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Recently the possibility to exploit quantum-mechanical effects to increase the performance of energy storage has raised a great interest. It consists of N two-level systems coupled to a single photonic mode in a cavity. We demonstrate the emergence of a quantum advantage in the charging power on this collective model (Dicke Quantum Battery) with respect to the one in which each two-level system is coupled to its own separate cavity mode (Rabi Quantum Battery). Moreover, we discuss the model of a Quantum Supercapacitor. This consists of two chains, one containing electrons and the other one holes, hosted by arrays of double quantum dots. The two chains are in close proximity and embedded in the same photonic cavity, in the same spirit of the Dicke model. We find the phase diagram of this model showing that, when transitioning from the ferro/antiferromagnetic to the superradiant phase, the quantum capacitance of the model is greatly enhanced.

Abstract Introduction Langerhans cell histiocytosis is a rare disease within the adult population, with very few cases reported as solitary hypophyseal lesions in adults. Of the reported cases, most have been treated successfully with surgery, radiotherapy, and/or chemotherapy. Radiotherapy has been thought to be curative at the relatively low dose of 20Gy. Here we report a case of recurrent hypophyseal Langerhans cell histiocytosis 9 months after radiotherapy with an interval period of symptomatic and radiographic response to therapy. Case presentation A 50-year-old Caucasian woman who had headaches, memory difficulties, and diabetes insipidus was found to have a 2.5cm suprasellar mass. Langerhans cell histiocytosis was diagnosed following stereotactic brain biopsy. Further workup revealed no other lesions. Initial radiation treatment succeeded in shrinking the tumor and relieving clinical symptoms temporarily; however, growth and recurrence of clinical symptoms was noted at 9 months. Re-irradiation was well tolerated and the patient had no acute side effects. Conclusion Isolated hypophyseal involvement by Langerhans cell histiocytosis in adults is a unique presentation of a rare disease. Although radiotherapy doses as low as 20Gy have been reported to offer control, this case demonstrates that higher doses may be warranted to ensure tumor control. With modern imaging and radiotherapy techniques higher doses should offer little increased more durable risk to surrounding critical structures.

Abstract Introduction Eagle syndrome is a condition characterized by an elongated (>3cm) styloid process with associated symptoms of recurrent facial or throat pain. In this report we present a case of Eagle syndrome exhibiting the typical findings of glossopharyngeal nerve involvement, as well as unusual involvement of the trigeminal nerve. Notably, this patient developed a classical trigeminal neuralgia post-styloidectomy. Case presentation A 68-year-old Caucasian woman presented with a 25-year history of dull pain along the right side of her throat, lateral neck, and jaw. Her symptoms were poorly controlled with medication until 15 years ago when she was diagnosed with Eagle syndrome, and underwent a manual fracture of her styloid process. This provided symptomatic relief until 5 years ago when the pain recurred and progressed. She underwent a styloidectomy via a lateral neck approach, which resolved the pain once again. However, 6 months ago a new onset of triggerable, electric shock-like facial pain began within the right V1 and V2 distributions. Conclusions Eagle syndrome is distressing to patients and often difficult to diagnose due to its wide variability in symptoms. It is easily confused with dental pain or temporomandibular joint disorder, leading to missed diagnoses and unnecessary procedures. Pain along the jaw and temple is an unusual but possible consequence of Eagle syndrome. An elongated styloid process should be considered a possible etiology of dull facial pain in the trigeminal distributions, in particular V3.

Abstract Background Brachytherapy as adjuvant treatment for early-stage breast cancer has become widely available and offers patients an expedited treatment schedule. Given this, many women are electing to undergo brachytherapy in lieu of standard fractionation radiotherapy. We compare outcomes between patients treated with accelerated partial breast irradiation (APBI) via multicatheter interstitial brachytherapy versus patients who were also eligible for and offered APBI but who chose whole breast radiation (WBI). Methods Patients treated from December 2002 through May 2007 were reviewed. Selection criteria included patients with pTis-T2N0 disease, ≤ 3 cm unifocal tumors, and negative margins who underwent breast conservation surgery. Local control (LC), cause-specific (CSS) and overall survival (OS) were analyzed. Results 202 patients were identified in the APBI cohort and 94 patients in the WBI cohort. Median follow-up for both groups exceeded 60 months. LC was 97.0% for the APBI cohort and 96.2% for the WBI cohort at 5 years (ns). Classification by 2010 ASTRO APBI consensus statement categories did not predict worse outcomes. Conclusion APBI via multicatheter interstitial brachytherapy provides similar local failure rates compared to WBI at 5 years for properly selected patients. Excellent results were seen despite the high fraction of younger patients (< 60 years old) and patients with DCIS.

Purpose: TMPRSS2:ERG gene fusion negatively regulates PSMA expression in prostate adenocarcinoma (PCa) cell lines. Therefore, immunohistochemical (IHC) ERG expression, a surrogate for an underlying ERG rearrangement, and PSMA expression patterns in radical prostatectomy (RPE) specimens of primary PCa, including corresponding PSMA-PET scans were investigated., Methods: Two cohorts of RPE samples (total n=148): In cohort #1 (n=62 patients) with available RPE and preoperative [ 68 Ga]Ga-PSMA-11 PET, WHO/ISUP grade groups, IHC-ERG (positive vs. negative) and IHC-PSMA expression (% PSMA-negative tumour area, PSMA %neg ) were correlated with the corresponding SUV max . In the second cohort #2 (n=86 patients) including RPE only, same histopathological parameters were evaluated., Results: Cohort #1: PCa with IHC-ERG expression (35.5%) showed significantly lower IHC-PSMA expression and lower SUV max values on the corresponding PET scans. Eight of 9 PCa with negative PSMA-PET scans had IHC-ERG positivity, and confirmed TMPRSS2::ERG rearrangement. In IHC-PSMA positive PCa, IHC-ERG positivity was significantly associated with lower SUV max values. In cohort #2, findings of higher IHC-PSMA %neg and IHC-ERG expression was confirmed with only 0-10% PSMA %neg tumour areas in IHC-ERG-negative PCa., Conclusion: IHC-ERG expression is significantly associated with more heterogeneous and lower IHC-PSMA tissue expression in two independent RPE cohorts. There is a strong association of ERG positivity in RPE tissue with lower [ 68 Ga]Ga-PSMA-11 uptake on corresponding PET scans. Results may serve as a base for future biomarker development to enable tumour-tailored, individualized imaging approaches., Competing Interests: Declarations. Ethics approval: The study was approved by the local Cantonal Ethics committee (BASEC Nr. 2018–01284, BASEC Nr. 2022-1778). Consent to participate: A general written informed consent for the use of their material and data was signed by all included patients. Consent to publish: Not applicable Competing interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s).)

The oncology field continues its remarkable evolution over the years, with promising advances leading to innovative and individualized treatments. The development of new molecules, the identification of new therapeutic targets and the search for new sequences or combinations promise to revolutionize cancer treatments and contribute to improving survival rates, patients' quality of life and to open new perspective in oncology research. In this article, the newest data released in 2023 are reviewed., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Purpose: To develop and evaluate a lymph node invasion (LNI) prediction model for men staged with [ 68 Ga]Ga-PSMA-11 PET., Methods: A consecutive sample of intermediate to high-risk prostate cancer (PCa) patients undergoing [ 68 Ga]Ga-PSMA-11 PET, extended pelvic lymph node dissection (ePLND), and radical prostatectomy (RP) at two tertiary referral centers were retrospectively identified. The training cohort comprised 173 patients (treated between 2013 and 2017), the validation cohort 90 patients (treated between 2016 and 2019). Three models for LNI prediction were developed and evaluated using cross-validation. Optimal risk-threshold was determined during model development. The best performing model was evaluated and compared to available conventional and multiparametric magnetic resonance imaging (mpMRI)-based prediction models using area under the receiver operating characteristic curves (AUC), calibration plots, and decision curve analysis (DCA)., Results: A combined model including prostate-specific antigen, biopsy Gleason grade group, [ 68 Ga]Ga Ga-PSMA-11 positive volume of the primary tumor, and the assessment of the [ 68 Ga]Ga-PSMA-11 report N-status yielded an AUC of 0.923 (95% CI 0.863-0.984) in the external validation. Using a cutoff of  ≥ 17%, 44 (50%) ePLNDs would be spared and LNI missed in one patient (4.8%). Compared to conventional and MRI-based models, the proposed model showed similar calibration, higher AUC (0.923 (95% CI 0.863-0.984) vs. 0.700 (95% CI 0.548-0.852)-0.824 (95% CI 0.710-0.938)) and higher net benefit at DCA., Conclusions: Our results indicate that information from [ 68 Ga]Ga-PSMA-11 may improve LNI prediction in intermediate to high-risk PCa patients undergoing primary staging especially when combined with clinical parameters. For better LNI prediction, future research should investigate the combination of information from both PSMA PET and mpMRI for LNI prediction in PCa patients before RP., (© 2023. The Author(s).)

Purpose: Recently, a significant association was shown between novel growth patterns on histopathology of prostate cancer (PCa) and prostate-specific membrane antigen (PSMA) uptake on [ 68 Ga]PSMA-PET. It is the aim of this study to evaluate the association between these growth patterns and ADC (mm 2 /1000 s) values in comparison to [ 68 Ga]PSMA uptake on PET/MRI., Methods: We retrospectively evaluated patients who underwent [ 68 Ga]PSMA PET/MRI for staging or biopsy guidance, followed by radical prostatectomy at our institution between 07/2016 and 01/2020. The dominant lesion per patient was selected based on histopathology and correlated to PET/MRI in a multidisciplinary meeting, and quantified using SUV max for PSMA uptake and ADC mean for diffusion restriction. PCa growth pattern was classified as expansive (EXP) or infiltrative (INF) according to its properties of forming a tumoral mass or infiltrating diffusely between benign glands by two independent pathologists. Furthermore, the corresponding WHO2016 ISUP tumor grade was evaluated. The t test was used to compare means, Pearson's test for categorical correlation, Cohen's kappa test for interrater agreement, and ROC curve to determine the best cutoff., Results: Sixty-two patients were included (mean PSA 11.7 ± 12.5). The interrater agreement between both pathologists was almost perfect with κ = 0.81. While 25 lesions had an EXP-growth with an ADC mean of 0.777 ± 0.109, 37 showed an INF-growth with a significantly higher ADC mean of 1.079 ± 0.262 (p < 0.001). We also observed a significant difference regarding PSMA SUV max for the EXP-growth (19.2 ± 10.9) versus the INF-growth (9.4 ± 6.2, p < 0.001). Within the lesions encompassing the EXP- or the INF-growth, no significant correlation between the ISUP groups and ADC mean could be observed (p = 0.982 and p = 0.861, respectively)., Conclusion: PCa with INF-growth showed significantly lower SUV max and higher ADC mean values compared to PCa with EXP-growth. Within the growth groups, ADC mean values were independent from ISUP grading., (© 2022. The Author(s).)

Background: Investigation of the clinical feasibility of dynamic whole-body (WB) [18F]FDG PET, including standardized uptake value (SUV), rate of irreversible uptake (Ki), and apparent distribution volume (Vd) in physiologic tissues, and comparison between inflammatory/infectious and cancer lesions. Methods: Twenty-four patients were prospectively included to undergo dynamic WB [18F]FDG PET/CT for clinically indicated re-/staging of oncological diseases. Parametric maps of Ki and Vd were generated using Patlak analysis alongside SUV images. Maximum parameter values (SUVmax, Kimax, and Vdmax) were measured in liver parenchyma and in malignant or inflammatory/infectious lesions. Lesion-to-background ratios (LBRs) were calculated by dividing the measurements by their respective mean in the liver tissue. Results: Seventy-seven clinical target lesions were identified, 60 malignant and 17 inflammatory/infectious. Kimax was significantly higher in cancer than in inflammatory/infections lesions (3.0 vs. 2.0, p = 0.002) while LBRs of SUVmax, Kimax, and Vdmax did not differ significantly between the etiologies: LBR (SUVmax) 3.3 vs. 2.9, p = 0.06; LBR (Kimax) 5.0 vs. 4.4, p = 0.05, LBR (Vdmax) 1.1 vs. 1.0, p = 0.18). LBR of inflammatory/infectious and cancer lesions was higher in Kimax than in SUVmax (4.5 vs. 3.2, p < 0.001). LBRs of Kimax and SUVmax showed a strong correlation (Spearman’s rho = 0.83, p < 0.001). Conclusions: Dynamic WB [18F]FDG PET/CT is feasible in a clinical setting. LBRs of Kimax were higher than SUVmax. Kimax was higher in malignant than in inflammatory/infectious lesions but demonstrated a large overlap between the etiologies.

Background: Magnetic resonance imaging (MRI) is recommended by the European Urology Association guidelines as the standard modality for imaging-guided biopsy. Recently positron emission tomography with prostate-specific membrane antigen (PSMA PET) has shown promising results as a tool for this purpose. The aim of this study was to compare the accuracy of positron emission tomography with prostate-specific membrane antigen/magnetic resonance imaging (PET/MRI) using the gallium-labeled prostate-specific membrane antigen ( 68 Ga-PSMA-11) and multiparametric MRI (mpMRI) for pre-biopsy tumour localization and interreader agreement for visual and semiquantitative analysis. Semiquantitative parameters included apparent diffusion coefficient (ADC) and maximum lesion diameter for mpMRI and standardized uptake value (SUV max ) and PSMA-positive volume (PSMA vol ) for PSMA PET/MRI., Results: Sensitivity and specificity were 61.4% and 92.9% for mpMRI and 66.7% and 92.9% for PSMA PET/MRI for reader one, respectively. RPE was available in 23 patients and 41 of 47 quadrants with discrepant findings. Based on RPE results, the specificity for both imaging modalities increased to 98% and 99%, and the sensitivity improved to 63.9% and 72.1% for mpMRI and PSMA PET/MRI, respectively. Both modalities yielded a substantial interreader agreement for primary tumour localization (mpMRI kappa = 0.65 (0.52-0.79), PSMA PET/MRI kappa = 0.73 (0.61-0.84)). ICC for SUV max , PSMA vol and lesion diameter were almost perfect (≥ 0.90) while for ADC it was only moderate (ICC = 0.54 (0.04-0.78)). ADC and lesion diameter did not correlate significantly with Gleason score (ρ = 0.26 and ρ = 0.16) while SUV max and PSMA vol did (ρ =  - 0.474 and ρ =  - 0.468)., Conclusions: PSMA PET/MRI has similar accuracy and reliability to mpMRI regarding primary prostate cancer (PCa) localization. In our cohort, semiquantitative parameters from PSMA PET/MRI correlated with tumour grade and were more reliable than the ones from mpMRI., (© 2022. The Author(s).)

Objectives: PSMA PET/MRI showed the potential to increase the sensitivity for extraprostatic disease (EPD) assessment over mpMRI; however, the interreader variability for EPD is still high. Therefore, we aimed to assess whether quantitative PSMA and mpMRI imaging parameters could yield a more robust EPD prediction., Methods: We retrospectively evaluated PCa patients who underwent staging mpMRI and [ 68 Ga]PSMA-PET, followed by radical prostatectomy at our institution between 01.02.2016 and 31.07.2019. Fifty-eight cases with PET/MRI and 15 cases with PET/CT were identified. EPD was determined on histopathology and correlated with quantitative PSMA and mpMRI parameters assessed by two readers: ADC (mm 2 /1000 s), longest capsular contact (LCC, mm), tumor volume (cm 3 ), PSMA-SUV max and volume-based parameters using a fixed threshold at SUV > 4 to delineate PSMA total (g/ml) and PSMA vol (cm 3 ). The t test was used to compare means, Pearson's test for categorical correlation, and ROC curve to determine the best cutoff. Interclass correlation (ICC) was performed for interreader agreement (95% CI)., Results: Seventy-three patients were included (64.5 ± 6.0 years; PSA 14.4 ± 17.1 ng/ml), and 31 had EPD (42.5%). From mpMRI, only LCC reached significance (p = 0.005), while both volume-based PET parameters PSMA total and PSMA vol were significantly associated with EPD (p = 0.008 and p = 0.004, respectively). On ROC analysis, LCC, PSMA total , and PSMA vol reached an AUC of 0.712 (p = 0.002), 0.709 (p = 0.002), and 0.718 (p = 0.002), respectively. ICC was moderate-good for LCC 0.727 (0.565-0.828) and excellent for PSMA total and PSMA vol with 0.944 (0.990-0.996) and 0.985 (0.976-0.991), respectively., Conclusions: Quantitative PSMA parameters have a similar potential as mpMRI LCC to predict EPD of PCa, with a significantly higher interreader agreement., (© 2022. The Author(s).)

Purpose: Prostate-specific membrane antigen (PSMA)-targeted PET is increasingly used for staging prostate cancer (PCa) with high accuracy to detect significant PCa (sigPCa). [ 68  Ga]PSMA-11 PET/MRI-guided biopsy showed promising results but also persisting limitation of sampling error, due to impaired image fusion. We aimed to assess the possibility of intraoperative quantification of [ 18 F]PSMA-1007 PET/CT uptake in core biopsies as an instant confirmation for accurate lesion sampling., Methods: In this IRB-approved, prospective, proof-of-concept study, we included five consecutive patients with suspected PCa. All underwent [ 18 F]PSMA-1007 PET/CT scans followed by immediate PET/CT-guided and saturation template biopsy (3.1 ± 0.3 h after PET). The activity in biopsy cores was measured as counts per minute (cpm) in a gamma spectrometer. Pearson's test was used to correlate counts with histopathology (WHO/ISUP), tumor length, and membranous PSMA expression on immunohistochemistry (IHC)., Results: In 43 of 113 needles, PCa was present. The mean cpm was overall significantly higher in needles with PCa (263 ± 396 cpm) compared to needles without PCa (73 ± 44 cpm, p < 0.001). In one patient with moderate PSMA uptake (SUV max 8.7), 13 out of 24 needles had increased counts (100-200 cpm) but only signs of inflammation and PSMA expression in benign glands on IHC. Excluding this case, ROC analysis resulted in an AUC of 0.81, with an optimal cut-off to confirm PCa at 75 cpm (sens/spec of 65.1%/87%). In all 4 patients with PCa, the first or second PSMA PET-guided needle was positive for sigPCa with high counts (156-2079 cpm)., Conclusions: [ 18 F]PSMA-1007 uptake in PCa can be used to confirm accurate lesion sampling of the dominant tumor intraoperatively. This technique could improve confidence in imaging-based biopsy guidance and reduce the need for saturation biopsy., Trial Registration Number: NCT03187990, 15/06/2017., (© 2021. The Author(s).)

Purpose: Prostate-specific membrane antigen (PSMA-) PET has become a promising tool in staging and restaging of prostate carcinoma (PCa). However, specific primary tumour features might impact accuracy of PSMA-PET for PCa detection. We investigated histopathological parameters and immunohistochemical PSMA expression patterns on radical prostatectomy (RPE) specimens and correlated them to the corresponding 68 Ga-PSMA-11-PET examinations., Methods: RPE specimens of 62 patients with preoperative 68 Ga-PSMA-11-PET between 2016 and 2018 were analysed. WHO/ISUP grade groups, growth pattern (expansive vs. infiltrative), tumour area and diameter as well as immunohistochemical PSMA heterogeneity, intensity and negative tumour area (PSMA %neg ) were correlated with spatially corresponding SUV max on 68 Ga-PSMA-11-PET in a multidisciplinary analysis., Results: All tumours showed medium to strong membranous (2-3 +) and weak to strong cytoplasmic (1-3 +) PSMA expression. Heterogeneously expressed PSMA was found in 38 cases (61%). Twenty-five cases (40%) showed at least 5% and up to 80% PSMA %neg . PSMA %neg , infiltrative growth pattern, smaller tumour area and diameter and WHO/ISUP grade group 2 significantly correlated with lower SUV max values. A ROC curve analysis revealed 20% PSMA %neg as an optimal cutoff with the highest sensitivity and specificity (89% and 86%, AUC 0.923) for a negative PSMA-PET scan. A multiple logistic regression model revealed tumoural PSMA %neg (p < 0.01, OR = 9.629) and growth pattern (p = 0.0497, OR = 306.537) as significant predictors for a negative PSMA-PET scan., Conclusions: We describe PSMA %neg , infiltrative growth pattern, smaller tumour size and WHO/ISUP grade group 2 as parameters associated with a lower 68 Ga-PSMA-11 uptake in prostate cancer. These findings can serve as fundament for future biopsy-based biomarker development to enable an individualized, tumour-adapted imaging approach., (© 2021. The Author(s).)

Purpose: Prostate-specific membrane antigen (PSMA) targeted positron emission tomography (PET) imaging significantly improved the detection of recurrent prostate cancer (PCa). However, the value of PSMA PET imaging in patients with advanced hormone-sensitive or hormone-resistant PCa is still largely unknown. The aim of this study was to analyze the detection rate and distribution of lesions using PSMA PET imaging in patients with advanced PCa and ongoing androgen deprivation therapy (ADT)., Methods: A total of 84 patients diagnosed with hormone-sensitive or hormone-resistant PCa who underwent 68 Ga-PSMA-11 PET/magnetic resonance imaging (MRI) or computer tomography (CT) under ongoing ADT were retrospectively analyzed. We assessed the detection of PSMA-positive lesions overall and for three PSA subgroups (0 to < 1 ng/mL, 1 to < 20 ng/mL and > 20 ng/mL). In addition, PSMA-positive findings were stratified by localization (prostatic fossa, pelvic, para-aortic, mediastinal/supraclavicular and axillary lymph nodes, bone lesions and visceral lesions) and hormone status (hormone-sensitive vs. hormone-resistant). Furthermore, we assessed how many patients would be classified as having oligometastatic disease (≤ 3 lesions) and theoretically qualify for metastasis-directed radiotherapy (MDRT) in a personalized patient management., Results: We detected PSMA-positive lesions in 94.0% (79 of 84) of all patients. In the three PSA subgroups detection rates of 85.2% (0 to < 1 ng/mL, n = 27), 97.3% (1 to < 20 ng/mL, n = 37) and 100% (> 20 ng/mL, n = 20) were observed, respectively. PSMA-positive visceral metastases were observed only in patients with a PSA > 1 ng/mL. Detection of PSMA-positive lesions did not significantly differ between patients with hormone-sensitive and hormone-resistant PCa. Oligometastatic PCa was detected in 19 of 84 patients (22.6%). Almost all patients, 94.7% (n = 18) would have been eligible for MDRT., Conclusions: In this study, we observed an overall very high detection rate of 94% using PSMA PET imaging in patients with advanced PCa and ongoing ADT. Even in a majority of patients with very low PSA values < 1 ng/ml PSMA-positive lesions were found., (© 2021. The Author(s).)

Purpose: Ultrasound-guided biopsy (US biopsy) with 10-12 cores has a suboptimal sensitivity for clinically significant prostate cancer (sigPCa). If US biopsy is negative, magnetic resonance imaging (MRI)-guided biopsy is recommended, despite a low specificity for lesions with score 3-5 on Prostate Imaging Reporting and Data System (PIRADS). Screening and biopsy guidance using an imaging modality with high accuracy could reduce the number of unnecessary biopsies, reducing side effects. The aim of this study was to assess the performance of positron emission tomography/MRI with 68 Ga-labeled prostate-specific membrane antigen (PSMA-PET/MRI) to detect and localize primary sigPCa (ISUP grade group 3 and/or cancer core length ≥ 6 mm) and guide biopsy., Methods: Prospective, open-label, single-center, non-randomized, diagnostic accuracy study including patients with suspected PCa by elevation of prostate-specific antigen (PSA) level and a suspicious lesion (PIRADS ≥3) on multiparametric MRI (mpMRI). Forty-two patients underwent PSMA-PET/MRI followed by both PSMA-PET/MRI-guided and section-based saturation template biopsy between May 2017 and February 2019. Primary outcome was the accuracy of PSMA-PET/MRI for biopsy guidance using section-based saturation template biopsy as the reference standard., Results: SigPCa was found in 62% of the patients. Patient-based sensitivity, specificity, negative and positive predictive value, and accuracy for sigPCa were 96%, 81%, 93%, 89%, and 90%, respectively. One patient had PSMA-negative sigPCa. Eight of nine false-positive lesions corresponded to cancer on prostatectomy and one in six false-negative lesions was negative on prostatectomy., Conclusion: PSMA-PET/MRI has a high accuracy for detecting sigPCa and is a promising tool to select patients with suspicion of PCa for biopsy., Trial Registration: This trial was retrospectively registered under the name "Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) Guided Biopsy in Men with Elevated PSA" (NCT03187990) on 06/15/2017 ( https://clinicaltrials.gov/ct2/show/NCT03187990 )., (© 2021. The Author(s).)

Introduction: The role of positron-emission tomography/computed-tomography (PET/CT) in the management of sarcomas and as a prognostic tool has been studied. However, it remains unclear which metric is the most useful. We aimed to investigate if volume-based PET metrics (Tumor volume (TV) and total lesions glycolysis (TLG)) are superior to maximal standardized uptake value (SUVmax) and other metrics in predicting survival of patients with soft tissue and bone sarcomas., Materials and Methods: In this retrospective cohort study, we screened over 52'000 PET/CT scans to identify patients diagnosed with either soft tissue, bone or Ewing sarcoma and had a staging scan at our institution before initial therapy. We used a Wilcoxon signed-rank to assess which PET/CT metric was associated with survival in different patient subgroups. Receiver-Operating-Characteristic curve analysis was used to calculate cutoff values., Results: We identified a total of 88 patients with soft tissue (51), bone (26) or Ewing (11) sarcoma. Median age at presentation was 40 years (Range: 9-86 years). High SUVmax was most significantly associated with short survival (defined as <24 months) in soft tissue sarcoma (with a median and range of SUVmax 12.5 (8.8-16.0) in short (n = 18) and 5.5 (3.3-7.2) in long survival (≥24 months) (n = 31), with ( p = 0.001). Similar results were seen in Ewing sarcoma (with a median and range of SUVmax 12.1 (7.6-14.7) in short (n = 6) and 3.7 (3.5-5.5) in long survival (n = 5), with ( p = 0.017). However, no PET-specific metric but tumor-volume was significantly associated ( p = 0.035) with survival in primary bone sarcomas (with a median and range of 217 cm 3 (186-349) in short survival (n = 4) and 60 cm 3 (22-104) in long survival (n = 19), with ( p = 0.035). TLG was significantly inversely associated with long survival only in Ewing sarcoma ( p = 0.03)., Discussion: Our analysis shows that the outcome of soft tissue, bone and Ewing sarcomas is associated with different PET/CT metrics. We could not confirm the previously suggested superiority of volume-based metrics in soft tissue sarcomas, for which we found SUVmax to remain the best prognostic factor. However, bone sarcomas should probably be evaluated with tumor volume rather than FDG PET activity.

Background: Positron emission tomography (PET) targeting the prostate-specific membrane antigen (PSMA) has superior sensitivity over conventional imaging (CI) to stage prostate cancer (PCa) and therefore is increasingly used in staging to stratify patients before radical therapy. Whether this improved diagnostic accuracy translates into improved outcome after radical prostatectomy (RPE) has not yet been shown. Therefore, the aim of this study was to compare the oncological outcome after RPE between patients that underwent preoperative staging with CI or PSMA-PET for intermediate and high-risk PCa., Methods: We retrospectively selected all patients that underwent RPE for intermediate- or high-risk PCa at our institution before PSMA-PET introduction (between March 2014 and September 2016) and compared the oncologic outcome of patients staged with PSMA-PET (between October 2016 and October 2018). Oncological pre-surgical risk parameters (age, PSA, D'Amico score, biopsy-ISUP, and cT stage) were compared between the groups. Oncological outcome was determined as PSA persistence, nerve-sparing rate, and surgical margin status. Wilcoxon rank-sum, Fisher's, and chi-square tests where used for statistical testing., Results: One hundred five patients were included, 53 in the CI group and 52 in the PSMA-group. Patients in the PSMA group had higher ISUP grade (p < 0.001) and D'Amico score (p < 0.05). The rate of free surgical margins and PSA persistence after RPE was 64% and 17% for the CI and 77% and 6% for the PSMA group (p = 0.15 and 0.13, respectively). Subgroup analysis with high-risk patients revealed PSA persistence in 7% (3/44) in the PSMA group and 25% (7/28) in the CI group (p = 0.04). Limitations include the retrospective design and choline-PET for some patients in the CI group., Conclusion: Immediate outcome after RPE was not worse in the PSMA group compared with the CI group, despite a higher-risk cohort. In a comparison of only high-risk patients, PSMA-PET staging was associated with a significantly lower rate of postsurgical PSA persistence.

Objectives: To investigate the potential of automatic lung cancer detection on submillisievert dose 18 F-fludeoxyglucose ( 18 F-FDG) scans using different positron emission tomography (PET) parameters, as a primary step towards a potential new indication for 18 F-FDG PET in lung cancer screening., Methods: We performed a retrospective cohort analysis with 83 patients referred for 18 F-FDG PET/CT, including of 34 patients with histology-proven lung cancer and 49 patients without lung disease. Aside clinical standard PET images (PET 100% ) two additional low-dose PET reconstructions were generated, using only 15 s and 5 s of the 150 s list mode raw data of the full-dose PET, corresponding to 10% and 3.3% of the original 18 F-FDG activity. The lungs were subdivided into three segments on each side, and each segment was classified as normal or containing cancer. The following standardized uptake values (SUVs) were extracted from PET per lung segment: SUV mean , SUV hot5 , SUV median , SUV std and SUV total . A multivariate linear regression model was used and cross-validated. The accuracy for lung cancer detection was tested with receiver operating characteristics analysis and T-statistics was used to calculate the weight of each parameter., Results: The T-statistics showed that SUV std was the most important discriminative factor for lung cancer detection. The multivariate model achieved an area under the curve of 0.97 for full-dose PET, 0.85 for PET 10% with PET 3.3% reconstructions resulting in a still high sensitivity the PET 10% reconstruction of 80%., Conclusion: This pilot study indicates that segment-based, quantitative PET parameters of low-dose PET reconstructions could be used to automatically detect lung cancer with high sensitivity., Advances in Knowledge: Automated assessment of PET parameters in low-dose PET may aid for an early detection of lung cancer.

Therapy response assessment is a critical step in cancer management, leading clinicians to optimize the use of therapeutic options during the course of the disease. Imaging is a pivotal biomarker for therapy response evaluation in oncology and has gained wider use through the development of reproducible data-based guidelines, of which the Response Evaluation Criteria in Solid Tumors is the most successful example. Disease-specific criteria have also been proposed, and the Prostate Cancer Working Group 3 criteria are the mainstay for prostate cancer (PC). However, conventional imaging evaluation in metastatic PC has several limitations, including (a) the inability to detect small-volume disease, (b) the high prevalence of bone (nonmeasurable) lesions at imaging, and (c) the established role of serum prostate-specific antigen (PSA) levels as the biomarker of choice for response assessment and disease progression. In addition, there are an increasing number of newer treatment options with various effects on imaging features. Prostate-specific membrane antigen (PSMA) PET has improved patient selection for newer treatments, such as metastasis-directed therapy (MDT) or radionuclide therapy. The role of PSMA PET in response assessment for many metastatic PC therapeutic options (MDT, androgen deprivation therapy, chemotherapy, radionuclide therapy, and immunotherapy) is an evolving issue, with emerging data showing good correlation with PSA levels and clinical outcome. However, there are specific implications of each therapy (especially androgen deprivation therapy and immunotherapy) on PSMA expression by PC cells, leading to potential pitfalls and inaccuracies that must be known by radiologists. Despite some limitations, PSMA PET is addressing gaps left by conventional imaging methods (eg, CT and bone scanning) and nonimaging biomarkers (PSA levels) in metastatic PC therapy response assessment, a role that can be improved with advances like refinement of interpretation criteria and whole-body tumor burden quantification. © RSNA, 2020See discussion on this article by Barwick and Castellucci.

Objectives: When increasing the PET acquisition time to match the longer MRI protocol in simultaneous PET/MR, the injected PET tracer dose can possibly be lowered to reduce radiation exposure. Moreover, applying new commercially available time-of-flight (TOF) block sequential regularized expectation maximization (BSREM)-based reconstruction algorithms could allow for further dose reductions. The purpose of this study was to find the minimal dose of the tracer targeting the prostate specific membrane antigen ( 68 Ga-PSMA-11) for a dedicated 15-min pelvic PET/MR scan that still matches the image quality of a reference 3-min scan at 100% (150 MBq) dose., Methods: In this retrospective analysis, 25 patients were included. PET emission datasets were edited to simulate stepwise reductions of injected tracer dose. Reference TOF ordered subset expectation maximum (OSEM) and new TOF BSREM reconstructions were performed and differences in the resulting PET images were visually and quantitatively assessed., Results: Visually, TOF BSREM reconstructions with relatively high regularization parameter (β) values are preferred. Quantitatively, however, high β-values result in lower lesion maximum standardized uptake values (SUV max ) compared to the reference. A β-value of 550 was considered the optimal compromise for the lowest possible 10% dose reconstructions, resulting in comparable visual assessment and lesion SUV max ., Conclusions: This study indicates that the injected 68 Ga-PSMA-11 tracer dose for a standard 3-min PET scan can be reduced to approximately 10% (15 MBq) when the PET acquisition time is matched to the 15-min pelvic MRI protocol, and when reconstructed with TOF BSREM using β = 550. This decreases the effective dose from 3.54 to 0.35 mSv., Key Points: • Low-dose dedicated pelvic 68 Ga-PSMA-11 PET/MR reduces radiation exposure for patients. • Retrospective study investigating the minimal dose needed for adequate image quality for 15-min PET frames over the pelvis showed using quantitative and qualitative analysis that a substantial dose reduction is possible without significant loss of image quality when using the TOF BSREM reconstruction algorithm. • With the introduction of low-dose pelvic 68 Ga-PSMA-11 PET/MR, new potential applications of 68 Ga-PSMA-11 PET for local staging or investigation of equivocal MRI findings could become applicable, even for patients without confirmed prostate cancer.

Prostate-specific membrane antigen (PSMA) targeted PET has a high detection rate for biochemical recurrence (BCR) of prostate cancer (PCa). Nevertheless, even at high prostate-specific antigen (PSA) levels (> 3 ng/ml), a relevant number of PSMA-PET scans are negative, mainly due to PSMA-negative PCa. Our objective was to investigate whether PSMA-expression patterns of the primary tumour on immunohistochemistry (IHC) are associated with PSMA-PET detection rate of recurrent PCa. Methods: Retrospective institutional review board approved single-centre analysis of patients who had undergone 68 Ga-PSMA-11-PET for BCR after radical prostatectomy (RPE) between 04/2016 and 07/2019, with tumour specimens available for PSMA-IHC. Clinical information (age, PSA-level, ongoing androgen deprivation therapy (ADT), Gleason score) and PSMA-IHC of the primary tumour were collected and their relationship to results from PSMA-PET (positive/negative) was investigated using a multiple logistic regression analysis. Results: 120 PSMA-PET scans in 74 patients were available for this analysis. Overall detection rate was 62% (74/120 scans), with a mean PSA value at scan time of 0.99 ng/ml (IQR 0.32-4.27). Of the clinical factors, only PSA-level and ADT were associated with PSMA-PET positivity. The percentage of PSMA-negative tumour area on IHC (PSMA %neg ) had a significant association to PSMA-PET negativity (OR = 2.88, p < 0.001), while membranous PSMA-expression showed no association ( p = 0.73). The positive predictive value of PSMA %neg ≥ 50% for a negative PSMA-PET was 85% (13/11) and for a PSMA %neg of 80% or more, 100% (9/9). Conclusions: PSMA-negative tumour area on IHC exhibited the strongest association with negative PSMA-PET scans, beside PSA-level and ADT. Even at very high PSA levels, PSMA-PET scans were negative in most of the patients with PSMA %neg ≥ 50%., Competing Interests: Competing Interests: IAB has received research grants and speaker honorarium from GE Healthcare, research grants from Swiss Life and speaker honorarium from Bayer Health Care and Astellas Pharma AG. MM received speaker fees from GE Healthcare. TH holds an advisory function for MSD and Bayer. Authors DAF, JHR, UJM, BK, JM, LH, DE, and NJR declare no conflict of interest. The Department of Nuclear Medicine holds an institutional Research Contract with GE Healthcare. The authors thank the Sick legat and the Iten-Kohaut foundation for their financial support., (© The author(s).)

Background: PET/MRI has a high potential in oncology imaging, especially for tumor indications where high soft tissue contrast is crucial such as genitourinary tumors. One of the challenges for PET/MRI acquisition is handling of metal implants. In addition to conventional methods, more innovative techniques have been developed to reduce artifacts caused by those implants such as the selective multiacquisition variable-image combination (MAVRIC-SL). The aim of this study is to perform a quantitative and qualitative assessment of metal artifact reduction in 68 Ga-PSMA-11 PET/MRI for prostate cancer patients with hip joint replacement using a selective MAVRIC-SL sequence for the whole pelvis., Methods: We retrospectively analyzed data of 20 men with 37 metal hip implants diagnosed with PCA, staged or restaged by 68 Ga-PSMA-11 PET/MRI from June 2016 to December 2017. Each signal cancellation per side or metal implant was analyzed on the reference sequence LAVA-FLEX, as well as T1-weighted fast spin echo (T1w-FSE) sequence and MAVRIC-SL. Two independent reviewers reported on a four-point scale whether abnormal pelvic 68 Ga-PSMA-11 uptake could be assigned to an anatomical structure in the tested sequences., Results: The smallest averaged signal void was observed on MAVRIC-SL sequences with a mean artifact size of 26.17 cm 2 (range 12.63 to 42.93 cm 2 , p < 0.001). The best image quality regarding anatomical assignment of pathological PSMA uptakes in the pelvis by two independent readers was noted for MAVRIC-SL sequences, followed by T1w-FSE with excellent interreader agreement., Conclusions: MAVRIC-SL sequence allows better image quality in the surrounding of hip implants by reducing MR signal voids and increasing so the accuracy of anatomical assignment of pathological 68 Ga-PSMA-11 uptake in the pelvis over LAVA-FLEX and T1w-FSE sequences.

Objectives: To evaluate the diagnostic performance of a deep learning algorithm for automated detection of small 18 F-FDG-avid pulmonary nodules in PET scans, and to assess whether novel block sequential regularized expectation maximization (BSREM) reconstruction affects detection accuracy as compared to ordered subset expectation maximization (OSEM) reconstruction., Methods: Fifty-seven patients with 92 18 F-FDG-avid pulmonary nodules (all ≤ 2 cm) undergoing PET/CT for oncological (re-)staging were retrospectively included and a total of 8824 PET images of the lungs were extracted using OSEM and BSREM reconstruction. Per-slice and per-nodule sensitivity of a deep learning algorithm was assessed, with an expert readout by a radiologist/nuclear medicine physician serving as standard of reference. Receiver-operator characteristic (ROC) curve of OSEM and BSREM were assessed and the areas under the ROC curve (AUC) were compared. A maximum standardized uptake value (SUV max )-based sensitivity analysis and a size-based sensitivity analysis with subgroups defined by nodule size was performed., Results: The AUC of the deep learning algorithm for nodule detection using OSEM reconstruction was 0.796 (CI 95%; 0.772-0.869), and 0.848 (CI 95%; 0.828-0.869) using BSREM reconstruction. The AUC was significantly higher for BSREM compared to OSEM (p = 0.001). On a per-slice analysis, sensitivity and specificity were 66.7% and 79.0% for OSEM, and 69.2% and 84.5% for BSREM. On a per-nodule analysis, the overall sensitivity of OSEM was 81.5% compared to 87.0% for BSREM., Conclusions: Our results suggest that machine learning algorithms may aid detection of small 18 F-FDG-avid pulmonary nodules in clinical PET/CT. AI performed significantly better on images with BSREM than OSEM., Key Points: • The diagnostic value of deep learning for detecting small lung nodules (≤ 2 cm) in PET images using BSREM and OSEM reconstruction was assessed. • BSREM yields higher SUV max of small pulmonary nodules as compared to OSEM reconstruction. • The use of BSREM translates into a higher detectability of small pulmonary nodules in PET images as assessed with artificial intelligence.

Background: Accurate staging is of major importance to determine the optimal treatment modality for patients with prostate cancer. Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) is a promising technique that outperformed conventional imaging in the detection of nodal and distant metastases in previous studies. However, it is still unclear whether the superior sensitivity and specificity also translate into improved patient management. The aim of this study was to assess the performance of 68 Ga-PSMA-11 PET for staging of intermediate and high-risk prostate cancer and its potential impact on disease management., Methods: In this retrospective analysis, 116 patients who underwent 68 Ga-PSMA-11 PET/CT or MRI scans for staging of their intermediate or high-risk prostate cancer between April 2016 and May 2018 were included. The potential impact of 68 Ga-PSMA-11 PET staging on patient management was assessed within a simulated multidisciplinary tumour board where hypothetical treatment decisions based on clinical information and conventional imaging alone was determined. This treatment decision was compared with the treatment recommendation based on clinical information and 68 Ga-PSMA-11 PET imaging., Results: The primary tumour was positive on 68 Ga-PSMA-11 PET in 113 patients (97%). Nodal metastases were detected in 28 patients (24%) and bone metastases in 14 patients (12%). Compared with clinical staging and conventional imaging, 68 Ga-PSMA-11 PET resulted in new information in 42 of 116 patients (36%). In 32 of 116 patients (27%), this information would most likely have changed the management into a different therapy modality (15 patients, 13%) or adjusted treatment details (e.g. modification of radiotherapy field or lymph node dissection template; 17 patients, 14%)., Conclusion: Information from 68 Ga-PSMA-11 PET staging has the potential to change the management in more than a fourth of the patients who underwent PET staging for their intermediate to high-risk prostate cancer. Whether these more personalized 68 Ga-PSMA-11 PET-based treatment decisions will improve patient outcome needs further investigation.

Positron-emission tomography (PET) with prostate-specific membrane antigen (PSMA) has been increasingly used to image prostate cancer in the last decade. In the staging setting several studies have already been published suggesting PSMA PET can be a valuable tool. They, however, did not translate into recommendations by guidelines. Both PSMA PET/computed tomography (CT) and PET/magnetic resonance imaging have been investigated in the staging setting, showing higher detection rate of prostate cancer lesions over the conventional imaging work-up and some studies already showed an impact on disease management. The aim of this review is to provide an overview of the existing published data regarding PSMA PET for staging prostate cancer, with emphasis on PET/magnetic resonance imaging. Despite the fact that PSMA is a relatively new tool and not officially recommended for staging yet, there are >50 original studies in the literature assessing PSMA PET performance in the staging setting of prostate cancer, and some meta-analyses.

Introduction: Radical prostatectomy with extended pelvic lymph node dissection (ePLND) is a curative treatment option for patients with clinically significant localised prostate cancer. The decision to perform an ePLND can be challenging because the overall incidence of lymph node metastasis is relatively low and ePLND is not free of complications. Using current clinical nomograms to identify patients with nodal involvement, approximately 75-85% of ePLNDs performed are negative. The aim of this study was to assess the added value of 68 Ga-PSMA-11 PET in predicting lymph node metastasis in men with intermediate- or high-risk prostate cancer., Methods: 68 Ga-PSMA-11 PET scans of 60 patients undergoing radical prostatectomy with ePLND were reviewed for qualitative (visual) assessment of suspicious nodes and assessment of quantitative parameters of the primary tumour in the prostate (SUV max , total activity (PSMA total ) and PSMA positive volume (PSMA vol )). Ability of quantitative PET parameters to predict nodal metastasis was assessed with receiver operating characteristics (ROC) analysis. A multivariable logistic regression model combining PSA, Gleason score, visual nodal status on PET and primary tumour PSMA total was built. Net benefit at each risk threshold was compared with five nomograms: MSKCC nomogram, Yale formula, Roach formula, Winter nomogram and Partin tables (2016)., Results: Overall, pathology of ePLND specimens revealed 31 pelvic metastatic lymph nodes in 12 patients. 68 Ga-PSMA-11 PET visual analysis correctly detected suspicious nodes in 7 patients, yielding a sensitivity of 58% and a specificity of 98%. The area under the ROC curve for primary tumour SUV max was 0.70, for PSMA total 0.76 and for PSMA vol 0.75. The optimal cut-off for nodal involvement was PSMA total > 49.1. The PET model including PSA, Gleason score and quantitative PET parameters had a persistently higher net benefit compared with all clinical nomograms., Conclusion: Our model combining PSA, Gleason score and visual lymph node analysis on 68 Ga-PSMA-11 PET with PSMA total of the primary tumour showed a tendency to improve patient selection for ePLND over the currently used clinical nomograms. Although this result has to be validated, 68 Ga-PSMA-11 PET showed the potential to reduce unnecessary surgical procedures in patients with intermediate- or high-risk prostate cancer.

The intense accumulation of prostate-specific membrane antigen (PSMA) radioligands in salivary glands is still not well understood. It is of concern for therapeutic applications of PSMA radioligands, because therapeutic radiation will damage these glands. A better understanding of the uptake mechanism is, therefore, crucial to find solutions to reduce toxicity. The aim of this study was to investigate whether the accumulation of PSMA-targeting radioligands in submandibular glands (SMGs) can be explained with PSMA expression levels using autoradiography (ARG) and immunohistochemistry (IHC). Methods: All patients gave written informed consent for further utility of the biologic material. The SMG of 9 patients, pancreatic tissue of 4 patients, and prostate cancer (PCA) lesions of 9 patients were analyzed. Tissue specimens were analyzed by means of PSMA-IHC (using an anti-PSMA-antibody and an immunoreactivity score system [IRS]) and ARG using 177 Lu-PSMA-617 (with quantification of the relative signal intensity compared with a PSMA-positive standard). The SUV max in salivary glands, pancreas, and PCA tissues were quantified in 60 clinical 68 Ga-PSMA-11 PET scans for recurrent disease as well as the 9 primary tumors selected for ARG and IHC. Results: PCA tissue samples revealed a wide range of PSMA staining intensity on IHC (IRS = 70-300) as well as in ARG (1.3%-22% of standard). This variability on PCA tissue could also be observed in 68 Ga-PSMA-11 PET (SUV max , 4.4-16) with a significant correlation between ARG and SUV max ( P < 0.001, R 2 = 0.897). On IHC, ARG, and 68 Ga-PSMA-11 PET, the pancreatic tissue was negative (IRS = 0, ARG = 0.1% ± 0.05%, SUV max of 3.1 ± 1.1). The SMG tissue displayed only focal expression of PSMA limited to the intercalated ducts on IHC (IRS = 10-15) and a minimal signal on ARG (1.3% ± 0.9%). In contrast, all SMG showed a high 68 Ga-PSMA-11 accumulation on PET scans (SUV max 23.5 ± 5.2). Conclusion: Our results indicate that the high accumulation of PSMA radioligands in salivary glands does not correspond to high PSMA expression levels determined using ARG and IHC. These findings provide evidence, that the significant accumulation of PSMA radioligands in SMG is not primarily a result of PSMA-mediated uptake., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

High-intensity focused ultrasound (HIFU) is a promising new modality for the treatment of localized prostate cancer (PCa). Follow-up of patients is recommended with biopsies and multiparametric MRI (mpMRI). However, mpMRI in the postinterventional setting is often false-negative. It was our aim to investigate if the new tracer targeting the prostate-specific membrane antigen ( 68 Ga-PSMA-11) could be used to localize recurrent disease with PET/MR in patients with discrepant findings between mpMRI and template biopsies. Methods: Interim analysis was performed of the first 10 patients scanned between September 2016 and May 2018 with positive template biopsy and negative mpMRI after HIFU from an ongoing clinical trial (NCT02265159). All patients underwent 68 Ga-PSMA-11 PET/MRI within 3 mo. Four prostatic quadrants were defined, and for every quadrant suspicion for recurrence was rated on a 5-point Likert scale from definitely no recurrence (1) to highly suspected of recurrence (5), with 4 used as a cutoff for suspected disease based on PET/MRI by a masked reader. 68 Ga-PSMA-11 uptake of suspected lesions and background areas was measured with the SUV max The apparent diffusion coefficient values of lesions and background were given for each segment. PET/MRI scans were compared with the template biopsy results, including corresponding Gleason scores (GS), number of positive cores, and tumor length. Results: The quadrant-based sensitivity, specificity, and positive and negative predictive values for PET/MRI were 55%, 100%, 100%, and 85%, respectively. Patient-based PET/MRI was negative in 4 cases with GS 3 + 4 and a tumor length between 0.1 and 3 mm. All tumor lesions with GS 4 + 3 or higher were detected on PET/MRI. Conclusion: Our preliminary results indicate that 68 Ga-PSMA-11-PET/MR has the potential to localize PCa recurrence after HIFU occult on mpMRI., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)

New oncological approaches using immune checkpoint inhibitors aim to reinvigorate lymphocytes against the tumor. The prognosis of cancer has been significantly improved by these treatments, which nonetheless lead to a new spectrum of immune-related side effects. The most frequent are skin rash, colitis, thyroid dysfunction, hypophysitis, hepatitis and pneumonitis. Early detection of these toxicities is crucial to determine the etiology and to introduce a temporary immunosuppressive therapy, allowing resolution of toxicity in most of cases. A multidisciplinary team is essential for optimal management., Competing Interests: Les auteurs ne déclarent aucun conflit d’intérêt en lien avec cet article.

Background: The tumour microenvironment is a critical regulator of malignant cancer progression. While endothelial cells have been widely studied in the context of tumour angiogenesis, their role as modulators of cancer cell invasion and migration is poorly understood., Methods: We have investigated the influence of endothelial cells on the invasive and migratory behaviour of human cancer cells in vitro., Results: Upon exposure to culture supernatants of endothelial cells, distinct cancer cells, such as SK-BR-3 cells, showed significantly increased invasion and cell migration concomitant with changes in cell morphology and gene expression reminiscent of an epithelial-mesenchymal transition (EMT). Interestingly, the pro-migratory effect on SK-BR-3 cells was significantly enhanced by supernatants obtained from subconfluent, proliferative endothelial cells rather than from confluent, quiescent endothelial cells. Systematically comparing the supernatants of subconfluent and confluent endothelial cells by quantitative MS proteomics revealed eight candidate proteins that were secreted at significantly higher levels by confluent endothelial cells representing potential inhibitors of cancer cell migration. Among these proteins, nidogen-1 was exclusively expressed in confluent endothelial cells and was found to be necessary and sufficient for the inhibition of SK-BR-3 cell migration. Indeed, SK-BR-3 cells exposed to nidogen-1-depleted endothelial supernatants showed increased promigratory STAT3 phosphorylation along with increased cell migration. This reflects the situation of enhanced SK-BR-3 migration upon stimulation with conditioned medium from subconfluent endothelial cells with inherent absence of nidogen-1 expression., Conclusion: The identification of nidogen-1 as an endothelial-derived inhibitor of migration of distinct cancer cell types reveals a novel mechanism of endothelial control over cancer progression.

Objective:: Positron emission tomography (PET) using 18 F-fludeoxyglucose ( 18 F-FDG) is an established imaging modality for tumor staging in patients with non-small cell lung cancer (NSCLC). There is a growing interest in using 18 F-FDG PET for therapy response assessment in NSCLC which relies on quantitative PET parameters such as standardized uptake values (SUV). Different reconstruction algorithms in PET may affect SUV. We sought to determine the variation of SUV in patients with NSCLC when using ordered subset expectation maximization (OSEM) and block sequential regularized expectation maximization (BSREM) in latest-generation digital PET/CT, including a subanalysis for adenocarcinoma and squamous cell carcinoma., Methods:: A total of 58 patients (34 = adenocarcinoma, 24 = squamous cell carcinoma) who underwent a clinically indicated 18 F-FDG PET/CT for staging were reviewed. PET images were reconstructed with OSEM and BSREM reconstruction with noise penalty strength β-levels of 350, 450, 600, 800 and 1200. Lung tumors maximum standardized uptake value (SUV max ) were compared., Results:: Lung tumors SUV max were significantly lower in adenocarcinomas compared to squamous cell carcinomas in all reconstructions evaluated (all p < 0.01). Comparing BSREM to OSEM, absolute SUV max differences were highest in lower β-levels of BSREM with + 2.9 ± 1.6 in adenocarcinoma and + 4.0 ± 2.9 in squamous cell carcinoma (difference between histology; p-values > 0.05). There was a statistically significant difference of the relative increase of SUV max in adenocarcinoma (mean + 34.8%) and squamous cell carcinoma (mean 23.4%), when using BSREM 350 instead of OSEM TOF (p < 0.05)., Conclusion:: In NSCLC the relative change of SUV when using BSREM instead of OSEM is significantly higher in adenocarcinoma as compared to squamous cell carcinoma., Advances in Knowledge:: The impact of BSREM on SUV may vary in different histological subtypes of NSCLC. This highlights the importance for careful standardization of β-value used for serial 18 F-FDG PET scans when following-up NSCLC patients.

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein expressed in the cytosol of normal prostate tissue and highly overexpressed on the membrane of prostate cancer, therefore increasingly used to image prostate cancer. We report a case of a 65-year-old man with two focal PSMA-positive areas on a Ga-PSMA-11 PET/MR, one corresponding to a prostate carcinoma (Gleason score 4 + 3) and another region without any evidence of malignancy, but with corresponding high PSMA-expression on immunohistochemistry.

Purpose: The fast-increasing use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) ligand for the imaging of prostate cancer (PCA) biochemical recurrence has led to a rapid change in treatment concepts. Since the superiority of 68 Ga-PSMA-11 PET in detecting recurrent PCA is well established, the aim of our study was to assess its effect on management and outcome in all patients imaged during the first year after its introduction into clinical routine., Methods: Of 327 patients imaged, 223 were referred for recurrent PCA and gave written informed consent for further analysis of their data for this retrospective consecutive cohort analysis. Twenty patients were lost to further follow-up. The rate of detection of recurrence by 68 Ga-PSMA-11 PET was based on the clinical reports. Management before the availability of PET diagnostic information was assessed according to guidelines (therapy option without 68 Ga-PSMA-11 PET). In the 203 patients with follow-up 6 months after 68 Ga-PSMA-11 PET, the therapies effectively implemented as well as follow-up PSA levels were evaluated, with a PSA value of <0.2 ng/ml representing a complete response and a decrease in PSA value of at least 50% from baseline representing a partial response., Results: 68 Ga-PSMA-11 PET was positive and identified recurrence in 166 of the 223 patients (74%), with a detection rate of 50% for recurrent disease at low PSA values of <0.5 ng/ml. 68 Ga-PSMA-11 PET led to a change in management in 122 of the 203 patients (60%). A substantial increase in the use of metastasis-targeted treatment and a reduction in the use of systemic treatment were observed, with 59 of the 203 patients (29%) undergoing targeted radiotherapy (RTXa) only, and 20 patients (10%) undergoing RTXa with hormonal therapy as the two most frequently selected therapy options. The proportion of patients in whom systemic therapy was selected decreased from 60% (133 of 223 patients) to 34% (70 of 203 patients) on the basis of the information provided by the 68 Ga-PSMA-11 PET scan. PSMA PET-directed metastasis-targeted treatment led to a complete response after 6 months in 45% of patients., Conclusion: The high rate of recurrence detection by PSMA PET was confirmed and PSMA PET led to a change in management in 60% of patients. Focal therapy for PSMA-positive lesions is a promising approach with complete responses in 45% of patients.

Objectives: We evaluated whether machine learning may be helpful for the detection of lung cancer in FDG-PET imaging in the setting of ultralow dose PET scans., Materials and Methods: We studied the performance of an artificial neural network discriminating lung cancer patients (n = 50) from controls (n = 50) without pulmonary malignancies. A total of 3936 PET slices including images in which the lung tumor is visually present and image slices of patients with no lung cancer were exported. The diagnostic performance of the artificial neural network based on clinical standard dose PET images (PET 100% ) as well as with a tenfold (PET 10% ) and thirtyfold (PET 3.3% ) reduced radiation dose (∼0.11 mSv) was assessed., Results: The area under the curve of the deep learning algorithm for lung cancer detection was 0.989, 0.983 and 0.970 for standard dose images (PET 100% ), and reduced dose PET 10% , and PET 3.3% reconstruction, respectively. The artificial neural network achieved a sensitivity of 95.9% and 91.5% and a specificity of 98.1% and 94.2%, at standard dose and ultralow dose PET 3.3% , respectively., Conclusion: Our results suggest that machine learning algorithms may aid fully automated lung cancer detection even at very low effective radiation doses of 0.11 mSv. Further improvement of this technology might improve the specificity of lung cancer screening efforts and could lead to new applications of FDG-PET., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To compare the degree of benign bone marrow uptake of 18 F-fluorodeoxyglucose ( 18 F-FDG) between Hodgkin lymphoma patients with and without B symptoms., Materials and Methods: We analyzed the medical charts of 74 Hodgkin lymphoma patients who underwent 18 F-FDG positron emission tomography/computed tomography (PET/CT) prior to the initiation of therapy between October 2010 and September 2013. In all of the patients, the bone marrow biopsy was negative and the 18 F-FDG PET/CT images did not suggest bone marrow involvement. Of the 74 patients evaluated, 54 presented inflammatory (B) symptoms and 20 did not. Regions of interest (ROIs) were drawn on the sternum, the proximal thirds of the humeri, the proximal thirds of the femora, and both iliac wings (totaling seven ROIs per patient). To compare the patients with and without B symptoms, in terms of standardized uptake values (SUVs) for the seven ROIs, we used the Mann-Whitney U test., Results: For six of the ROIs, the SUVs were higher in the patients with B symptoms than in those without, and the difference was statistically significant ( p < 0.05). There was also a tendency toward a statistically significant difference between the two groups in terms of the SUV for the right iliac wing ROI ( p = 0.06)., Conclusion: In our sample, the presence of B symptoms was associated with increased 18 F-FDG uptake in bone marrow.

Background: The distinction between chronic telogen effluvium (CTE) and female pattern hair loss (FPHL) is important because of their different prognosis and treatment. Non-invasive methods have been described to be useful in differentiating FPHL from CTE. This prospective study investigated the use of the washing method to differentiate CTE from mild FPHL., Methods: Twenty patients with CTE and 17 with FPHL were recruited and followed for 18 months. The diagnosis was established through clinical, laboratory, and histological studies. The patients were asked to abstain from washing their hair for 5 days and then shampoo and collect all hair shed in the process. Hair shafts were then counted and divided into two groups: up to 3 cm in length or longer., Results: In the CTE group, the mean hair count was high (438), and in all cases, <10% were short. In patients with FPHL, the mean count was not as high (215) and in only one patient, short hairs comprised <10% of the total. The greater the number of long hairs, the higher was the density of terminal follicles seen histologically. The CTE group presented a greater number of patients with serum iron values <70 μg/dl. Ferritin levels ranged from 6.98 to 128.33, average of 66.65 (CTE), and 16.5-304.8, average of 114.97 ng/ml (FPHL), but no significant differences were found., Conclusion: The washing test can be useful to avoid biopsy procedures. Iron serum levels are possibly an additional parameter that may improve CTE diagnosis if combined with an earlier test., (© 2015 The International Society of Dermatology.)

Background: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer., Methods: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy., Results: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34-64%) in the chemotherapy arm and 58% (95% CI 42-72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively., Conclusions: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

The extensive intratumor heterogeneity revealed by sequencing cancer genomes is an essential determinant of tumor progression, diagnosis, and treatment. What maintains heterogeneity remains an open question because competition within a tumor leads to a strong selection for the fittest subclone. Cancer cells also cooperate by sharing molecules with paracrine effects, such as growth factors, and heterogeneity can be maintained if subclones depend on each other for survival. Without strict interdependence between subclones, however, nonproducer cells can free-ride on the growth factors produced by neighboring producer cells, a collective action problem known in game theory as the "tragedy of the commons," which has been observed in microbial cell populations. Here, we report that similar dynamics occur in cancer cell populations. Neuroendocrine pancreatic cancer (insulinoma) cells that do not produce insulin-like growth factor II (IGF-II) grow slowly in pure cultures but have a proliferation advantage in mixed cultures, where they can use the IGF-II provided by producer cells. We show that, as predicted by evolutionary game theory, producer cells do not go extinct because IGF-II acts as a nonlinear public good, creating negative frequency-dependent selection that leads to a stable coexistence of the two cell types. Intratumor cell heterogeneity can therefore be maintained even without strict interdependence between cell subclones. Reducing the amount of growth factors available within a tumor may lead to a reduction in growth followed by a new equilibrium, which may explain relapse in therapies that target growth factors.

Amplified HER2, which encodes a member of the epidermal growth factor receptor (EGFR) family, is a target of effective therapies against breast cancer. In search for similarly targetable genomic aberrations, we identified copy number gains in SYNJ2, which encodes the 5'-inositol lipid phosphatase synaptojanin 2, as well as overexpression in a small fraction of human breast tumors. Copy gain and overexpression correlated with shorter patient survival and a low abundance of the tumor suppressor microRNA miR-31. SYNJ2 promoted cell migration and invasion in culture and lung metastasis of breast tumor xenografts in mice. Knocking down SYNJ2 impaired the endocytic recycling of EGFR and the formation of cellular lamellipodia and invadopodia. Screening compound libraries identified SYNJ2-specific inhibitors that prevented cell migration but did not affect the related neural protein SYNJ1, suggesting that SYNJ2 is a potentially druggable target to block cancer cell migration., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Chronic telogen effluvium (CTE), a poorly understood condition, can be confused with or may be a prodrome to female pattern hair loss (FPHL). The pathogenesis of both is related to follicle cycle shortening and possibly to blood supply changes., Aim: To analyze a number of histomorphometric and immunohistochemical findings through vascular endothelial growth factor (VEGF), Ki-67, and CD31 immunostaining in scalp biopsies of 20 patients with CTE, 17 patients with mild FPHL and 9 controls., Methods: Ki-67 index and VEGF optical density were analyzed at the follicular outer sheath using ImageJ software. CD31 microvessel density was assessed by a Chalkley grid., Results: Significant follicle miniaturization and higher density of nonanagen follicles were found in FPHL, compared with patients with CTE and controls. Ki-67+ index correlated positively with FPHL histological features. The FPHL group showed the highest VEGF optical density, followed by the CTE and control groups. No differences were found in CD31 microvessel density between the three groups., Conclusions: Histomorphometric results establish CTE as a distinct disorder, separate from FPHL from its outset. Its pathogenic mechanisms are also distinct. These findings support the proposed mechanism of 'immediate telogen release' for CTE, leading to cycle synchronization. For FPHL, accelerated anagen follicular mitotic rates and, thus, higher Ki-67 and VEGF values, would leave less time for differentiation, resulting in hair miniaturization., (© 2014 British Association of Dermatologists.)

Breast tumors lacking expression of human epidermal growth factor receptor 2 (HER2) and the estrogen and the progesterone receptors (triple negative; TNBC) are more aggressive than other disease subtypes, and no molecular targeted agents are currently available for their treatment. Because TNBC commonly displays EGF receptor (EGFR) expression, and combinations of monoclonal antibodies to EGFR effectively inhibit other tumor models, we addressed the relevance of this strategy to treatment of TNBC. Unlike a combination of the clinically approved monoclonal antibodies, cetuximab and panitumumab, which displaced each other and displayed no cooperative effects, several other combinations resulted in enhanced inhibition of TNBC's cell growth both in vitro and in animals. The ability of certain antibody mixtures to remove EGFR from the cell surface and to promote its intracellular degradation correlated with the inhibitory potential. However, unlike EGF-induced sorting of EGFR to lysosomal degradation, the antibody-induced pathway displayed independence from the intrinsic kinase activity and dimer formation ability of EGFR, and it largely avoided the recycling route. In conclusion, although TNBC clinical trials testing EGFR inhibitors reported lack of benefit, our results offer an alternative strategy that combines noncompetitive antibodies to achieve robust degradation of EGFR and tumor inhibition.

Once stimulated, the epidermal growth factor receptor (EGFR) undergoes self-phosphorylation, which, on the one hand, instigates signaling cascades, and on the other hand, recruits CBL ubiquitin ligases, which mark EGFRs for degradation. Using RNA interference screens, we identified a deubiquitinating enzyme, Cezanne-1, that opposes receptor degradation and enhances EGFR signaling. These functions require the catalytic- and ubiquitin-binding domains of Cezanne-1, and they involve physical interactions and transphosphorylation of Cezanne-1 by EGFR. In line with the ability of Cezanne-1 to augment EGF-induced growth and migration signals, the enzyme is overexpressed in breast cancer. Congruently, the corresponding gene is amplified in approximately one third of mammary tumors, and high transcript levels predict an aggressive disease course. In conclusion, deubiquitination by Cezanne-1 curtails degradation of growth factor receptors, thereby promotes oncogenic growth signals.

Monoclonal antibodies (mAbs) to HER2 are currently used to treat breast cancer, but low clinical efficacy, along with primary and acquired resistance to therapy, commonly limit clinical applications. We previously reported that combinations of antibodies directed at non-overlapping epitopes of HER2 are endowed with enhanced antitumor effects, probably due to accelerated receptor degradation. Here, we extend these observations to three-dimensional mammary cell models, and compare the effects of single mAbs with the effects of antibody combinations. Collectively, our in vitro assays and computational image analyses indicate that combining mAbs against different epitopes of HER2 better inhibits invasive growth. Importantly, while growth factors are able to reduce intraluminal apoptosis and induce an invasive phenotype, combinations of mAbs better than single mAbs can reverse the growth factor-induced phenotypes of HER2-overexpressing spheroids. In conclusion, our studies propose that mAb combinations negate the biological effects of growth factors on invasive growth of HER2-overexpressing cells. Hence, combining mAbs offers a therapeutic strategy, potentially able to enhance clinical efficacy of existing antireceptor immunotherapeutics.