The impact of modern preoperative high-dose-rate brachytherapy in early-stage cervical cancer.

PURPOSE: To analyze the clinical outcomes and the safety of preoperative high-dose-rate (HDR) image-guided adaptive brachytherapy (IGABT) followed by minimally invasive surgery (MIS) in the multidisciplinary management of early-stage cervical cancer. METHODS AND MATERIALS: Medical records of all consecutive patients with early-stage cervical cancer treated at our institution between 2012 and 2018 with preoperative IGABT in a multidisciplinary approach were reviewed. Treatment schedule was pelvic node dissection, preoperative IGABT followed 6-8 week later by MIS hysterectomy. RESULTS: Seventy patients with cervical cancer FIGO stages (IB1 18.6%, IB2 75.7% and IIA1 5.7%) were treated by preoperative HDR brachytherapy. With a median follow-up of 37.4 months [95% confidence interval, 32.1-39.7 months] isolated vaginal vault recurrence was not observed, 3 pelvic relapses were reported (4.3%). None of patients received postoperative radiotherapy (EBRT) or radiochemotherapy. The estimated 3-year local and pelvis relapse free survival for the entire population were respectively 98% [95% confidence interval, 89%-100%] and 90% [80%-96%]. The estimated 3-year disease-free survival (DFS) for the entire population was 88% [77-94%]. The 3-year overall survival (OS) rate was 97% [88%-99%]. Microscopic vaginal resection margin (R1) was observed in one patient ([1].4%). Lymph-vascular space invasion (LVSI) was found found in 6 (8.6%) patients. Forty-eight late complications in 36 patients (51.4%) were observed. Five (7.1%) grade 3 vaginal wound dehiscence toxicities were observed. Urinary and gastrointestinal toxicities were grade 1-2. No grade 4-5 complications were observed. CONCLUSIONS: Preoperative image-guided adaptive brachytherapy followed by minimally invasive surgery allows high local control, reduces positive surgical margins and rates of lymph-vascular space invasion avoiding adjuvants treatments. Surgical approaches must be discussed with patients including preoperative brachytherapy as a down-staging treatment.

Nivolumab in routine practice for older patients with advanced or metastatic non-small cell lung cancer.

BACKGROUND: Nivolumab is approved worldwide as second-line treatment for metastatic non-small cell lung cancer (NSCLC). Despite the fact that most of these cancers are being diagnosed in the older patients, few of the patients were included in pivotal trials. We aimed to describe efficacy and safety in a "real-world" older population. PATIENTS AND METHODS: We retrospectively collected data from older patients (≥70 years old) with advanced or metastatic NSCLC treated with Nivolumab in our institution. We analyzed safety (CTCAE v4.0 criteria), efficacy (clinical benefit rate, progression-free survival, and overall survival), and correlated these features to geriatric parameters and PD-L1 expression. Along with this cohort, we assessed safety at a national level by retrieving all cases of Nivolumab (prescribed for NSCLC) induced adverse events analyzed by the French pharmacovigilance network during the inclusion period. RESULTS: From July 2015 to September 2016, 30 patients were enrolled with a median age of 75.2. Clinical benefit rate was 30.6%. Median progression-free survival and overall survival were 3.3 and 7.1 months, respectively. Fifteen patients (50%) presented an immune-related adverse event (IrAE) of any grade, including four high grade IrAEs. Two hundred and eighty IrAEs had been notified to the French pharmacovigilance network including 91 (35.2%) concerning older patients. Frequency and pattern of IrAEs were similar for older patients and younger subjects. CONCLUSIONS: Even though frequency and patterns of IrAEs are different from pivotal studies, these results don't seem specific to older patients. Further prospective investigations are needed to better characterize and predict the impact of Nivolumab on older patients with NSCLC.

Targeted NGS, array-CGH, and patient-derived tumor xenografts for precision medicine in advanced breast cancer: a single-center prospective study.

BACKGROUND: Routine feasibility and clinical impact of genomics-based tumor profiling in advanced breast cancer (aBC) remains to be determined. We conducted a pilot study to evaluate whether precision medicine could be prospectively implemented for aBC patients in a single center and to examine whether patient-derived tumor xenografts (PDX) could be obtained in this population. RESULTS: Thirty-four aBC patients were included. Actionable targets were found in 28 patients (82%). A targeted therapy could be proposed to 22 patients (64%), either through a clinical trial (n=15) and/or using already registered drugs (n=21). Ten patients (29%) eventually received targeted treatment, 2 of them deriving clinical benefit. Of 22 patients subjected to mouse implantation, 10 had successful xenografting (45%), mostly in triple-negative aBC. METHODS: aBC patients accessible to tumor biopsy were prospectively enrolled at the Institut Paoli-Calmettes in the BC-BIO study (ClinicalTrials.gov, NCT01521676). Genomic profiling was established by whole-genome array comparative genomic hybridization (aCGH) and targeted next-generation sequencing (NGS) of 365 candidate cancer genes. For a subset of patients, a sample of fresh tumor was orthotopically implanted in humanized cleared fat pads of NSG mice for establishing PDX. CONCLUSIONS: Precision medicine can be implemented in a single center in the context of clinical practice and may allow genomic-driven treatment in approximately 30% of aBC patients. PDX may be obtained in a significant fraction of cases.

Impact of delay to cryopreservation on RNA integrity and genome-wide expression profiles in resected tumor samples.

The quality of tissue samples and extracted mRNA is a major source of variability in tumor transcriptome analysis using genome-wide expression microarrays. During and immediately after surgical tumor resection, tissues are exposed to metabolic, biochemical and physical stresses characterized as "warm ischemia". Current practice advocates cryopreservation of biosamples within 30 minutes of resection, but this recommendation has not been systematically validated by measurements of mRNA decay over time. Using Illumina HumanHT-12 v3 Expression BeadChips, providing a genome-wide coverage of over 24,000 genes, we have analyzed gene expression variation in samples of 3 hepatocellular carcinomas (HCC) and 3 lung carcinomas (LC) cryopreserved at times up to 2 hours after resection. RNA Integrity Numbers (RIN) revealed no significant deterioration of mRNA up to 2 hours after resection. Genome-wide transcriptome analysis detected non-significant gene expression variations of -3.5%/hr (95% CI: -7.0%/hr to 0.1%/hr; p = 0.054). In LC, no consistent gene expression pattern was detected in relation with warm ischemia. In HCC, a signature of 6 up-regulated genes (CYP2E1, IGLL1, CABYR, CLDN2, NQO1, SCL13A5) and 6 down-regulated genes (MT1G, MT1H, MT1E, MT1F, HABP2, SPINK1) was identified (FDR <0.05). Overall, our observations support current recommendation of time to cryopreservation of up to 30 minutes and emphasize the need for identifying tissue-specific genes deregulated following resection to avoid misinterpreting expression changes induced by warm ischemia as pathologically significant changes.

Impact of point spread function reconstruction on thoracic lymph node staging with 18F-FDG PET/CT in non-small cell lung cancer.

AIM: The aim of the present study was to evaluate the impact of point spread function (PSF) reconstruction on quantitative values and diagnostic accuracy of FDG PET/CT for nodal staging in non-small cell lung cancer. PATIENTS AND METHODS: Fifty-eight consecutive PET/CT examinations were reconstructed with both ordered subset expectation maximization (OSEM) and PSF algorithms. Two readers independently performed a randomized blinded review of PET/CT examinations and gave a nodal status (N0, N1, N2, or N3) to each PET data set. When discordant, a consensus was reached with a third reader. Sensitivity, specificity, positive and negative predictive values (NPV), and positive and negative likelihood ratios (LRs) were assessed and compared using a McNemar test. All PET data sets were then independently analyzed to extract quantitative PET values in 208 nodes and compare them using Bland-Altman analysis. RESULTS: Bland-Altman analysis showed that, on average, PSF reconstruction increased SUVmax, SUVmean, and node/background ratios by 48%, 28%, and 27%, respectively. This increase was more marked for nodes less than 1 cm than for nodes 1 cm or greater (P < 0.0001 for SUVmax, SUVmean, and node/background ratios). Point spread function PET had higher sensitivity (97%) and NPV (92%) than OSEM PET (78% and 57%, respectively; P = 0.01 and P = 0.04, respectively). Negative LR was 0.04 for PSF PET and 0.31 for OSEM PET. CONCLUSIONS: By improving activity recovery, especially for nonenlarged nodes, PSF significantly improves the sensitivity, NPV, and negative LR of FDG-PET for nodal staging in non-small cell lung cancer. These data suggest that preoperative invasive nodal staging may be omitted in the case of a negative PSF FDG-PET/CT.

Usefulness of automatic quantification of immunochemical staining on whole tumor sections for correlation with oncological small animal PET studies: an example with cell proliferation, glucose transporter 1 and FDG.

AIM: To highlight the use of automatic quantification of immunochemical staining on digitized images of whole tumor sections in preclinical positron emission tomography (PET) studies. MATERIALS AND METHODS: Xenografted human testicular tumors (36) were imaged with 2-deoxy-2[F-18]fluoro-D: -glucose (FDG) small animal PET (SA-PET). Tumor cell proliferation and glucose transportation were assessed with cyclin A and Glut-1 immunostaining. Tumor slides were digitized and processed with PixCyt software enabling whole slide quantification, then compared with junior and senior pathologist manual scoring. Manual and automatic quantification results were correlated to FDG uptake. RESULTS: For cyclin A, inter- and intra-observer agreement for manual scoring was 0.52 and 0.72 and concordance between senior pathologist and automatic quantification was 0.84. Correlations between Tumor/Background ratio and tumor cell proliferation assessed by automatic quantification, junior and senior pathologists were 0.75, 0.55, and 0.61, respectively. Correlation between Tumor/Background ratio and Glut-1 assessed by automatic quantification was 0.74. CONCLUSION: Automatic quantification of immunostaining is a valuable tool to overcome inter- and intra-observer variability for correlation of cell proliferation or other markers with tumor tracer uptake.