an inhibitor of several CYP metabolic pathways, aprepitant is suspected of drug-drug-interaction on ifosfamide pharmacokinetics. The pharmacokinetics of ifosfamide and two of its metabolites (2-dechloroifosfamide and 3-dechloroifosfamide) was studied in patients with soft tissue sarcomas to evaluate the impact of aprepitant administration. METHODS: A population pharmacokinetic approach was applied to analyze data obtained in 42 patients at cycle 1 (without aprepitant) and cycle 2 (with aprepitant for 34 of them). RESULTS: A previously published pharmacokinetic model including a time-dependency process well fit the data. Aprepitant had no impact on ifosfamide or its two metabolite pharmacokinetic parameters. CONCLUSION: This study suggests that aprepitant does not lead to a significant modification of ifosfamide metabolization, even though other metabolites such as 4 hydroxyifosfamide and chloroacetaldehyde were not monitored in this study.

Impact of radiation on host immune system in patients treated with chemoradiotherapy and durvalumab consolidation for unresectable locally advanced non-small cell lung cancer.

Background: The optimal modalities of radiotherapy when combining concurrent chemoradiation (CCRT) and immunotherapy (IO) for locally advanced non-small cell lung cancer (LA-NSCLC) remain to be determined. The aim of this study was to investigate the impact of radiation on different immune structures and immune cells in patients treated with CCRT followed by durvalumab. Material and methods: Clinicopathologic data, pre- and post-treatment blood counts, and dosimetric data were collected in patients treated with CCRT and durvalumab consolidation for LA-NSCLC. Patients were divided into two groups according to the inclusion (NILN-R+) or not (NILN-R-) of at least one non-involved tumor-draining lymph node (NITDLN) in the clinical target volume (CTV). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Fifty patients were included with a median follow-up of 23.2 months (95% CI 18.3-35.2). Two-year PFS and 2-year OS were 52.2% (95% CI 35.8-66.3) and 66.2% (95% CI 46.5-80.1), respectively. In univariable analysis, NILN-R+ (hazard ratio (HR) 2.60, p = 0.028), estimated dose of radiation to immune cells (EDRIC) >6.3 Gy (HR 3.19, p = 0.049), and lymphopenia ≤ 500/mm3 at IO initiation (HR 2.69, p = 0.021) were correlated with poorer PFS; lymphopenia ≤ 500/mm3 was also associated with poorer OS (HR 3.46, p = 0.024). In multivariable analysis, NILN-R+ was the strongest factor associated with PFS (HR 3.15, p = 0.017). Conclusion: The inclusion of at least one NITDLN station within the CTV was an independent factor for poorer PFS in the context of CCRT and durvalumab for LA-NSCLC. The optimal sparing of immune structures might help in achieving better synergy between radiotherapy and immunotherapy in this indication.

Consolidative Radiotherapy for Metastatic Urothelial Bladder Cancer Patients with No Progression and with No More than Five Residual Metastatic Lesions Following First-Line Systemic Therapy: A Retrospective Analysis.

Local consolidative radiotherapy in the treatment of metastatic malignancies has shown promising results in several types of tumors. The objective of this study was to assess consolidative radiotherapy to the bladder and to residual metastases in metastatic urothelial bladder cancer with no progression following first-line systemic therapy. MATERIALS/METHODS: Patients who received first-line therapy for the treatment of metastatic urothelial bladder cancer (mUBC) and who were progression-free following treatment with no more than five residual metastases were retrospectively identified through the database of four Comprehensive Cancer Centers, between January 2005 and December 2018. Among them, patients who received subsequent definitive radiotherapy (of EQD2Gy > 45Gy) to the bladder and residual metastases were included in the consolidative group (irradiated (IR) group), and the other patients were included in the observation group (NIR group). Progression-free survival (PFS) and overall survival (OS) were determined from the start of the first-line chemotherapy using the Kaplan-Meier method. To prevent immortal time bias, a Cox model with time-dependent covariates and 6-month landmark analyses were performed to examine OS and PFS. RESULTS: A total of 91 patients with at least stable disease following first-line therapy and with no more than five residual metastases were analyzed: 51 in the IR group and 40 in the NIR group. Metachronous metastatic disease was more frequent in the NIR group (19% vs. 5%, p = 0.02); the median number of metastases in the IR group vs. in the NIR group was 2 (1-9) vs. 3 (1-5) (p = 0.04) at metastatic presentation, and 1 (0-5) vs. 2 (0-5) (p = 0.18) after completion of chemotherapy (residual lesions), respectively. Two grade 3 toxicities (3.9%) and no grade 4 toxicity were reported in the IR group related to radiotherapy. With a median follow up of 85.9 months (95% IC (36.7; 101.6)), median OS and PFS were 21.7 months (95% IC (17.1; 29.7)) and 11.1 months (95% IC (9.9; 14.1)) for the whole cohort, respectively. In multivariable analysis, consolidative radiotherapy conferred a benefit in both PFS (HR = 0.49, p = 0.007) and OS (HR = 0.47, p = 0.015) in the whole population; in the landmark analysis at 6 months, radiotherapy was associated with improved OS (HR = 0.48, p = 0.026), with a trend for PFS (HR = 0.57, p = 0.082). CONCLUSION: Consolidative radiotherapy for mUBC patients who have not progressed after first-line therapy and with limited residual disease seems to confer both OS and PFS benefits. The role of consolidative radiotherapy in the context of avelumab maintenance should be addressed prospectively.