Site-specific therapy guided by a 90-gene expression assay versus empirical chemotherapy in patients with cancer of unknown primary (Fudan CUP-001): a randomised controlled trial.

BACKGROUND: Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP. METHODS: This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m2 by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m2 or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m2 by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600). FINDINGS: Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequent of these in the site-specific therapy and empirical chemotherapy groups were decreased neutrophil count (36 [44%] vs 42 [49%]), decreased white blood cell count (17 [21%] vs 26 [31%]), and anaemia (ten [12%] vs nine [11%]). Treatment-related serious adverse events were reported in five (6%) patients in the site-specific therapy group and two (2%) in the empirical chemotherapy group. No treatment-related deaths were observed. INTERPRETATION: This single-centre randomised trial showed that site-specific therapy guided by the 90-gene expression assay could improve progression-free survival compared with empirical chemotherapy among patients with previously untreated CUP. Site-specific prediction by the 90-gene expression assay might provide more disease information and expand the therapeutic armamentarium in these patients. FUNDING: Clinical Research Plan of Shanghai Hospital Development Center, Program for Shanghai Outstanding Academic Leader, and Shanghai Anticancer Association SOAR PROJECT. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The Application of 68Ga-Somatostatin Analog and 18F-FDG PET/CT for Bone Metastasis from Neuroendocrine Tumors.

INTRODUCTION: Aims of the study were to assess the differences in the diagnostic efficacy of 68Ga-somatostatin receptor analogs (68Ga-SSAs) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for detecting bone metastases in neuroendocrine neoplasm (NEN) and to analyze the correlation between imaging features and clinical features of BMs. METHODS: We retrospectively analyzed the clinical and imaging data of 213 NEN patients who underwent 68Ga-SSA PET/CT and were finally diagnosed as BMs by pathology or follow-up. Of those, 103 patients underwent 18F-FDG PET/CT within 7 days after 68Ga-SSA PET/CT. RESULT: The BM detection rate of 68Ga-SSA PET/CT was higher than 18F-FDG PET/CT (86.4% vs. 66.0%, p = 0.02) in 103 patients with dual scanning. Meanwhile, the number of positive lesions in 68Ga-SSA PET/CT was significantly more than in 18F-FDG PET/CT (3.37 ± 1.95 vs. 2.23 ± 2.16, t = 4.137, p < 0.001). Most bone metastasis lesions presented as osteogenic change in CT (55.4%, 118/213). Concerning the primary tumor, the most frequent were of pancreatic origin (26.3%, 56/213), followed by rectal origin (22.5%, 48/213), thymic origin in 33 cases (15.5%), pulmonary origin in 29 cases (13.6%), paraganglioma in 20 cases (9.4%). The efficiency of 68Ga-SSA PET/CT to detect BMs was significantly correlated with the primary site (p = 0.02), with thymic carcinoid BMs being the most difficult to detect, and the positive rate was only 60.6% (20/33). However, 18F-FDG PET/CT positive rate was 76.92% (10/13) in thymic carcinoid BMs. In addition, the BMs of 7 patients in this study were detected by 68Ga-SSA PET earlier than CT for 4.57 months (range: 2-10 months). CONCLUSION: 68Ga-SSA PET/CT has higher sensitivity for detecting the BMs of NEN than 18F-FDG and detects the BM earlier than CT. Moreover, 18F-FDG PET/CT should be a complement for diagnosing the BMs of thymic carcinoids.

The added value of [68Ga]Ga-DOTA-FAPI-04 PET/CT in pancreatic cancer: a comparison to [18F]F-FDG.

OBJECTIVES: We aimed to compare the diagnostic and prognostic performance of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in pancreatic cancer. METHODS: This single-center retrospective study enrolled 51 patients who underwent [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT. The final diagnosis on PET/CT images was verified by histopathology or 1-year follow-up. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 PET/CT were calculated to compare the diagnostic efficacy. Progression-free survival (PFS) was the endpoint for the survival analysis. Twenty-six patients were eligible for the Kaplan-Meier survival analysis using a log-rank test. And multivariate analysis including age, sex, stage, CA199 level, and SUVmax of [18F]FDG and [68Ga]Ga-DOTA-FAPI-04 was also performed. Two-tailed p < 0.05 was considered statistically significant. RESULTS: [68Ga]Ga-DOTA-FAPI-04 showed a higher sensitivity than [18F]FDG for detecting primary tumor (100% vs. 95.0%), metastatic lymph nodes (96.2% vs. 61.5%), and distant metastases (100% vs. 84.0%) (p < 0.0001, respectively). For [68Ga]Ga-DOTA-FAPI-04, the tumor-to-liver background ratio (TLBR) of liver metastases was higher (5.7 ± 3.2 vs. 3.2 ± 1.3, p < 0.0001). Furthermore, SUVmax > 14.9 on [68Ga]Ga-DOTA-FAPI-04 was significantly associated with PFS rates (chi-square = 12.05, p = 0.001). The Cox regression analysis showed that SUVmax of [68Ga]Ga-DOTA-FAPI-04 was an independent prognostic factor for PFS (p = 0.001; hazard ratio, 8.877). CONCLUSIONS: [68Ga]Ga-DOTA-FAPI-04 PET/CT showed a higher sensitivity and accuracy than [18F]FDG PET/CT in diagnosing pancreatic cancer and might have an independent prognostic value for pancreatic cancer patients. KEY POINTS: • [68Ga]Ga-DOTA-FAPI-04 PET/CT had a higher sensitivity and accuracy in detecting primary tumors, metastatic lymph nodes, and distant metastases than [18F]FDG PET/CT. • SUVmax > 14.9 on [68Ga]Ga-DOTA-FAPI-04 PET/CT before chemotherapy was significantly associated with progress-free status rates (chi-square = 12.05, p = 0.001) in pancreatic cancer patients.

Head-to-head evaluation of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT in recurrent soft tissue sarcoma.

PURPOSE: We aimed to evaluate the value of [68 Ga]Ga-DOTA-FAPI-04 PET/CT for the diagnosis of recurrent soft tissue sarcoma (STS), compared with [18F]FDG PET/CT. METHODS: A total of 45 patients (21 females and 24 males; median age, 46 years; range, 18-71 years) with 13 subtypes of STS underwent [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 PET/CT examination within 1 week for assessment local relapse or distant metastasis. Positive lesions on PET/CT images were verified by biopsy or 3-month follow-up. Wilcoxon matched-pairs signed-rank test was used to compare the semiquantitative values (SUVmax and TBR) of [18F]FDG and [68 Ga]Ga-DOTA-FAPI-04 in tumor lesions, and McNemar test was applied to test for differences of both tracers. RESULTS: Among the 45 patients, 282 local relapses and distant metastases were identified. Compared to [18F]FDG, [68 Ga]Ga-DOTA-FAPI-04 PET/CT detected more lesions (275 vs. 186) and outperformed in sensitivity, specificity, PPV, NPV, and accuracy for the diagnosis of recurrent lesions (P < 0.001). [68 Ga]Ga-DOTA-FAPI-04 demonstrated significantly higher values of SUVmax and TBR than [18F]FDG PET/CT in liposarcoma (P = 0.011 and P < 0.001, respectively), malignant solitary fibrous tumor (MSFT) (P < 0.001 and P < 0.001, respectively), and interdigitating dendritic cell sarcoma (IDCS) (P < 0.001and P < 0.001, respectively). While mean SUVmax and TBR presented favorable uptake of [18F]FDG over [68 Ga]Ga-DOTA-FAPI-04 in undifferentiated pleomorphic sarcoma (UPS) (P = 0.003 and P < 0.001, respectively) and rhabdomyosarcoma (RMS) (P < 0.001 and P < 0.001, respectively). CONCLUSION: [68 Ga]Ga-DOTA-FAPI-04 PET/CT is a promising new imaging modality for recurrent surveillance of STS, and compares favorably with [18F]FDG for identifying recurrent lesions of liposarcoma, MSFT, and IDCS.

Sentinel node theory helps tracking of primary lesions of cancers of unknown primary.

BACKGROUND: Sentinel lymph node is the first stop of lymphatic spreading of cancer with known primary. The lymph node metastasis pattern of cancer of unknown primary (CUP) is unclear and has been presumed to follow the same pathway. To test this hypothesis, data of all 716 patients clinically diagnosed as CUP in our center were collected. METHODS: Diagnoses of lymph node metastasis were established by 18F-FDG PET-CT and/or biopsy pathology. Three hundred and forty-seven cases meeting the criteria were divided into three groups: pathology-confirmed primary with invasive biopsy or surgery of the suspicious lesion (group A, n = 64), primary still unknown even with invasive biopsy or surgery of the suspicious lesion (group B, n = 204), and others with no suspicious lesion or lesions who had not been sampled due to medical or other reasons (group C, n = 79). We assessed the clinicopathological features between these groups, and the relationship between lymph node metastasis pattern and confirmed primary site. RESULTS: In group A, the primary sites of 61 cases were compatible with sentinel node theory, resulting in a positive predictive value of 95%. No significant differences in age, sex, bone metastasis, or visceral metastasis observed between group A and group B, except that group A had a higher ratio of differentiated carcinoma (94% vs. 77%, P = 0.003). CONCLUSION: To our knowledge, this is the first evidence indicating that the majority of clinical CUP cases follow the sentinel node theory to spread in lymph nodes, which helps tracking the primary, especially for differentiated carcinoma.

The Value of 99mTc-PSMA SPECT/CT-Guided Surgery for Identifying and Locating Lymph Node Metastasis in Prostate Cancer Patients.

BACKGROUND: This study evaluated the effect of technetium-99m (99mTc)-labeled prostate-specific membrane antigen (PSMA)-based image-guided surgery on the oncologic outcomes for patients with primary or recurrent prostate cancer (PCa). METHODS: This study retrospectively analyzed 54 consecutive patients with PCa who underwent 99mTc-labeled PSMA-based image-guided surgery between January 2016 and September 2017. These patients received a radical prostatectomy (RP) with pelvic lymph node dissection (PLND) or salvage lymph node dissection (sLND). The resected specimens were compared with findings of postoperative histologic analysis. The responses to the treatment were recorded during the follow-up period. RESULTS: In 31 patients, PSMA single-photon emission computerized tomography (SPECT) and computed tomography (CT) could find 52 suspicious lymph node metastases (LNMs). With the help of PSMA SPECT/CT, 12 patients with recurrence received sLND, 19 primary PCa patients received RP with extended PLND, and 23 primary PCa patients received RP with standard PLND. The findings showed that PSMA SPECT/CT could detect LNMs with high sensitivity and specificity. In six patients, PSMA SPECT/CT could find more LNMs that were not found by MRI and help to modify the extent of lymphadenectomy. At the latest follow-up evaluation, 39 patients showed a biochemical response (BR), 9 patients showed a biochemical recurrence (BCR) after BR, and 6 patients never exhibited BR. The patients who received RP with standard PLND or extended PLND had a better prostate-specific antigen (PSA) response than the patients who received sLND. The patients with pelvic LNMs also had a better PSA response than the patients with retroperitoneal LNMs. CONCLUSIONS: This study showed that 99mTc-PSMA SPECT/CT-guided surgery can remove more LNMs than conventional imaging with high sensitivity and specificity and delay disease progression in PCa patients.

Relationship between PSA kinetics and Tc-99m HYNIC PSMA SPECT/CT detection rates of biochemical recurrence in patients with prostate cancer after radical prostatectomy.

BACKGROUND: Prostate-specific antigen (PSA) levels should reflect or be proportional to the size and the metabolic activity of prostatic metastases. Moreover, a rapid change in PSA kinetics, either before or after treatment, is an indicator of poor prognosis after radical prostatectomy. Therefore, the purpose of this study was to investigate the effect of total PSA at the time of Tc-99m HYNIC PSMA SPECT/CT (trigger PSA), PSA velocity (PSAvel), and PSA doubling time (PSAdt) on the Tc-99m HYNIC PSMA SPECT/CT detection rate in prostate cancer patients who showed biochemical recurrence after radical prostatectomy during follow-up. METHODS: In total, 208 patients who showed an increase in PSA were evaluable for this retrospective analysis covering November 2015 to March 2017. Data were available for calculation of PSAvel in 112 patients and for PSAdt in 157 patients. Logistic regression analysis was used to determine whether there was a relationship between the PSA levels and PSA kinetics and the rate of detection of relapse using Tc-99m HYNIC PSMA SPECT/CT. RESULTS: Tc-99m HYNIC PSMA SPECT/CT detected disease relapse in 151 of 208 patients (72.6%). The PSA level (P < 0.0001) and PSAdt (P = 0.0036) were significantly different between SPECT-positive patients (higher PSA level, shorter PSAdt) and SPECT-negative patients (lower PSA, longer PSAdt). ROC analysis showed that a PSA level of 1.30 ng/mL and a PSAdt of 2.9 months were optimal cut-off values. Patients with purely local recurrence had lower PSAvel and longer PSAdt values (P < 0.001). According to the multivariate analysis, a pathological positive SPECT/CT scan was associated with the PSA level (P < 0.001), PSAdt <6 months (P < 0.05), and Gleason scores (GSC) >7 (P < 0.05). CONCLUSION: The Tc-99m HYNIC PSMA SPECT/CT detection rate is influenced by trigger PSA, PSAdt, and PSAvel. Like PSA, PSAdt is an independent predictor of Tc-99m HYNIC PSMA SPECT/CT. PSAdt should be taken into account by physicians especially when PSA <1 ng/mL.

Differentiation of cancer of unknown primary and lymphoma in head and neck metastatic poorly differentiated cancer using 18 F-FDG PET/CT tumor metabolic heterogeneity index.

OBJECTIVE: To explore the value of 18 F-FDG PET/CT tumor metabolic heterogeneity index (HI) and establish and validate a nomogram model for distinguishing head and neck cancer of unknown primary (HNCUP) from lymphoma with head and neck metastatic poorly differentiated cancer. METHODS: This retrospective analysis was conducted on 1242 patients with cervical metastatic poorly differentiated cancer. 108 patients, who were clinically and pathologically confirmed as HNCUP or lymphoma, were finally enrolled. Two independent sample t-tests and χ 2 test were used to compare the clinical and imaging features. Binary logistic regression was used to screen for independent predictive factors. RESULTS: Among the 108 patients), 65 patients were diagnosed with HNCUP and 43 were lymphoma. Gender ( P  = 0.001), SUV max ( P  < 0.001), SUV mean ( P  < 0.001), TLG ( P  = 0.012), and HI ( P  < 0.001) had statistical significance in distinguishing HNCUP and lymphoma. Female ( OR  = 4.546, P  = 0.003) and patients with HI ≥ 2.37 ( OR  = 3.461, P  = 0.047) were more likely to be diagnosed as lymphoma. CONCLUSION: For patients with cervical metastatic poorly differentiated cancer, gender and HI were independent predictors of pathological type. For such patients, clinical attention should be paid to avoid misdiagnosing lymphoma as HNCUP, which may delay treatment.

Imaging of Tumor Stroma Using 68Ga-FAPI PET/CT to Improve Diagnostic Accuracy of Primary Tumors in Head and Neck Cancer of Unknown Primary: A Comparative Imaging Trial.

The low detection rate of primary tumors by current diagnostic techniques remains a major concern for patients with head and neck cancer of unknown primary (HNCUP). Therefore, in this study, we aimed to investigate the potential role of 68Ga-labeled fibroblast activation protein inhibitor (68Ga-FAPI) PET/CT compared with 18F-FDG PET/CT for the detection of primary tumors of HNCUP. Methods: In this prospective comparative imaging trial conducted at Fudan University Shanghai Cancer Center, 91 patients with negative or equivocal findings of a primary tumor by comprehensive clinical examination and conventional imaging were enrolled from June 2020 to September 2022. The presence of a primary tumor was recorded by 3 experienced nuclear medicine physicians. Primary lesions were validated by histopathologic analysis and a composite reference standard. Results: Of the 91 patients (18 women, 73 men; median age, 60 y; age range, 24-76 y), primary tumors were detected in 46 (51%) patients after a thorough diagnostic work-up. 68Ga-FAPI PET/CT detected more primary lesions than 18F-FDG PET/CT (46 vs. 17, P < 0.001) and showed better sensitivity, positive predictive value, and accuracy in locating primary tumors (51% vs. 25%, 98% vs. 43%, and 51% vs. 19%, respectively). Furthermore, 68Ga-FAPI PET/CT led to treatment changes in 22 of 91 (24%) patients compared with 18F-FDG PET/CT. The Kaplan-Meier curve illustrated that patients with unidentified primary tumors had a significantly worse prognosis than patients with identified primary tumors (hazard ratio, 5.77; 95% CI, 1.86-17.94; P = 0.0097). Conclusion: 68Ga-FAPI PET/CT outperforms 18F-FDG PET/CT in detecting primary lesions and could serve as a sensitive, reliable, and reproducible imaging modality for HNCUP patients.

Dosimetry estimation and preliminary clinical application of [99mTc]Tc-HYNIC-PSMA-XL-2 in prostate cancer.

OBJECTIVE: Molecular imaging of prostate-specific membrane antigen (PSMA) inhibitors has become a favorite for prostate cancer (PCa). This study aimed to estimate the dosimetry and the preliminary clinical application of the [99mTc]Tc-HYNIC-PSMA-XL-2, which is a novel imaging tracer invented by our team that can specifically targets PSMA for PCa and its metastases. METHODS: The single-photon emission computed tomography (SPECT) whole-body (WB) planar images were collected on 6 patients at 0.5, 1.0, 2.0, 4.0 and 8.0 h after 99mTc-PSMA-XL-2 injection, respectively. The SPECT/computed tomography (CT) scan was carried out immediately following the WB planar image scan performed after 2.0 h. The volumes of interest (VOIs) of the bladder, heart wall, intestines, kidneys, liver, lungs, and spleen were segmented in the SPECT/CT images. VOIs of the salivary glands and the whole body were drawn in SPECT planar images. The dosimetry toolkit was used to process the data and project the SPECT/CT images onto planar images. The dosimetry analysis was performed using the IDAC-Dose dosimetry software. Furthermore, other PCa patients were enrolled to study the preliminary clinical application of [99mTc]Tc-HYNIC-PSMA-XL-2. RESULTS: The clearance of [99mTc]Tc-HYNIC-PSMA-XL-2 is primarily by the hepatobiliary and intestinal system, due to its lipophilic characteristic. The effective half-life of [99mTc]Tc-HYNIC-PSMA-XL-2 is about 3.90 h. High absorbed doses were observed in the salivary glands (1.93E-02 ± 3.88E-03 mSv/MBq), kidneys (1.63E-02 ± 7.32E-03 mSv/MBq) and spleen (1.21E-02 ± 2.64E-03 mSv/MBq). The total body effective dose was 4.84E-03 ± 9.30E-05 mSv/MBq. The preliminary clinical case indicated that [99mTc]Tc-HYNIC-PSMA-XL-2 SPECT/CT could detect the primary prostate lesion, lymph node and bone metastases comprehensively. CONCLUSION: [99mTc]Tc-HYNIC-PSMA-XL-2 is a safe SPECT/CT tracer, which can detect prostate malignant lesions without interference from the bladder. In addition, the malignant lesions of the lymph node and bone of PCa patients also can be detected efficiently.

Calcified metastases from ovarian carcinoma highlighted by F-18 FDG PET/CT: report of two cases.

Two cases of postoperative female patients with ovarian serous papillary carcinoma were referred for F-18 Fluorodeoxyglucose (F-18 FDG) PET/CT to evaluate suspicious recurrence and/or metastasis. One patient presented with multiple extensive calcified lesions with increased FDG uptake in the abdominopelvic cavity and the series of PET/CT scans showed progression of disease after chemotherapy. The other patient presented with three calcified masses with intensive uptake of FDG located in the left pelvis, the right subphrenic region, and the right supradiaphragmatic area, respectively. These suggest that F-18 FDG PET/CT can be useful in identifying malignant calcification and assessing therapeutic response of calcified malignancy.

Clinical value of whole body fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of metastatic bladder cancer.

OBJECTIVES: To investigate the value of whole-body fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography for the detection of metastatic bladder cancer. METHODS: From December 2006 to August 2010, 60 bladder cancer patients (median age 60.5 years old, range 32-96) underwent whole body positron emission tomography/computed tomography positron emission tomography/computed tomography. The diagnostic accuracy was assessed by performing both organ-based and patient-based analyses. Identified lesions were further studied by biopsy or clinically followed for at least 6 months. RESULTS: One hundred and thirty-four suspicious lesions were identified. Among them, 4 primary cancers (2 pancreatic cancers, 1 colonic and 1 nasopharyngeal cancer) were incidentally detected, and the patients could be treated on time. For the remaining 130 lesions, positron emission tomography/computed tomography detected 118 true positive lesions (sensitivity = 95.9%). On the patient-based analysis, the overall sensitivity and specificity resulted to be 87.1% and 89.7%, respectively. There was no difference of sensitivity and specificity in patients with or without adjuvant treatment in terms of detection of metastatic sites by positron emission tomography/computed tomography. Compared with conventional imaging modality, positron emission tomography/computed tomography correctly changed the management in 15 patients (25.0%). CONCLUSIONS: Positron emission tomography/computed tomography has excellent sensitivity and specificity in the detection of metastatic bladder cancer and it provides additional diagnostic information compared to standard imaging techniques.

Case Report: Molecular Profiling Assists in the Diagnosis and Treatment of Cancer of Unknown Primary.

Background: For cancer of unknown primary (CUP), non-selective empiric chemotherapy is usually used. However, patients suffering from CUP are generally assumed to have a dismal prognosis with median overall survival of less than 1 year. Therefore, clinicians eagerly await the establishment of effective strategies for diagnosis and treatment. In recent years, the remarkable advances in next-generation sequencing (NGS) technology have enabled the wide usage of DNA/RNA sequencing to comprehensively analyze the molecular information of individual tumors and identify potential targets for patients' diagnosis and treatment. Here, we describe a patient of CUP who was successfully diagnosed and treated with targeted therapy directed by comprehensive molecular profiling. Case Presentation: A 61-year-old Asian woman with a painless, slow-growing mass lesion in the mesosternum underwent fluorodeoxyglucose-positron emission tomography/computed tomography and was found to have malignant metastatic tumors in the mesosternum. Conventional pathological examination of metastatic lesions could not conclude the primary origin of the tumors. The patient was diagnosed with CUP at first. Then, comprehensive molecular profiling was employed to identify the tumor origin and genetic alterations. A gene expression-based tissue origin assay was performed using a tissue biopsy sample. The test result suggested that the lesion tumors might be breast cancer metastasis. Furthermore, liquid biopsy-based circulating tumor DNA profiling detected an ERBB2 copy number amplification. Subsequent surgery and additional postoperative pathology analysis confirmed that the primary tumor site was indeed located in the right outer upper quadrant of the breast. After local surgical resection, the patient received 8 cycles of Docetaxel + Carboplatin + Trastuzumab + Pertuzumab (TCbHP) chemotherapy with subsequent human epidermal growth factor receptor 2 (HER2)-targeted maintenance therapy. Currently, the patient is on regular follow-up and has achieved disease control for up to 6 months. Conclusion: Our findings suggest that molecular identification of the tumor origin and the detection of actionable molecular alterations may offer promise for improved diagnostic accuracy and important therapeutic implications for patients with the CUP syndrome.

The Added Value of 68Ga-FAPI PET/CT in Patients with Head and Neck Cancer of Unknown Primary with 18F-FDG-Negative Findings.

18F-FDG PET/CT plays an important role in locating the primary tumor for patients with head and neck cancer of unknown primary (HNCUP). Nevertheless, in some cases it can be challenging to locate the primary malignancy on 18F-FDG PET/CT scans. Because 68Ga-radiolabeled fibroblast activation protein inhibitor (FAPI) PET/CT has promising results in detecting different tumor entities, our study aimed to evaluate the performance of 68Ga-FAPI PET/CT for detecting the primary tumor in HNCUP patients with negative 18F-FDG findings. Methods: Eighteen patients (16 men and 2 women; median age, 55 y; age range, 24-72 y) with negative 18F-FDG findings were enrolled in this study. All patients underwent 18F-FDG and 68Ga-FAPI PET/CT within 1 wk. Biopsy and histopathologic examinations were performed in the sites with positive 68Ga-FAPI PET/CT findings. Results:68Ga-FAPI PET/CT detected the primary tumor in 7 of 18 patients (38.89%). Among these 7 patients, primary tumor sites included the nasopharynx (n = 1), palatine tonsil (n = 2), submandibular gland (n = 2), and hypopharynx (n = 2). The primary tumors showed moderate to intensive uptake of 68Ga-FAPI (mean SUVmax, 8.79; range, 2.60-16.50) and excellent tumor-to-contralateral normal-tissue ratio (mean SUVmax ratio, 4.50; range, 2.17-8.21). In lesion-based analysis, 65 lymph nodes and 17 bone metastatic lesions were identified. The mean SUVmax of lymph node metastases was 9.05 ± 5.29 for 18F-FDG and 9.08 ± 4.69 for 68Ga-FAPI (P = 0.975); the mean SUVmax of bone metastases was 8.11 ± 3.00 for 18F-FDG and 6.96 ± 5.87 for 68Ga-FAPI (P = 0.478). The mean tumor-to-background ratios of lymph node and bone metastases were 10.65 ± 6.59 versus 12.80 ± 8.11 (P = 0.100) and 9.08 ± 3.35 versus 9.14 ± 8.40 (P = 0.976), respectively. Conclusion: We present the first evidence, to our knowledge, of a diagnostic role of 68Ga-FAPI PET/CT in HNCUP. Our study demonstrated that 68Ga-FAPI PET/CT has the potential to improve the detection rate of primary tumor in HNCUP patients with negative 18F-FDG findings. Moreover, 68Ga-FAPI had a performance in assessing metastases similar to that of 18F-FDG.

Combination of 99mTc-Labeled PSMA-SPECT/CT and Diffusion-Weighted MRI in the Prediction of Early Response After Carbon Ion Therapy in Prostate Cancer: A Non-Randomized Prospective Pilot Study.

PURPOSE: The purpose of this study was to assess the potential of 99mTc-labeled PSMA-SPECT/CT and diffusion-weighted image (DWI) for predicting treatment response after carbon ion radiotherapy (CIRT) in prostate cancer. PATIENTS AND METHODS: We prospectively registered 26 patients with localized prostate cancer treated with CIRT. All patients underwent 99mTc-labeled PSMA-SPECT/CT and multiparametric magnetic resonance imaging (MRI) before and after CIRT. The tumor/background ratio (TBR) and mean apparent diffusion coefficient (ADCmean) were measured on the tumor and the percentage changes before and after therapy (ΔTBR and ΔADCmean) were calculated. Patients were divided into two groups: good response and poor response according to clinical follow-up. RESULTS: The median follow up time was 38.3months. The TBR was significantly decreased (p=0.001), while the ADCmean was significantly increased compared with the pretreatment value (p<0.001). The ΔTBR and ΔADCmean were negatively correlated with each other (p = 0.002). On ROC curve analysis for predicting treatment response, the area under the ROC curve (AUC) of ΔTBR (0.867) for predicting good response was higher than that of ΔADCmean (0.819). The AUC of combined with ΔTBR and ΔADCmean (0.895) was higher than that of either ΔADCmean or ΔTBR alone. The combined use of ΔTBR and ΔADCmean showed 91.4% sensitivity and 95.2% specificity. CONCLUSION: Our preliminary data indicate that the changes of TBR and ADCmean maybe an early bio-marker for predicting prognosis after CIRT in localized prostate cancer patients. In addition, the ΔTBR seems to be a more powerful prognostic factor than ΔADCmean in prostate cancer treated with CIRT.

Author Correction: Evaluation of Radiation dosimetry of 99mTc-HYNIC-PSMA and imaging in prostate cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evaluation of Radiation dosimetry of 99mTc-HYNIC-PSMA and imaging in prostate cancer.

This study aims to evaluate the radiation dosimetry of a new technetium-99m‒labelled small-molecule inhibitor of prostate-specific membrane antigen (HYNIC-Glu-Urea-A, 99mTc-HYNIC-PSMA) and its feasibility as a tumor-imaging agent in prostate cancer (PCa) patients. A total of 15 PCa patients were enrolled in this study. For the dosimetry study, 5 PCa patients received whole-body planar scans at 0.5 h, 1 h, 2 h, 4 h and 8 h after 99mTc-HYNIC-PSMA injection. The Dosimetry Toolkit (GE, Milwaukee) was used to process the data and segment the organs in the SPECT/CT images, which were then projected onto planar images. The organ-specific absorbed doses, total-body absorbed doses and 99mTc-HYNIC-PSMA effective doses of patients were calculated using OLINDA/EXM 1.1 software. Whole-body SPECT/CT images were also acquired from additional 10 prostate patients to investigate the feasibility of 99mTc-HYNIC-PSMA for imaging tumors by calculating the ratio of tumor-to-background tracer uptake at 2 h after 740 MBq administration. The total-body absorbed dose was 1.54E-03 ± 2.43E-04 mGy/MBq, and the effective dose was 3.72E-03 ± 4.5E-04 mSv/MBq. Compared to published studies of other similar PSMA tracers and 99mTc-targeted conventional tracers, the absorbed doses of 99mTc-HYNIC-PSMA in all organs showed that it could be used safely in the human body. In addition, 99mTc-HYNIC-PSMA showed high tracer uptake (with a tumor-to-background ratio of 9.42 ± 2.62) in the malignant lesions of PCa patients, making it a promising radiopharmaceutical imaging method for site-specific management of PCa.

Preliminary results of targeted prostate-specific membrane antigen imaging in evaluating the efficacy of a novel hormone agent in metastatic castration-resistant prostate cancer.

To investigate the feasibility and effectiveness of prostate-specific membrane antigen (PSMA) imaging to make response assessment regarding novel hormone treatment and to predict the outcomes for metastatic castration-resistant prostate cancer (mCRPC) patients. This retrospective study enrolled 68 mCRPC patients who had daily received a novel hormone agent named abiraterone. Tc-99m PSMA single-photon emission computed tomography (SPECT/CT) was performed at the baseline (SPECT/CT1) and after 3-6 months of treatment (SPECT/CT2). The treatment response was determined by visual analysis based on molecular imaging PSMA (miPSMA) scores framework and was compared with conventional biochemical analysis. We chose either the hottest lesion (target A) or five of the hottest lesions (target B) to calculate the tumor/background ratio (TBR) and the maximum standardized uptake value (SUVmax) and compared their performances in predicting progression-free survival (PFS). Changes in PSMA expression between SPECT/CT1 and SPECT/CT2 were well associated with the results of the visual analysis. The TBR and the SUVmax of both targets were significantly associated with the baseline serum PSA level (P < .0001). The biochemical and radiological responses were concordant in 56 of the 68 patients (P < .001). The median PFS of the nonresponse group patients was significantly shorter than that of the patients in the response group (6.8 vs 12.1 months, P = .012). For predicting PFS, most of the indexes tested were significant on SPECT/CT2, with %ΔTBR being the most significant prognostic factor. Our preliminary results suggest that molecular imaging-targeted PSMA is of great value for treatment response assessment and clinical outcome prediction in mCRPC patients with long-term abiraterone treatment.

A Prospective Trial of 68Ga-PSMA and 18F-FDG PET/CT in Nonmetastatic Prostate Cancer Patients with an Early PSA Progression During Castration.

PURPOSE: Tumor heterogeneity and burden, which impact treatment outcome in prostate cancer, are rarely evaluated using next-generation imaging. EXPERIMENTAL DESIGN: The trial prospectively included 37 patients who had an early PSA progression (≤2 ng/mL) during castration and high-risk (PSA doubling time ≤10 months) nonmetastatic disease by conventional imaging. All patients underwent both 68Ga-PSMA and 18F-FDG PET/CT. Lesions were classified into PSMA+FDG± lesions and PSMA-FDG+ lesions. The primary endpoint was the prevalence of PSMA-FDG+ disease. Tumor burden, predictors for positive imaging, and suitability for oligometastases-directed therapy (OMDT) were also evaluated. RESULTS: All patients were treated with RP and the median duration of castration was 23 months. The median PSA at imaging was 0.57 ng/mL. Overall, 114 lesions were detected in 29 of the 37 patients. A high prevalence (73%) of N+/M+ disease was observed. Of the 114 lesions, 81 were PSMA+FDG± and 33 were PSMA-FDG+. Per patient level, 9 men (24%; 95% confidence interval: 10%-39%) showed at least one new PSMA-FDG+ lesions. A short PSA doubling time (P = 0.009, OR = 8.000) was associated with PSMA+FDG± disease, while a high Gleason grade group (P = 0.022, OR = 13.091) with PSMA-FDG+ disease. Nineteen patients (51%) with 51 lesions, including 10 PSMA-FDG+ lesions, could be enrolled for OMDT. Among different disease stages, PSMA-FDG+ disease was rarely detected in the hormone-sensitive cohort, but frequently found in the castration-resistant cohort. CONCLUSIONS: Using 68Ga-PSMA and 18F-FDG PET, we observed a high prevalence of N+/M+ disease and a significant proportion of PSMA-FDG+ disease in patients with an early PSA progression during castration (ChiCTR1900022634).

The significant value of predicting prognosis in patients with colorectal cancer using 18F-FDG PET metabolic parameters of primary tumors and hematological parameters.

OBJECTS: The purpose was to evaluate the correlation of the pre-treatment hematological parameters with metabolic parameters of primary tumor in baseline 18F-FDG PET/CT in patients with colorectal cancer (CRC) and estimate the prognostic value of both. METHODS: We retrospectively investigated 231 patients with CRC who underwent baseline 18F-FDG PET/CT. Routine blood sampling was tested in the same term. PET parameters in term of hematological parameters and pathological characteristics of primary tumor were compared. Kaplan-Meier survival analysis was performed in the patients without distant metastasis. The differences of disease-free survival between groups were compared by log-rank tests. RESULTS: Neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) were significantly correlated with all the metabolic parameters including maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and tumor lesion glycolysis (TLG). The patients with NLR > 3 had higher MTV (24.82 ± 18.16 vs 19.06 ± 13.30, P = 0.039) and TLG (219.04 ± 186.94 vs 166.45 ± 146.39, P = 0.047) than those whose NLR ≤ 3. NLR in those patients with distant metastasis was significantly higher than those without distant metastasis (P = 0.018) while LMR in those patients with distant metastasis was significantly lower than those without distant metastasis (P = 0.032). Survival analysis showed that those patients with low MTV (P = 0.015), low NLR (P = 0.008) and high LMR (P = 0.027) revealed significant survival benefit. CONCLUSIONS: There was a significant association between the pre-treatment hematological parameters and metabolic parameters of baseline 18F-FDG PET/CT in the patients with CRC. It might be helpful in those patients with high NLR and low LMR to undergo 18F-FDG PET/CT to detect distant metastasis and predict prognosis.