Immunohistochemical characterisation of the immune landscape in primary uveal melanoma and liver metastases.

BACKGROUND: The immune landscape of uveal melanoma liver metastases (UMLM) has not been sufficiently studied. METHODS: Immune cell infiltrates (ICIs), PD-1 and PD-L1 were characterised in 62 UMLM and 28 primary uveal melanomas (PUM). ICI, PD-1 and PD-L1 were scored as: (1) % tumoral area occupied by tumour-infiltrating lymphocytes or macrophages (TILs, TIMs) and (2) % perTumoral (perT) area. ICIs and other variables including histopathologic growth patterns (HGPs), replacement and desmoplastic, of UMLM were analysed for their prognostic value. RESULTS: ICIs recognised by haematoxylin-eosin-saffron (HES) and IHC (e.g., T cells (CD3), B cells (CD20). Macrophages (CD68), (CD163), were primarily localised to the perT region in PUM and UMLM and were more conspicuous in UMLM. HES, CD3, CD4, FoxP3, CD8, CD20, PD-1 TILs were scant (<5%). TIMs were more frequent, particularly in UMLM than in PUM. Both CD68+ TIMs and HGPs remained significant on multivariate analysis, influencing overall (OS) and metastasis-specific overall survival (MSOS). CD68 + , CD163+ and CD20+ perT infiltrates in UMLM predicted increased OS and MSOS on univariate analysis. CONCLUSIONS: TILs and PD-L1 have no predictive value in PUM or UMLM. CD68+ and CD163+TIMs, CD20+ perT lymphocytes, and HGPs are important prognostic factors in UMLMs.

Circulating Tumor DNA as a Prognostic Factor in Patients With Resectable Hepatic Metastases of Uveal Melanoma.

OBJECTIVE: We report here the results of a prospective study of circulating tumor DNA (ctDNA) detection in patients undergoing uveal melanoma (UM) liver metastases resection (NCT02849145). BACKGROUND: In UM patients, the liver is the most common and often only site of metastases. Local treatments of liver metastases, such as surgical resection, have a likely benefit in selected patients. METHODS: Upon enrollment, metastatic UM patients eligible for curative liver surgery had plasma samples collected before and after surgery. GNAQ / GNA11 mutations were identified in archived tumor tissue and used to quantify ctDNA by droplet digital polymerase chain reaction which was then associated with the patient's surgical outcomes. RESULTS: Forty-seven patients were included. Liver surgery was associated with a major increase of cell-free circulating DNA levels, with a peak 2 days after surgery (∼20-fold). Among 40 evaluable patients, 14 (35%) had detectable ctDNA before surgery, with a median allelic frequency of 1.1%. These patients experienced statistically shorter relapse-free survival (RFS) versus patients with no detectable ctDNA before surgery (median RFS: 5.5 vs 12.2 months; hazard ratio=2.23, 95% CI: 1.06-4.69, P =0.04), and had a numerically shorter overall survival (OS) (median OS: 27.0 vs 42.3 months). ctDNA positivity at postsurgery time points was also associated with RFS and OS. CONCLUSIONS: This study is the first to report ctDNA detection rate and prognostic impact in UM patients eligible for surgical resection of their liver metastases. If confirmed by further studies in this setting, this noninvasive biomarker could inform treatment decisions in UM patients with liver metastases.

Percutaneous Uterine Needle Biopsy with Microscopic and Array-CGH Analyses for Preoperative Sarcoma Diagnosis in Patients with Suspicious Myometrial Tumors on MRI: A Prospective Pilot Study (SARCGYN).

BACKGROUND: Unlike for soft tissue sarcomas, percutaneous biopsy is not validated for uterine myometrial tumors, leading to leiomyosarcoma inadvertent morcellation and overtreatment in childbearing patients. This study aimed to evaluate preoperative percutaneous uterine needle biopsy (PUB) with microscopic examination (M-PUB) and array-comparative genomic hybridization (MCGH-PUB). METHODS: This was a prospective single-center cohort study including all consecutive patients who were candidates for hysterectomy because of suspected uterine leiomyosarcoma on magnetic resonance imaging (MRI) who received PUB. Microscopic and array-CGH analyses with genomic index (GI) counts were performed to guide the therapeutic strategy. Smooth-muscle tumors with suspect features with a GI above 15 were deemed malignant, as were tumors without microscopic malignant features with a complex genomic profile (GI above 30 or malignant profile). Preoperative diagnoses based on M-PUB and MCGH-PUB were compared with the postsurgical pathological specimen or follow-up. RESULTS: From November 2016 to February 2022, 34 patients were included. Based on the surgical specimen (N = 23) or follow-up (N = 11), final diagnoses were 11 sarcomas and 23 non-sarcomas. The median follow-up was 12 months (IQR 6-37). The diagnostic accuracies of M-PUB and MCGH-PUB were 94% and 100%, respectively. The sensitivity, specificity, and negative predictive value of MCGH-PUB were 100%, 100%, and 100%, respectively. A high GI was significantly associated with malignancy (P < 0.001). Genomic analyses allowed malignancy upgrades for four tumors. There were no complications and no dissemination along the biopsy track. CONCLUSION: MCGH-PUB is safe and accurate for preoperatively diagnosing uterine sarcomas and should be used routinely after suspicious MRI to tailor surgery.

L1CAM and laminin vascular network: Association with the high-risk replacement histopathologic growth pattern in uveal melanoma liver metastases.

The replacement histopathologic growth pattern (rHGP) in melanoma liver metastases connotes an aggressive phenotype (vascular co-option; angiotropic extravascular migratory spread) and adverse prognosis. Herein, replacement and desmoplastic HGP (dHGP) were studied in uveal melanoma liver metastases (MUM). In particular, L1CAM and a "laminin vascular network" were detected at the advancing front of 14/20 cases (p = 0.014) and 16/20 cases (p = 6.4e-05) rHGPs, respectively, but both were absent in the dHGP (8/8 cases) (p = 0.014, and p = 6.3e-05, respectively). L1CAM highlighted progressive extension of angiotropic melanoma cells along sinusoidal vessels in a pericytic location (pericytic mimicry) into the hepatic parenchyma. An inverse relationship between L1CAM expression and melanin index (p = 0.012) suggested differentiation toward an amelanotic embryonic migratory phenotype in rHGP. Laminin labeled the basement membrane zone interposed between sinusoidal vascular channels and angiotropic melanoma cells at the advancing front. Other new findings: any percentage of rHGP and pure rHGP had a significant adverse effect on metastasis-specific overall survival (p = 0.038; p = 0.0064), as well as predominant rHGP (p = 0.0058). Pure rHGP also was associated with diminished metastasis-free survival relative to dHGP (p = 0.040), possibly having important implications for mechanisms of tumor spread. In conclusion, we report for the first time that L1CAM and a laminin vascular network are directly involved in this high-risk replacement phenotype. Further, this study provides more detailed information about the adverse prognostic effect of the rHGP in MUM.

Tumour growth rate improves tumour assessment and first-line systemic treatment decision-making for immunotherapy in patients with liver metastatic uveal melanoma.

BACKGROUND: The RECIST-based response variably matches the clinical benefit of systemic therapies for liver metastatic uveal melanoma (LMUM). The aims were to determine whether the tumour growth rate (TGR) can help predict the survival in patients with LMUM and to provide information for the management of first-line systemic treatment. METHODS: This retrospective study included 147 (training: n = 110, validation: n = 37) patients with LMUM treated with first-line systemic treatment between 2010 and 2021. Two TGR-derived parameters were calculated, TGR0 and TGR3m. Multivariate Cox analyses identified independent predictors of progression-free survival (PFS) and overall survival (OS). RESULTS: TGR3m was a strong independent prognostic factor of PFS and OS (p < 0.001). The RECIST-based response was no longer significant in the OS analyses. Only immunotherapy regimens correlated with higher OS (HR = 0.2; 95% CI, 0.1-0.5; p < 0.001) in the low-TGR3m (≤50%/m) subgroup. These findings were confirmed in the validation cohort. TGR0, disease-free interval (DFI), and the sum of target lesions at baseline were predictive factors of low TGR3m. DISCUSSION: The use of TGR3m would improve tumour assessment by identifying patients who would benefit from first-line immunotherapy regimens despite PD. TGR0, DFI and the sum of target lesions were correlated with TGR3m, which can support first-line treatment decision-making for immunotherapy.

Tumor Growth Rate as a Predictive Marker for Recurrence and Survival After Liver Resection in Patients with Liver Metastases of Uveal Melanoma.

BACKGROUND: Surgical management of liver metastases of uveal melanoma (LMUM) is associated with the best survival rates, especially for patients with a low tumor burden in the liver. The aim was to determine whether the tumor growth rate (TGR0) before liver resection helps predict survival in patients with resectable LMUM. METHODS: This retrospective study included 99 patients with LMUM treated with liver resection between November 2007 and November 2020. TGR0 was expressed as the percentage change in tumor volume over 1 month according to two pretreatment imaging scans. Multivariate Cox analyses identified independent predictors of disease-free survival (DFS) and overall survival (OS). RESULTS: DFS and OS had a statistically significant positive linear relationship (Spearman correlation r = 0.68, p < 0.001). A disease-free interval (DFI) > 24 months and a TGR0 ≤ 50%/month were independent factors associated with better DFS and OS. The 2-component model including TGR0 and DFI had a mean time-dependent area under the curve (AUC) of 0.81 (95% CI, 0.75-0.86) and 0.77 (95% CI, 0.67-0.87), respectively, for predicting DFS and OS. DFI with TGR0 defined three kinetic risk groups that had distinct DFS and OS outcomes (p < 0.001). Cytogenetic alterations at baseline were partially predictive factors of the kinetic risk score based on TGR0 and DFI. DISCUSSION: The assessment of TGR0 improves prognostic stratification by identifying patients at high risk of recurrence and poor survival after liver resection. TGR0 and DFI, reflecting tumor aggressivity, have the potential to be important markers for systemic adjuvant decisions.

Evaluation of the early adverse effects of radiotherapy in breast cancer patients with COVID-19: Prospective single institutional study.

The COVID-19 caused by the SARS-CoV-2 coronavirus is at the origin of a global pandemic. This pandemic has prompted the current health system to reorganize and rethink the care offered by health establishments. We report the early toxicity in patients infected with COVID-19 treated at the same time for early-stage breast cancer (BC). This is a monocentric prospective study of patients treated in our hospital between March 2020 and June 2020 and were diagnosed with COVID-19 infection. The inclusion criteria were to be irradiated for early-stage BC and to have a positive COVID-19 diagnosis on a PCR test and/or a lung computed tomography (CT) scan and/or suggestive clinical symptoms. Radiotherapy (RT) consisted of breast or chest wall irradiation with or without lymph node irradiation, with protocols adapted to pandemic situation. The treatment-related toxicity was graded according to the CTCAE (version 4.03). All 350 patients treated for early-stage BC were studied. Of them, 16 were presented with clinical symptoms of COVID-19 infection and of them, 12 had clinical, CT scan, and PCR confirmation. This entire cohort of 12 pts with median age of 56 (42-72) underwent their RT. During the radiotherapy, there were 9 pts presented radiation dermatitis, 8 (66%) were grade 1 and one was (8%) grade 2. Two patients with lymph nodes irradiation presented esophagitis grade 2. This prospective COVID-19 cohort, treated for early-stage BC demonstrated an acceptable toxicity profile with few low-grade adverse events. Longer follow-up is needed to confirm these findings.

COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area.

BACKGROUND: Cancer patients have been reported to be at higher risk of COVID-19 complications and deaths. We report the characteristics and outcome of patients diagnosed with COVID-19 during breast cancer treatment at Institut Curie hospitals (ICH, Paris area, France). METHODS: An IRB-approved prospective registry was set up at ICH on March 13, 2020, for all breast cancer patients with COVID-19 symptoms or radiologic signs. Registered data included patient history, tumor characteristics and treatments, COVID-19 symptoms, radiological features, and outcome. Data extraction was done on April 25, 2020. COVID-19 patients were defined as those with either a positive RNA test or typical, newly appeared lung CT scan abnormalities. RESULTS: Among 15,600 patients actively treated for early or metastatic breast cancer during the last 4 months at ICH, 76 patients with suspected COVID-19 infection were included in the registry and followed. Fifty-nine of these patients were diagnosed with COVID-19 based on viral RNA testing (N = 41) or typical radiologic signs: 37/59 (63%) COVID-19 patients were treated for metastatic breast cancer, and 13/59 (22%) of them were taking corticosteroids daily. Common clinical features mostly consisted of fever and/or cough, while ground-glass opacities were the most common radiologic sign at diagnosis. We found no association between prior radiation therapy fields or extent of radiation therapy sequelae and extent of COVID-19 lung lesions. Twenty-eight of these 59 patients (47%) were hospitalized, and 6 (10%) were transferred to an intensive care unit. At the time of analysis, 45/59 (76%) patients were recovering or had been cured, 10/59 (17%) were still followed, and 4/59 (7%) had died from COVID-19. All 4 patients who died had significant non-cancer comorbidities. In univariate analysis, hypertension and age (> 70) were the two factors associated with a higher risk of intensive care unit admission and/or death. CONCLUSIONS: This prospective registry analysis suggests that the COVID-19 mortality rate in breast cancer patients depends more on comorbidities than prior radiation therapy or current anti-cancer treatment. Special attention must be paid to comorbidities when estimating the risk of severe COVID-19 in breast cancer patients.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

Dynamic contrast-enhanced imaging in localizing local recurrence of prostate cancer after radiotherapy: Limited added value for readers of varying level of experience.

BACKGROUND: The incremental value of dynamic contrast-enhanced (DCE) imaging in localizing radiorecurrent prostate cancer is uncertain. PURPOSE: To assess the added-value of DCE imaging to the combination T2 -weighted imaging (T2 W)+diffusion-weighted imaging (DWI) in detecting locally radiorecurrent prostate cancer (PCa), by radiologists with different levels of experience. STUDY TYPE: Analytic retrospective study. POPULATION: In all, 52 men with biological suspected PCa recurrence after radiotherapy were retrospectively included. FIELD STRENGTH/SEQUENCE: All men underwent prostatic MRI (1.5T or 3T), including T2 W, DWI, and DCE imagings, before biopsies. ASSESSMENT: Two junior (6 months' experience) and two senior readers (more than 3 years' experience) independently assigned a Likert score for each prostatic sextant on T2 W+DW+DCE imagings, then on T2 W+DW imagings, 4 weeks later. STATISTICAL TESTS: The reference standard was prostatic biopsies. For two levels of positivity of Likert score, 3/5 and 4/5, sensitivity, specificity, area under the receiver operating curve (AUC), and interreader agreement were compared. RESULTS: T2 W+DWI+DCE and T2 W+DWI imaging had similar AUC at lobe and sextant level (0.853-0.946 vs. 0.819-0.955, P from 0.071-0.534). Using a Likert score ≥4/5, T2 W+DWI+DCE significantly improved the sensitivity for junior readers at the patient, lobe, and sextant level (40-80% vs. 22-66%, P < 0.0001-0.041). Sensitivity was not significantly modified with DCE imaging for senior readers (54-95% vs. 50-91%, P from 0.074-1). Specificity was not modified for all readers (50-100% vs. 50%-100%, P from 0.134-1). DCE imaging improved interreader agreement for a Likert score ≥4/5 (kappa from 0.6-0.73 vs. 0.38-0.73). DATA CONCLUSION: The addition of DCE imaging did not significantly improve accuracy in recurrent PCa detection after radiotherapy, whatever the level of experience of the readers. However, the addition of DCE imaging slightly improved the sensitivity for less-experienced readers and increased their diagnostic confidence. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1012-1023.

HPV circulating tumor DNA to monitor the efficacy of anti-PD-1 therapy in metastatic squamous cell carcinoma of the anal canal: A case report.

Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV-associated cancer with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab, an anti PD-1 immune checkpoint inhibitor, demonstrated significant efficacy as single-agent therapy in metastatic SCCA patients. Nevertheless, imaging assessment by standard RECIST criteria of the efficacy of immune therapy can be difficult in some patients due to tumor immune cell infiltration, and biomarkers of treatment efficacy are needed. We have previously developed a quantitative droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV ctDNA), with excellent sensitivity and specificity. Here, we report, for the first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic SCCA, who obtained sustained partial response to single-agent nivolumab. We observed an early and very significant decrease of HPV ctDNA during therapy from the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks, and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides proof-of-concept that HPV ctDNA can be used as a noninvasive early dynamic biomarker to monitor the efficacy of new immunotherapy agents.

Phase II Trial of Bevacizumab in Combination With Temozolomide as First-Line Treatment in Patients With Metastatic Uveal Melanoma.

BACKGROUND: In experimental models, bevacizumab suppressed in vitro growth and in vivo hepatic metastasis of ocular melanoma cells. Additional preclinical data suggested a potential benefit when combining bevacizumab with dacarbazine. METHODS: This noncomparative phase II study evaluated a combination of bevacizumab (10 mg/kg on days 8 and 22) with temozolomide (150 mg/m(2) on days 1-7 and 15-21) in 36 patients with metastatic uveal melanoma (MUM). The primary endpoint was the progression-free rate (PFR) at 6 months. Using a modified 2-step Fleming plan, at least 10 of 35 patients were required to support a predefined PFR at 6 months of 40%. Secondary objectives were progression-free survival (PFS), overall survival (OS), and safety; liver perfusion computed tomography (CT) for response imaging; and impact of VEGF-A gene polymorphisms on bevacizumab pharmacodynamics. RESULTS: First- and second-step analyses revealed nonprogression at 6 months in 3 of 17 and 8 of 35 patients, respectively. Finally, the 6-month PFR was 23% (95% confidence interval [CI]: 10-39), with long-lasting stable disease in 5 patients (14%). Median PFS and OS were 12 weeks and 10 months, respectively. No unexpected toxicity occurred. Liver perfusion CT imaging was not useful in assessing tumor response, and VEGF-A gene polymorphisms were not correlated with toxicity or survival. CONCLUSION: In patients with MUM, a combination of bevacizumab plus temozolomide achieved a 6-month PFR of 23%.

Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.

BACKGROUND: Molecularly targeted agents have been reported to have anti-tumour activity for patients whose tumours harbour the matching molecular alteration. These results have led to increased off-label use of molecularly targeted agents on the basis of identified molecular alterations. We assessed the efficacy of several molecularly targeted agents marketed in France, which were chosen on the basis of tumour molecular profiling but used outside their indications, in patients with advanced cancer for whom standard-of-care therapy had failed. METHODS: The open-label, randomised, controlled phase 2 SHIVA trial was done at eight French academic centres. We included adult patients with any kind of metastatic solid tumour refractory to standard of care, provided they had an Eastern Cooperative Oncology Group performance status of 0 or 1, disease that was accessible for a biopsy or resection of a metastatic site, and at least one measurable lesion. The molecular profile of each patient's tumour was established with a mandatory biopsy of a metastatic tumour and large-scale genomic testing. We only included patients for whom a molecular alteration was identified within one of three molecular pathways (hormone receptor, PI3K/AKT/mTOR, RAF/MEK), which could be matched to one of ten regimens including 11 available molecularly targeted agents (erlotinib, lapatinib plus trastuzumab, sorafenib, imatinib, dasatinib, vemurafenib, everolimus, abiraterone, letrozole, tamoxifen). We randomly assigned these patients (1:1) to receive a matched molecularly targeted agent (experimental group) or treatment at physician's choice (control group) by central block randomisation (blocks of size six). Randomisation was done centrally with a web-based response system and was stratified according to the Royal Marsden Hospital prognostic score (0 or 1 vs 2 or 3) and the altered molecular pathway. Clinicians and patients were not masked to treatment allocation. Treatments in both groups were given in accordance with the approved product information and standard practice protocols at each institution and were continued until evidence of disease progression. The primary endpoint was progression-free survival in the intention-to-treat population, which was not assessed by independent central review. We assessed safety in any patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01771458. FINDINGS: Between Oct 4, 2012, and July 11, 2014, we screened 741 patients with any tumour type. 293 (40%) patients had at least one molecular alteration matching one of the 10 available regimens. At the time of data cutoff, Jan 20, 2015, 195 (26%) patients had been randomly assigned, with 99 in the experimental group and 96 in the control group. All patients in the experimental group started treatment, as did 92 in the control group. Two patients in the control group received a molecularly targeted agent: both were included in their assigned group for efficacy analyses, the patient who received an agent that was allowed in the experimental group was included in the experimental group for the purposes of safety analyses, while the other patient, who received a molecularly targeted agent and chemotherapy, was kept in the control group for safety analyses. Median follow-up was 11·3 months (IQR 5·8-11·6) in the experimental group and 11·3 months (8·1-11·6) in the control group at the time of the primary analysis of progression-free survival. Median progression-free survival was 2·3 months (95% CI 1·7-3·8) in the experimental group versus 2·0 months (1·8-2·1) in the control group (hazard ratio 0·88, 95% CI 0·65-1·19, p=0·41). In the safety population, 43 (43%) of 100 patients treated with a molecularly targeted agent and 32 (35%) of 91 patients treated with cytotoxic chemotherapy had grade 3-4 adverse events (p=0·30). INTERPRETATION: The use of molecularly targeted agents outside their indications does not improve progression-free survival compared with treatment at physician's choice in heavily pretreated patients with cancer. Off-label use of molecularly targeted agents should be discouraged, but enrolment in clinical trials should be encouraged to assess predictive biomarkers of efficacy.

Diffusion-weighted MRI for uveal melanoma liver metastasis detection.

OBJECTIVES: We aimed to assess the sensitivity of diffusion-weighted (DW) magnetic resonance (MR) imaging for the detection of pathologically confirmed uveal melanoma liver metastases (UMLM). METHODS: Twenty patients who underwent complete surgical resection of their UMLM (N = 83) were included. Pre-surgery liver MR imaging included T2-weighted, T1-weighted, DW and dynamic-gadolinium-enhanced MR sequences. Two radiologists independently reviewed three sets of images (DW / morphologic-dynamic / combined) for each patient using intraoperative and pathological findings as a standard of reference. RESULTS: The sensitivities of the morphologic-dynamic and DW images for UMLM detection were 63 % and 59 %, respectively, for reader #1 (R1) and 64 % and 53 %, for reader #2 (R2). Sensitivity of the combined set was higher than sensitivity in the two other sets (R1:69 %, R2:67 %), but was only significantly different than the sensitivity of the DW images (McNemar test). For the three sets and the two readers, the sensitivity for UMLM smaller than 5 mm (37-46 %) was significantly lower than that for UMLM larger than 5 mm (67-90 %). The sensitivity for UMLM located in the subcapsular area (41-54 %) was significantly lower than that for intraparenchymal UMLM (68-86 %) (Chi-square test). CONCLUSION: Our study shows that the addition of DW imaging to morphologic-dynamic images does not significantly increase MR sensitivities for UMLM detection. KEY POINTS: • The MR imaging sensitivity for uveal melanoma liver metastases (UMLM) was 69 %. • Addition of DW imaging to morphologic-dynamic images does not increase sensitivity significantly. • Sensitivity for subcapsular UMLM was significantly lower than sensitivity for intraparenchymal UMLM. • The T2 shortening effect does not appear to influence lesion detection in DWI.

Detection rate and prognostic value of circulating tumor cells and circulating tumor DNA in metastatic uveal melanoma.

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) have been recently investigated in several cancer types, but their respective clinical significance remains to be determined. In our prospective study, we compared the detection rate and the prognostic value of these two circulating biomarkers in patients with metastatic uveal melanoma. GNAQ/GNA11 mutations were characterized in archived tumor tissue. Using a highly sensitive and mutation-specific bidirectional pyrophosphorolysis-activated polymerization (bi-PAP) technique, GNAQ c.626A>T, GNAQ c.626A>C and GNA11 c.626A>T copy numbers were quantified in plasma from 12 mL of blood. CTCs were detected at the same time in 7.5 mL of blood by the CellSearch technique. Patient characteristics and outcome were prospectively collected. CTCs (≥1) were detected in 12 of the 40 included patients (30%, range 1-20). Among the 26 patients with known detectable mutations, ctDNA was detected and quantified in 22 (84%, range 4-11,421 copies/mL). CTC count and ctDNA levels were associated with the presence of miliary hepatic metastasis (p = 0.004 and 0.03, respectively), with metastasis volume (p = 0.005 and 0.004) and with each other (p < 0.0001). CTC count and ctDNA levels were both strongly associated with progression-free survival (p = 0.003 and 0.001) and overall survival (p = 0.0009 and <0.0001). In multivariate analyses, ctDNA appeared to be a better prognostic marker than CTC. In conclusion, ctDNA and CTC are correlated and both have poor prognostic significance. CTC detection can be performed in every patient but, in patients with detectable mutations, ctDNA was more frequently detected than CTC and has possibly more prognostic value.

Diagnostic accuracy and safety of percutaneous core needle biopsy of retroperitoneal tumours.

BACKGROUND: Histologic subtype of cancer guides treatment sequencing and the extent of surgery for retroperitoneal tumours (RPTs) but concerns persist regarding percutaneous core needle biopsy (CNB). OBJECTIVE: Endpoints were the incidence of early complications, needle tract seeding (NTS) after CNB, diagnostic accuracy. METHODS: Between 2015 and 2022, data from patients with RPT who underwent a CNB and who operated on at Institut Curie were collected. We retrospectively reviewed the medical records and microscopic analysis of both CNB and surgical specimens to evaluate the diagnostic accuracy of CNB (quantified using positive and negative predictive values, PPV/NPV). RESULTS: 313 patients underwent CNB. In 10/326 (3 %) procedures, minor complications were observed. One of 212 (0.47 %) resected RPSs exhibited a local recurrence compatible with NTS. Microscopic analysis of CNB specimens allowed the classification of tumours between groups of cancers and benign/intermediate mesenchymal tumours in 307/313 (98 %) patients. Among the 204 patients with retroperitoneal sarcoma, the overall concordance between CNB and final pathology following resection was 178/204 (87.2 %). The respective PPVs of solitary fibrous tumour, dedifferentiated liposarcoma, leiomyosarcoma and well-differentiated liposarcoma were 100 %, 98 %, 97 % and 68 %, respectively. The diagnosis of a high-grade (G 2-3) sarcoma resulted in a high specificity (97 %) and PPV (98 %) but low sensitivity (76 %). CONCLUSIONS: CNB allowed the classification of RPT in the vast majority of patients with a low morbidity rate. Concordance with final diagnosis was high for sarcomas with the exception of well-differentiated liposarcoma. As a result, CNB results should be integrated with imaging/radiomics by multidisciplinary tumour boards.

Pretreatment Tumor Growth Rate and Radiological Response as Predictive Markers of Pathological Response and Survival in Patients with Resectable Lung Cancer Treated by Neoadjuvant Treatment.

INTRODUCTION: Predictive biomarkers associated with pathological response, progression precluding surgery, and/or recurrence after surgery are needed for patients with resectable non-small cell lung carcinoma (NSCLC) treated by neoadjuvant treatment. We evaluated the clinical impact of the pretreatment tumor growth rate (TGR0) and radiological response for patients with resectable NSCLC treated with neoadjuvant therapies. METHODS: Consecutive patients with resectable stage IB (≥4 cm) to IIIA NSCLC treated by neoadjuvant platinum-doublet chemotherapy with or without nivolumab at our tertiary center were retrospectively analyzed. TGR0 and RECIST objective responses were determined. Multivariable analyses identified independent predictors of event-free survival (EFS), overall survival (OS), and major pathological response (MPR). RESULTS: Between November 2017 and December 2022, 32 patients (mean [SD] age, 63.8 [8.0] years) were included. At a median follow-up of 54.8 months (95% CI, 42.3-60.4 months), eleven patients (34%) experienced progression or recurrence, and twelve deaths (38%) were recorded. The TGR0 cutoff of 30%/month remained the only independent factor associated with EFS (HR = 0.04; 95% CI, 0.01-0.3; p = 0.003) and OS (HR = 0.2; 95% CI, 0.03-0.7; p = 0.01). The TGR0 cut-off had a mean time-dependent AUC of 0.83 (95% CI, 0.64-0.95) and 0.80 (95% CI, 0.62-0.97) for predicting EFS and OS, respectively. Fifteen of 26 resection cases (58%) showed MPR including nine with pathological complete responses (35%). Only the objective response of the primary tumor was associated with MPR (OR = 27.5; 95% CI, 2.6-289.1; p = 0.006). CONCLUSIONS: Assessment of TGR0 can identify patients who should benefit from neoadjuvant treatment. A tumor objective response might be a predictor of MPR after neoadjuvant treatment, which will help to adapt surgical management.

Radiation Exposure of Cardiac Conduction Nodes During Breast Proton Therapy.

Purpose: The exposition of cardiac conduction system during breast radiation therapy has never been studied, despite the increasing use of intensity-modulated radiation therapy, which exposes larger volume to low-dose bath. We evaluated conduction node exposure during breast irradiation with volumetric modulated arc therapy and estimated the potential dosimetric benefit with intensity-modulated proton therapy. Materials and Methods: Atrioventricular (AVN) and sinoatrial (SAN) nodes were retrospectively delineated according to published guidelines on the simulation computed tomography scans of 12 breast cancer patients having undergone conserving surgery and adjuvant locoregional volumetric modulated arc therapy. Intensity-modulated proton therapy treatment was replanned on the simulation computed tomography scans for all breast cancer patients. Mean and maximum doses delivered to the SAN and the AVN were retrieved and compared. Correlation coefficients were calculated between doses to the SAN or the AVN and the whole heart. Results: Average mean doses delivered to the SAN and AVN were 2.8 and 2.3 Gy, respectively, for left-sided irradiation and 9.6 and 3.6 Gy, respectively, for right-sided irradiation. Average maximum doses to the SAN and AVN were 3.5 Gy and 2.8 Gy, respectively, for left-sided irradiation and 13.1 and 4.6 Gy, respectively, for right-sided irradiation. Intensity-modulated proton therapy significantly reduced mean and maximum doses to the SAN and AVN. Correlations between doses to the SAN or AVN and whole heart were usually significant. Conclusion: SAN and AVN can be substantially exposed during breast volumetric modulated arc therapy, especially for right-sided irradiation. Cardiotoxicity studies evaluating conduction node exposure might define dose constraints and criteria for additional cardiac-sparing techniques, such as respiratory techniques or proton therapy, which could benefit patients with underlying rhythmic or conduction disorders.

Single-Probe Percutaneous Cryoablation with Liquid Nitrogen for the Treatment of T1a Renal Tumors.

Kidney cancer accounts for 3% of adult malignancies and is increasingly detected through advanced imaging techniques, highlighting the need for effective treatment strategies. This retrospective study assessed the safety and efficacy of a new single-probe percutaneous cryoablation system using liquid nitrogen for treating T1a renal cancers. From May 2019 to May 2022, 25 consecutive patients from two academic hospitals, with a median age of 64.8 years [IQR 59; 75.5], underwent cryoablation for 26 T1a renal tumors. These tumors had a median size of 25.3 mm [20; 30.7] and a median RENAL nephrometry score, indicating tumor complexity, of 7 [5; 9]. No major complications arose, but three non-clinically relevant perirenal hematomas were detected on post-procedure CT scans. With a median follow-up of 795 days [573; 1020], the primary local control rate at one month stood was 80.8% (21 out of 26). The five recurrent lesions, which exhibited a higher renal score (p = 0.016), were treated again using cryoablation, achieving a secondary local control rate of 100%. No patient died, and the disease-free survival rate was 92% (23 out of 25). In conclusion, single-probe percutaneous cryoablation emerges as a promising modality for managing small renal masses. Notably, recurrence rates appear influenced by RENAL nephrometry scores, suggesting a need for further research to refine the technique.