Delaying Surgery After Neoadjuvant Chemotherapy Affects Survival in Patients with Colorectal Peritoneal Metastases: A BIG-RENAPE Network Multicentric Study.

BACKGROUND: Multimodal treatment for patients with peritoneal metastases (PM) from colorectal cancer (CRC), including perioperative chemotherapy (CT) plus complete resection, is associated with prolonged survival. The oncologic impact of therapeutic delays is unknown. OBJECTIVE: The aim of this study was to assess the survival impact of delaying surgery and CT. METHODS: Medical records from the national BIG RENAPE network database of patients with complete cytoreductive (CC0-1) surgery of synchronous PM from CRC who received at least one neoadjuvant CT cycle plus one adjuvant CT cycle were retrospectively reviewed. The optimal interval between the end of neoadjuvant CT to surgery, surgery to adjuvant CT, and total interval without systemic CT were estimated using Contal and O'Quigley's method plus restricted cubic spline methods. RESULTS: From 2007 to 2019, 227 patients were identified. After a median follow-up of 45.7 months, the median overall survival (OS) and progression-free survival (PFS) was 47.6 and 10.9 months, respectively. The best cut-off period was 42 days in the preoperative interval, no cut-off period was optimal in the postoperative interval, and the best cut-off period in the total interval without CT was 102 days. In multivariate analysis, age, biologic agent use, high peritoneal cancer index, primary T4 or N2 staging, and delay to surgery of more than 42 days (median OS 63 vs. 32.9 months; p = 0.032) were significantly associated with worse OS. Preoperative delay of surgery was also significantly associated with PFS, but only in univariate analysis. CONCLUSION: In selected patients undergoing complete resection plus perioperative CT, a period of more than 6 weeks from completion of neoadjuvant CT to cytoreductive surgery was independently associated with worse OS.

68Ga-PSMA-11 PET-CT study in prostate cancer patients with biochemical recurrence and non-contributive 18F-Choline PET-CT: Impact on therapeutic decision-making and biomarker changes.

BACKGROUND: In this retrospective study, we investigated the impact of 68 Ga-PSMA-11 PET-CT (PSMA PET-CT) upon the treatment plan and therapeutic response obtained for Prostate Cancer (PCa) patients presenting an occult biochemical recurrence. METHODS: Forty-two patients with previously negative or doubtful 18F-Choline (FCH) were enrolled. PET images were recorded 1 h after injection of tracer. Only a few months after treatment ended, a PSA assay was requested to evaluate the therapeutic efficacy of the treatment based on PSMA results. RESULTS: PSMA-positive lesions were detected in 34/42 (80.9%) patients. Detection rates were 85.7% and 89.3% for serum PSA levels lower than 2 ng/mL, and >2 ng/mL, respectively. One hundred seventy-three lesions were detected: 132/173 in lymph nodes (76.3%), 22/173 as metastatic sites (bone or lung) (12.7%), and 19/173 in the prostate bed (10.9%). As a result of the PSMA PET-CT, therapeutic management changed in 31/42 patients (73.8%). With a follow-up of 4.9 ± 2.27 months, 32/42 (76.2%) PSA assays after treatment guided by PSMA PET-CT were collected. For 37.5% (12/32) of patients, the serum PSA level was lower than 0.2 ng/mL and a PSA decrease of over 50% in 8 (25.0%) other patients were obtained. CONCLUSION: Performing a PSMA PET-CT when FCH PET-CT was doubtful or negative allows the recurrence localization in more 80% of patients and this had a major clinical impact, as it resulted in treatment change in more than 70% of patients as well as a significant decrease in PSA levels in more than 60% of them.

Preliminary results of a 68 Ga-PSMA PET/CT prospective study in prostate cancer patients with occult recurrence: Diagnostic performance and impact on therapeutic decision-making.

BACKGROUND: In this prospective study (NCT03443609), we investigated the impact of 68Ga-PSMA-11 PET-CT on the treatment plan and therapeutic response obtained for patients with prostate cancer (PCa) presenting a recurrence with a low rising PSA. METHODS: One hundred thirty hormone-naive (PSA < 1.5 ng/mL) patients were enrolled. All patients received radical treatment. PET images were recorded 1 and 2 hours after injection of tracer and interpreted by two independent nuclear physicians. Six months after treatment ended, a PSA assay was requested to evaluate the therapeutic efficacy of the treatment based on PSMA results. RESULTS: Data analysis for the first 52 included patients has been completed. 68Ga-PSMA-11-positive lesions were detected in 38/52 (73.1%) patients. Ninety-four lesions were detected as follows, 53/94 in lymph nodes (56.4%), 25/94 in bone (26.6%), and 12/94 into the prostate bed (12.7%). Detection rates were 58%, 81%, and 82% for serum PSA levels lower than 0.25 ng/mL, between 0.25 to ≤ 0.69 ng/mL and 0.70 ng/mL, respectively. As a result of the PSMA PET-CT, therapeutic management changed in 38/52 patients (73.1%). Patients had undetectable serum PSA levels after treatment guided by 68Ga-PSMA-11 PET-CT results in 10/52 (19.2%) cases and with a PSA decrease of over 60% in 18/52 (34.6%) patients. CONCLUSION: Whilst our patient population presented a very low PSA level, preliminary results of the 68Ga-PSMA PET-CT study showed recurrence localization in more than half of the patients and this had a major clinical impact, as it resulted in treatment change in more than half of the patients and a significant decrease in PSA levels in a third of patients.

Efficacy of palbociclib plus fulvestrant after everolimus in hormone receptor-positive metastatic breast cancer.

BACKGROUND: Palbociclib, a CDK4-6 inhibitor, combined with endocrine therapy (ET) is a new standard of treatment for Hormone Receptor-positive Metastatic Breast Cancer. We present the first real-life efficacy and tolerance data of palbociclib plus fulvestrant in this population. METHODS: From November 2015 to November 2016, patients receiving in our institution palbociclib + fulvestrant according to the Temporary Authorization for Use were prospectively analyzed. RESULTS: 60 patients were treated accordingly; median age was 61 years; 50 patients (83.3%) had visceral metastasis, and 10 (16.7%) had bone-only disease. Patients had previously received a median of 5 (1-14) lines of treatment, including ET (median 3) and chemotherapy (median 2); 28 (46.7%) received previously fulvestrant and all everolimus. With a median follow-up of 10.3 months, median progression-free survival (mPFS) was 5.8 months (95% CI 3.9-7.3). Patients pretreated with fulvestrant had a similar PFS of 6.4 months (HR 1.00; 95% CI 0.55-1.83; P = 1.00). The most common AEs (adverse events) were neutropenia (93%), anemia (65%), and thrombocytopenia (55%). CONCLUSION: In this heavily pretreated population including everolimus, fulvestrant plus palbociclib provides an mPFS of 5.8 months with the same magnitude of benefit for fulvestrant-pretreated patients.

Totally implantable venous access ports: a prospective long-term study of early and late complications in adult patients with cancer.

PURPOSE: Totally implantable venous access ports (TIVAP) have been widely used for many years in the management of patients suffering from cancer. The implantation and long-term use of TIVAPs are associated with mechanical, thrombotic, and infectious complications. This is the first exhaustive prospective study of all complications occurring in a whole population on long-term follow-up and therefore allows an objective assessment to be made of the safety of TIVAPs. METHODS: We carried out a prospective single-center observational study. All adult patients with cancer who had a TIVAP implanted between January 1 and December 31, 2006 were registered. Early and late complications were recorded until the removal of the device, the patient's death, or until December 31, 2013. Exhaustive data concerning patients and TIVAP was recorded at time of implantation. RESULTS: Four hundred and ninety-three TIVAPs were implanted in 483 adult cancer patients and were followed during a period from 1 to 94 months (median = 18 months) representing a global quantity of 367,359 catheter-days. Eighty-seven complications were recorded (0.237/1000 catheter-days), including 37 infections (0.101/1000 catheter-days), 17 thrombotic events (0.046/1000 catheter-days), and 9 extravasations. Out of the 87 events, 62 (71.3%) occurred during the first year after implantation. Events were therefore extremely rare after 1 year. Thromboembolic and infectious complications were rare and no risk factors for these were found. CONCLUSIONS: This study demonstrates excellent tolerability, with only occasional complications. Most of these occurred during the year following implantation. A TIVAP may also be left in place for an extremely long time.

Prediction of Recurrence and Survival for Triple-Negative Breast Cancer (TNBC) by a Protein Signature in Tissue Samples.

To date, there is no available targeted therapy for patients who are diagnosed with triple-negative breast cancers (TNBC). The aim of this study was to identify a new specific target for specific treatments. Frozen primary tumors were collected from 83 adjuvant therapy-naive TNBC patients. These samples were used for global proteome profiling by iTRAQ-OFFGEL-LC-MS/MS approach in two series: a training cohort (n = 42) and a test set (n = 41). Patients who remains free of local or distant metastasis for a minimum of 5 years after surgery were classified in the no-relapse group; the others were in the relapse group. OPLS and Kaplan-Meier analyses were performed to select candidate markers, which were validated by immunohistochemistry. Three proteins were identified in the training set and validated in the test set by Kaplan-Meier method and immunohistochemistry (IHC): TrpRS as a good prognostic markers and DP and TSP1 as bad prognostic markers. We propose the establishment of an IHC test to calculate the score of TrpRS, DP, and TSP1 in TNBC tumors to evaluate the degree of aggressiveness of the tumors. Finally, we propose that DP and TSP1 could provide therapeutic targets for specific treatments.

Higher Early Monocyte and Total Lymphocyte Counts Are Associated with Better Overall Survival after Standard Total Body Irradiation, Cyclophosphamide, and Fludarabine Reduced-Intensity Conditioning Double Umbilical Cord Blood Allogeneic Stem Cell Transplantation in Adults.

This single-center retrospective study aimed to report the impact of early hematopoietic and immune recoveries after a standard total body irradiation, cyclophosphamide, and fludarabine (TCF) reduced-intensity conditioning (RIC) regimen for double umbilical cord blood (dUCB) allogeneic stem cell transplantation (allo-SCT) in adults. We analyzed 47 consecutive patients older than 17 years who engrafted after a dUCB TCF allo-SCT performed between January 2006 and April 2013 in our department. Median times for neutrophil and platelet recoveries were 17 (range, 6 to 59) and 37 days (range, 0 to 164), respectively. The 3-year overall (OS) and disease-free survivals, relapse incidence, and nonrelapse mortality were 65.7%, 57.2%, 27.1%, and 19%, respectively. In multivariate analysis, higher day +30 monocyte (≥615/mm(3); hazard ratio [HR], .04; 95% confidence interval [CI], .004 to .36; P < .01) and day +42 lymphocyte (≥395/mm(3); HR, .16; 95% CI, .03 to .78; P = .02) counts were independently associated with better OS. These results suggest that early higher hematopoietic and immune recovery is predictive of survival after dUCB TCF RIC allo-SCT in adults. Factors other than granulocyte colony-stimulating factor, which was used in all cases, favoring expansion of monocytes or lymphocytes, should be tested in the future as part of the UCB transplantation procedure.

Laparoscopic sentinel lymph node dissection in prostate cancer patients: the additional value depends on preoperative data.

AIM: In intermediate- or high-risk prostate cancer (PC) patients, to avoid extended pelvic lymph node dissection (ePLND), the updated Briganti nomogram is recommended with the cost of missing 1.5 % of patients with lymph node invasion (LNI). Is it possible to reduce the percentage of unexpected LNI patients (nomogram false negative)? We used the isotopic sentinel lymph node (SLN) technique systematically associated with laparoscopic ePLND to assess the potential value of isotopic SLN method to adress this point. METHODS: Two hundred and two consecutive patients had procedures with isotopic SLN detection associated with laparoscopic ePLND for high or intermediate risk of PC. The area under the curve (AUC) of the receiver operating characteristics (ROC) analysis was used to quantify the accuracy of different models as: the updated Briganti nomogram, the percentage of positive cores, and an equation of the best predictors of LNI. We tested the model cutoffs associated with an optimal negative predictive value (NPV) and the best cutoff associated with avoiding false negative SLN detection, in order to assist the clinician's decision of when to spare ePLND. RESULTS: LNI was detected in 35 patients (17.2 %). Based on preoperative primary Gleason grade and percentage of positive cores, a bivariate model was built to calculate a combined score reflecting the risk of LNI. For the Briganti nomogram, the 5 % probability cutoff avoided ePLND in 53 % (108/202) of patients, missing three LNI patients (8.6 %), but all were detected by the SLN technique. For our bivariate model, the best cutoff was <10, leaving no patient with LNI due to positive SLN detection (four patients = 11.4 %), and avoiding ePLND in 52 % (105/202) of patients. CONCLUSION: For patients with a low risk of LNI determined using the updated Briganti nomogram or bivariate model, SLN technique could be used alone for lymph node staging in intermediate- or high-risk PC patients.

Gene-expression molecular subtyping of triple-negative breast cancer tumours: importance of immune response.

INTRODUCTION: Triple-negative breast cancers need to be refined in order to identify therapeutic subgroups of patients. METHODS: We conducted an unsupervised analysis of microarray gene-expression profiles of 107 triple-negative breast cancer patients and undertook robust functional annotation of the molecular entities found by means of numerous approaches including immunohistochemistry and gene-expression signatures. A triple-negative external cohort (n=87) was used for validation. RESULTS: Fuzzy clustering separated triple-negative tumours into three clusters: C1 (22.4%), C2 (44.9%) and C3 (32.7%). C1 patients were older (mean=64.6 years) than C2 (mean=56.8 years; P=0.03) and C3 patients (mean=51.9 years; P=0.0004). Histological grade and Nottingham prognostic index were higher in C2 and C3 than in C1 (P<0.0001 for both comparisons). Significant event-free survival (P=0.03) was found according to cluster membership: patients belonging to C3 had a better outcome than patients in C1 (P=0.01) and C2 (P=0.02). Event-free survival analysis results were confirmed when our cohort was pooled with the external cohort (n=194; P=0.01). Functional annotation showed that 22% of triple-negative patients were not basal-like (C1). C1 was enriched in luminal subtypes and positive androgen receptor (luminal androgen receptor). C2 could be considered as an almost pure basal-like cluster. C3, enriched in basal-like subtypes but to a lesser extent, included 26% of claudin-low subtypes. Dissection of immune response showed that high immune response and low M2-like macrophages were a hallmark of C3, and that these patients had a better event-free survival than C2 patients, characterized by low immune response and high M2-like macrophages: P=0.02 for our cohort, and P=0.03 for pooled cohorts. CONCLUSIONS: We identified three subtypes of triple-negative patients: luminal androgen receptor (22%), basal-like with low immune response and high M2-like macrophages (45%), and basal-enriched with high immune response and low M2-like macrophages (33%). We noted out that macrophages and other immune effectors offer a variety of therapeutic targets in breast cancer, and particularly in triple-negative basal-like tumours. Furthermore, we showed that CK5 antibody was better suited than CK5/6 antibody to subtype triple-negative patients.

OLIGOPELVIS - GETUG P07: a multicentre phase II trial of combined salvage radiotherapy and hormone therapy in oligometastatic pelvic node relapses of prostate cancer.

BACKGROUND: Metastatic prostate cancer remains a common cause of death in Europe, and improvements in management of the disease are urgently needed. The advent of positron-emission tomography (PET) imaging enhanced with fluorocholine has led to the identification of a new sub-group of metastatic prostate cancer patients: those with so-called oligometastatic disease. Presenting with a low burden of metastatic disease (≤5 lesions), this new sub-group lies between true metastatic prostate cancer patients for whom androgen- deprivation therapy (ADT) is the mainstay of treatment, and patients with a rising PSA, but no visible lesion on conventional imaging, in whom intermittent ADT has been shown to be no less effective than continuous ADT. One might conclude that intermittent ADT would also be the standard of care for oligometastatic prostate cancer patients, but radical strategies such as extensive lymphadenectomy or high-dose radiotherapy have been suggested as another means to delay the need for ADT, and increase its effectiveness once initiated. This study will explore the role of salvage pelvic image-guided intensity-modulated radiation therapy (IMRT) combined with ADT administered for 6 months in pelvic oligometastatic patients in prolonging the failure-free interval between two consecutive ADT courses, or even to cure selected patients with limited metastatic burden. METHODS/DESIGN: We plan to assess the two year outcome in oligometastatic prostate cancer patients (1-5 pelvic oligometastases) treated concomitantly with high-dose IMRT (54 Gy, 30 fractions to the pelvis and 66 Gy, 30 fractions to the lymph nodes) and ADT for six months. DISCUSSION: This multicenter prospective phase II study will yield new data regarding the safety and efficacy of high-dose radiotherapy combined with ADT and will provide a basis for a larger phase III study to examine the role of radiotherapy in this population currently treated only with hormone therapy. TRIAL REGISTRATION: NCT02274779 , date of registration: 23/10/14.

Survival benefit of hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer: a multi-institutional case control study.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) and complete surgical removal of the tumor, in relapsing patients may provide a clinical benefit. There is no consensus considering the place of HIPEC for patients who had first ovarian cancer relapse. To assess for possible efficacy of HIPEC on overall survival (OS) rates in this situation, we performed a multi-institutional study. METHODS: The current study was a retrospective case control multi-institutional study comparing a group of patients treated with HIPEC to a group of patients treated without HIPEC. Inclusion criteria were first relapse of a serous ovarian carcinoma and >6 months after the end of initial treatment. Exclusion criteria were another pathological subtype of ovarian cancer, a relapse at <6 months after initial treatment, and a second relapse or more. We aimed to assess OS, morbidity, and mortality rates and prognostic factors. RESULTS: From June 1997-July 2011, 42 patients were included, 23 in the HIPEC group and 19 in the control group. Each patient from the two groups had a complete secondary surgery at the time of the first relapse. At 4 years OS was 75.6 % in the HIPEC group and 19.4 % in the control group (p = 0.013). In a multivariate analysis, HIPEC and interval-free before the end of initial treatment were both independent prognostic factors. CONCLUSION: When compared to the control group, complete secondary surgery and HIPEC appear to afford a better OS rate than complete secondary surgery alone, in case of first ovarian cancer relapse. Further randomized trials are warranted to confirm these results.

¹8F-FDG PET predicts survival after pretargeted radioimmunotherapy in patients with progressive metastatic medullary thyroid carcinoma.

PURPOSE: PET is a powerful tool for assessing targeted therapy. Since (18)F-FDG shows a potential prognostic value in medullary thyroid carcinoma (MTC), this study evaluated (18)F-FDG PET alone and combined with morphological and biomarker evaluations as a surrogate marker of overall survival (OS) in patients with progressive metastatic MTC treated with pretargeted anti-CEA radioimmunotherapy (pRAIT) in a phase II clinical trial. METHODS: Patients underwent PET associated with morphological imaging (CT and MRI) and biomarker evaluations, before and 3 and 6 months, and then every 6 months, after pRAIT for 36 months. A combined evaluation was performed using anatomic, metabolic and biomarker methods. The prognostic value of the PET response was compared with demographic parameters at inclusion including age, sex, RET mutation, time from initial diagnosis, calcitonin and CEA concentrations and doubling times (DT), SUVmax, location of disease and bone marrow involvement, and with response using RECIST, biomarker concentration variation, impact on DT, and combined methods. RESULTS: Enrolled in the study were 25 men and 17 women with disease progression. The median OS from pRAIT was 3.7 years (0.2 to 6.5 years) and from MTC diagnosis 10.9 years (1.7 to 31.5 years). After pRAIT, PET/CT showed 1 patient with a complete response, 4 with a partial response and 24 with disease stabilization. The combined evaluation showed 20 responses. For OS from pRAIT, univariate analysis showed the prognostic value of biomarker DT (P = 0.011) and SUVmax (P = 0.038) calculated before pRAIT and impact on DT (P = 0.034), RECIST (P = 0.009), PET (P = 0.009), and combined response (P = 0.004) measured after pRAIT. PET had the highest predictive value with the lowest Akaike information criterion (AIC 74.26) as compared to RECIST (AIC 78.06), biomarker variation (AIC 81.94) and impact on DT (AIC 79.22). No benefit was obtained by combining the methods (AIC 78.75). This result was confirmed by the analysis of OS from MTC diagnosis. CONCLUSION: (18)F-FDG PET appeared as the most potent and simplest prognostic method to predict survival in patients with progressive MTC treated with pRAIT. Biomarker DT before pRAIT also appeared as an independent prognostic factor, but no benefit was found by adding morphological and biomarker evaluation to PET assessment.

Correlation between ERK1 and STAT3 expression and chemoresistance in patients with conventional osteosarcoma.

BACKGROUND: The standard therapy regimen of conventional osteosarcoma includes neoadjuvant chemotherapy followed by surgical resection and postoperative chemotherapy. The percentage of necrotic tissue following induction chemotherapy is assessed by using the Huvos grading system, which classifies patients as "poor responders" (PR) and "good responders" (GR). The aim of this study was to identify molecular markers expressed differentially between good and poor responders to neoadjuvant chemotherapy in order to predict the response to chemotherapy in conventional osteosarcomas before beginning treatment. METHODS: Suppression Substractive Hybridization (SSH) was performed by using cDNA from frozen biopsy specimens. Expression of selected relevant genes identified by SSH was validated by using QRT-PCR. Immunohistochemistry (IHC) on tissue microarray (TMA) sections of 52 biopsies was performed to investigate protein expression in an independent cohort. RESULTS: ERK1 and STAT3 mRNA level were significantly different between PR and GR in an independent cohort. Phosphorylated STAT3 and ERK1 expressions by IHC on TMA were correlated with poor response to chemotherapy. CONCLUSIONS: Our results suggest that ERK1 and STAT3 expression are good predictive markers for chemotherapy response and that inhibitors might be used in combination with common chemotherapeutic drugs in conventional osteosarcomas.

Between Pathological Prostate Cancer Lymph Nodes and Sentinel Nodes: Which Information Is the Leader?

PURPOSE: On the basis of the concept of sentinel lymph node biopsy (SLNB), SLNs should contain decisive information for clinical outcomes. In localized prostate cancer patients, this study assessed retrospectively clinical outcome after radical laparoscopic prostatectomy associated with SLNB and extensive pelvic lymph node dissection. METHODS: A total of 231 consecutive patients of intermediate to high risk were analyzed. Recurrence-free survival (RFS) was assessed with Kaplan-Meier curves. Various pathological parameters were analyzed using univariable and multivariable analyses through Cox regression analysis. The study was approved and registered under 2007-R41. RESULTS: The median follow-up was 7.1 years (95% confidence interval, 6.6-7.5). In total, 38/231 (16.5%) patients were pN1. Of these 38 patients, 27 had only SLN involvement (SLNI), 10 patients had both SLN and non-SLNI, and 1 patient had isolated non-SLNI, indicating a false-negative (FN). If the updated Briganti nomogram threshold set at >7% for recommending extensive pelvic lymph node dissection had been applied to these patients, we would have missed 44% (12/27) of patients with SLNI and 50% (5/10) of patients with SLNI and non-SLNI, as well as the FN patient. At the time of final follow-up, 84/231 (36.5%) patients had recurrence. In multivariable analysis, and regarding node status, the most significant prognostic factor was SLN with macrometastases and/or micrometastases, respectively, P = 10-3 and P < 10-3. No more information was obtained with non-SLN status. Probabilities of RFS between negative and positive SLN patients presented a major significant difference (P < 10-15) with a risk of event 8.75 times more frequent if SLN was involved than if it was metastasis-free. CONCLUSIONS: SLNB seems to contain decisive information for the clinical outcome of patients with localized intermediate- and high-risk prostate cancer patients. The question raised is thus whether immediate additional postoperative treatment should be offered to patients with metastatic SLN.

Prognostic Factors of Mandibular Osteoradionecrosis Including Accurate Colocalization of Avulsions and Dosimetric Dental Mapping Software, a Case-control Study.

PURPOSE: Osteoradionecrosis (ORN) of the mandible remains a significant complication in the intensity modulated radiation therapy (IMRT) era. Dental dose cannot be predicted from heterogeneous IMRT dose distributions; mandibular dose metrics cannot guide dentist avulsion decisions in high-risk ORN situations. Using a mapping tool to report dental root dose, avulsions, and ORN sites, we re-examined ORN risk factors in a case-control study. METHODS AND MATERIALS: From 2008 to 2019, 897 consecutive patients with oral cavity/oropharynx or unknown primary cancer undergoing IMRT were analyzed to identify ORN cases. These were matched (1 ORN/2 controls) retrospectively for tumor location, surgery, and tobacco consumption in a monocentric case-control study. Univariate and multivariate analyses integrated ORN factors and accurate dental dose data (grouped into 4 mandibular sectors). Generalizability was investigated in a simulated population database. RESULTS: A total of 171 patients were included. The median follow-up was 5.2 and 4.5 years in the ORN and control groups, respectively. The median time to ORN was 12 months. In univariate analysis, post-IMRT avulsions at the ORN site (hazard ratio [HR] = 3.6; 95% confidence interval [CI] = 1.5-8.9; P = .005), tumor laterality (HR, 4.4; 95% CI, = 1.4-14, P = .01), mean mandibular dose (HR, 1.1; 95% CI, = 1.01-1.1; P = .018) and mean dose to the ORN site (HR, 1.1; 95% CI, = 1.1-1.2; P < .001) correlated with higher ORN risk. In multivariate analysis, mean dose to the ORN site (HR, 1.1; 95% CI, = 1.1-1.2; P < .001) and post-IMRT avulsions at the ORN site (HR, 4.6; 95% CI, = 1.5-14.7; P = .009) were associated with ORN. For each increase in gray in dental dose, the ORN risk increased by 12%. Simulations confirmed study observations. CONCLUSIONS: Dental dose and avulsions are associated with ORN, with a 12% increase in risk with each additional gray. Accurate dose information can help dentists in their decisions after IMRT.

Combination of Abiraterone Acetate, Prostate Bed Radiotherapy, and Luteinizing Hormone-releasing Hormone Agonists in Biochemically Relapsing Patients After Prostatectomy (CARLHA): A Phase 2 Clinical Trial.

BACKGROUND: The relevance of next-generation hormone therapies and circulating tumor cells (CTCs) are not elucidated in biochemical recurrence after prostatectomy. OBJECTIVE: To evaluate the combination of abiraterone acetate plus prednisone (AAP), prostate bed radiotherapy (PBRT), and goserelin in biochemically relapsing men after prostatectomy, and to investigate the utility of CTCs. DESIGN, SETTING, AND PARTICIPANTS: In this single-arm multicenter phase 2 trial, 46 biochemically relapsing men were enrolled between December 2012 and January 2019. The median follow-up was 47 mo. INTERVENTION: All patients received AAP 1000 mg daily (but 750 mg during PBRT), salvage PBRT, and goserelin. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was 3-yr biochemical recurrence-free survival (bRFS) when prostate-specific antigen (PSA) levels were ≥0.2 ng/ml. The secondary outcomes included alternative bRFS (alt-bRFS) when PSA levels were ≥0.5 ng/ml and safety assessment. CTC count was assessed. RESULTS AND LIMITATIONS: The 3-yr bRFS and alt-bRFS were 81.5% (95% confidence interval or CI [66.4-90.3%]) and 95.6% (95% CI [83.5-98.9%]), respectively. The most common acute radiotherapy-related adverse effect (AE; all grades was pollakiuria (41.3%). The most common late AE (all grades) was urinary incontinence (15.2%). Grade 3-4 acute or late radiotherapy-related AEs were scarce. Most frequent AEs nonrelated to radiotherapy were hot flashes (76%), hypertension (63%), and hepatic cytolysis (50%, of which 20% were of grades 3-4). Of the patients, 11% had a CTC count of ≥5, which was correlated with poorer bRFS (p = 0.042) and alt-bRFS (p = 0.008). The association between CTC count and higher rates of relapse was independent of the baseline PSA level and PSA doubling time (p = 0.42 and p = 0.09, respectively). This study was nonrandomized with a limited number of patients, and few clinical events were reported. CONCLUSIONS: Adding AAP to salvage radiation therapy and goserelin resulted in high bRFS and alt-bRFS. AEs remained manageable, although a close liver surveillance is advised. CTC count appears as a promising biomarker for prognosis and predicting response to treatment. PATIENT SUMMARY: Our study was a phase 2 clinical trial that exhibited the efficacy and tolerance of a novel androgen-receptor targeting agent (abiraterone acetate plus prednisone) in patients with prostate cancer who experienced rising prostate-specific antigen after radical prostatectomy, in combination with prostate bed radiotherapy. The results also indicated the feasibility and potential value of circulating tumor cell detection, which constitutes a possible advance in managing prostate cancers.

PIPAC in patients with peritoneal metastases from gastrointestinal tract (PIPOX01): An open label, non-comparative phase 1/2 dose escalation and expansion trial.

BACKGROUND: Despite modern systemic chemotherapy, survival remains poor for patients with advanced isolated peritoneal metastases from the gastrointestinal tract. We aimed to assess the safety and efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) with oxaliplatin. PATIENTS AND METHODS: We conducted a phase 1/2, open label, non-comparative, dose escalation and expansion trial of PIPAC with oxaliplatin in patients with a peritoneal cancer index (PCI) of more than 5, 13 and 15 for respectively a gastric, small bowel and colorectal primary cancer, and who had received at least three months of systemic chemotherapy. PIPAC cycle lengths were 4-6 weeks with systemic chemotherapy allowed 15 days after each PIPAC. PCI and oxaliplatin tumor concentration were assessed every PIPAC cycle. The main endpoints were tolerability, tumor response, and survival. RESULTS: Between 2017 and 2020, 34 patients were enrolled in three centers, in this phase 1/2 study, of whom 25 were evaluable at the recommended dose determined in the phase I trial (90 mg/m2 plus systemic 5-FU). Before inclusion, patients received a median of 2 [1-4] chemotherapy lines and had a median PCI of 22.5 [7-29]. At this dose, the safety profile showed acceptable tolerability. Eight patients (32 %) had grade 3/4 treatment-related adverse events. Minor (grade 1/2) adverse events were mainly abdominal pain (n = 19, 76 %) and nausea (n = 16, 64 %). Median PFS was 6.1 months and median OS was 13 months. CONCLUSION: In patients with advanced and refractory peritoneal metastasis, PFS of 6.1 months is encouraging. A prospective randomized phase II study is required.

Pilot Feasibility Study: 18 F-DPA-714 PET/CT Macrophage Imaging in Triple-Negative Breast Cancers (EITHICS).

ABSTRACT: Tumor-associated macrophages are targets of interest in triple-negative breast cancer (TNBC). The translocator protein 18 kDa (TSPO) is a sensitive marker for macrophages and holds potential relevance in TNBC stratification. This pilot prospective study (EITHICS, NCT04320030) aimed to assess the potential of TSPO PET/CT imaging using 18 F-DPA-714 in primary TNBC, compared with immunohistochemistry, autoradiography, and TSPO polymorphism. PATIENTS AND METHODS: Thirteen TNBC patients were included. They underwent TSPO genotyping (HAB, MAB, LAB), 18 F-FDG PET/CT, and breast MRI. Semiquantitative PET parameters were computed. VOIs were defined on the tumor lesion, healthy breast tissue, and pectoral muscle to obtain SUV, tumor-to-background ratio (TBR), and time-activity curves (TACs). Additionally, immunohistochemistry, 3 H-DPA-714, and 3 H-PK-11195 autoradiography were conducted. RESULTS: The majority of TNBC tumors (11/13, 84%) had a preponderance of M2-polarized macrophages with a median proportion of 82% (range, 44%-94%). 18 F-DPA-714 PET/CT clearly identified TNBC tumors with an excellent TBR. Three distinct patterns of 18 F-DPA-714 TACs were identified, categorized as "above muscular," "equal to muscular," and "below muscular" with reference to the muscular background. For the "above muscular" group (2 HAB and 2 MAB), "equal muscular" group (3 HAB, 3 MAB, and 1 LAB), and "below muscular" group (1 LAB and 1 MAB), tumor TACs showed a 18 F-DPA-714 accumulation slope of 1.35, 0.62, and 0.22, respectively, and a median SUV mean of 4.02 (2.09-5.31), 1.66 (0.93-3.07), and 0.61 (0.43-1.02). CONCLUSIONS: This study successfully demonstrated TNBC tumor targeting by 18 F-DPA-714 with an excellent TBR, allowing to stratify 3 patterns of uptake potentially influenced by the TSPO polymorphism status. Further studies in larger populations should be performed to evaluate the prognostic value of this new biomarker.

Margin width should not still enforce a systematic surgical re-excision in the conservative treatment of early breast infiltrative ductal carcinoma.

BACKGROUND: In cases where breast conservative surgery was performed for infiltrative ductal carcinoma (IDC), margin status is an independent prognostic factor for local ipsilateral relapse (LIR). There is no validated definition of a clear margin. We investigated factors associated with residual disease on re-excision specimen and the impact of margin status on the risk of LIR. METHODS: From January 1992 to December 2002, 454 patients were retrospectively included. Patients had undergone conservative surgery and radiotherapy for IDC. Two groups were defined: group 1, involved or close margin (<3 mm) and a re-excision; and group 2, involved or close margin without re-excision. The risk factors for residual disease in the re-excision specimen were analyzed in group 1, and the rate of 5-year LIR was analyzed in both groups. RESULTS: Among patients who experienced a surgical re-excision for involved or close margin, 21% (55 of 206) had residual tumor. The multivariate analysis showed that only a margin involved with intraductal carcinoma remained predictive for residual disease. According to the multivariate analysis, only hormone therapy (p < 10(-6)), diffuse involved margins (p = 0.003), and margins involved with intraductal component (p < 10(-6)) were predictive of LIR. Re-excision for a margin involved with intraductal carcinoma significantly improved local relapse-free survival (p < 0.001). CONCLUSIONS: In cases of IDC, re-excision for a close margin or a focally involved margin had no impact on local relapse-free survival. The decision to perform a surgical re-excision for an involved margin should not be systematic but should take multiple risk factors into consideration, such as patient age or margin diffuse involvement.