Papillary thyroid carcinoma tall cell variant shares accumulation of mitochondria, mitochondrial DNA mutations, and loss of oxidative phosphorylation complex I integrity with oncocytic tumors.

Papillary thyroid carcinoma tall cell variant (PTC-TCV), a form of PTC regarded as an aggressive subtype, shares several morphologic features with oncocytic tumors. Pathogenic homoplasmic/highly heteroplasmic somatic mitochondrial DNA (mtDNA) mutations, usually affecting oxidative phosphorylation (OXPHOS) complex I subunits, are hallmarks of oncocytic cells. To clarify the relationship between PTC-TCV and oncocytic thyroid tumors, 17 PTC-TCV and 16 PTC non-TCV controls (cPTC) were subjected to: (1) transmission electron microscopy (TEM) to assess mitochondria accumulation, (2) next-generation sequencing to analyze mtDNA and nuclear genes frequently mutated in thyroid carcinoma, and (3) immunohistochemistry (IHC) for prohibitin and complex I subunit NDUFS4 to evaluate OXPHOS integrity. TEM showed replacement of cytoplasm by mitochondria in PTC-TCV but not in cPTC cells. All 17 PTC-TCV had at least one mtDNA mutation, totaling 21 mutations; 3/16 cPTC (19%) had mtDNA mutations (p < 0.001). PTC-TCV mtDNA mutations were homoplasmic/highly heteroplasmic, 16/21 (76%) mapping within mtDNA-encoded complex I subunits. MtDNA mutations in cPTC were homoplasmic in 2 cases and at low heteroplasmy in the third case, 2/3 mapping to mtDNA-encoded complex I subunits; 2/3 cPTC with mtDNA mutations had small tall cell subpopulations. PTC-TCV showed strong prohibitin expression and cPTC low-level expression, consistent with massive and limited mitochondrial content, respectively. All 17 PTC-TCV showed NDUFS4 loss (partial or complete) and 3 of 16 cPTC (19%) had (partial) NDUFS4 loss, consistent with lack of complex I integrity in PTC-TCV (p < 0.001). IHC loss of NDUFS4 was associated with mtDNA mutations (p < 0.001). Four BRAF V600E mutated PTCs had loss of NDUSF4 expression limited to neoplastic cell subpopulations with tall cell features, indicating that PTCs first acquire BRAF V600E and then mtDNA mutations. Similar to oncocytic thyroid tumors, PTC-TCV is characterized by mtDNA mutations, massive accumulation of mitochondria, and loss of OXPHOS integrity. IHC loss of NDUFS-4 can be used as a surrogate marker for OXPHOS disruption and to reliably diagnose PTC-TCV.

The influence of breast cancer subtypes on axillary ultrasound accuracy: A retrospective single center analysis of 583 women.

INTRODUCTION: Axillary ultrasound staging (AUS) is an important tool to guide clinical decisions in breast cancer therapy, especially regarding axillary surgery but also radiation therapy. It is unknown whether biological subtypes influence axillary staging using ultrasound (AUS). METHOD: This is a retrospective single center analysis. All patients with breast cancer, a preoperative axillary ultrasound and a complete surgical axillary staging were included between 1999 and 2014, except patients with neoadjuvant chemotherapy (NACT). The results of the AUS were compared with final pathological results. Biological subtypes were identified by immunohistochemistry. RESULTS: 583 women were included in the study. Sensitivity, Specificity, positive and negative predictive value for AUS were 39%, 96%, 91% and 83%. While sensitivity was significantly lower in Luminal A and B patients (25.0%; 39.8%) as compared to non Luminal breast cancer patients (TN 68.8%; Her2+ 71.4%; p = 0.0032), there were no significant differences between the groups with respect to specificity, PPV and NPV. CONCLUSION: Solely regarding sensitivity of AUS, our study could show significant differences between biological subtypes of breast cancer with lower sensitivity in Luminal patients. While PPV was excellent, standing for a low overtreatment rate using AUS for clinical decision making, sensitivity was poor overall, comparable to the results of other studies.

Positron emission tomography/computed tomography with F-18-fluorocholine for restaging of prostate cancer patients: meaningful at PSA < 5 ng/ml?

UNLABELLED: According to reports, re-staging of patients suffering from prostate cancer by positron emission tomography (PET) using C-11-choline has failed to produce positive findings at a PSA level of < 5 ng/ml. Hence, the purpose of our study has been to determine whether this is true also for PET/CT using F-18-fluorocholine (FCH PET/CT) or whether it is possible to obtain true positive results by FCH PET/CT even at lower PSA levels. METHODS: In 34 patients with prostate cancer who had undergone initial therapy (radical prostatectomy n = 31, radiotherapy n = 3), a PET/CT scan was performed using F-18-fluorocholine (FCH) during follow-up in case of demonstrable or rising PSA levels. Current PSA levels were determined in all patients at the time of examination. RESULTS: Median PSA in FCH positive patients was 6.1 ng/ml (mean PSA 17.1 ng/ml), median PSA in FCH negative patients was 2.3 ng/ml (mean PSA 3.4 ng/ml), respectively (p < 0.05). In eight of 17 examinations (47%) with PSA < 5 ng/ml, at least one FCH-positive focus was detected. So far the findings could be confirmed by correlating imaging methods (CT and/or MR), biopsy/histology and the course of the disease, respectively, in seven of the eight FCH-positive cases with PSA < 5 ng/ml, so that a true positive FCH PET/CT finding was obtained all in all in seven of 17 (41%) examinations with PSA < 5 ng/ml. In four of these seven FCH PET-positive patients with PSA < 5 ng/ml, adjuvant hormonal therapy was administered at the time of the examination or prior to the examination. CONCLUSION: In re-staging patients with prostate cancer, FCH PET/CT is able to yield true positive findings even at PSA < 5 ng/ml. Therefore, FCH PET/CT should not be restricted to patients with PSA > 5 ng/ml.

BAY 1075553 PET-CT for Staging and Restaging Prostate Cancer Patients: Comparison with [18F] Fluorocholine PET-CT (Phase I Study).

PURPOSE: (2RS,4S)-2-[(18)F]Fluoro-4-phosphonomethyl-pentanedioic acid (BAY1075553) shows increased uptake in prostate cancer cells. We compared the diagnostic potential of positron emission tomography (PET)-X-ray computed tomography (CT) imaging using BAY1075553 versus [(18)F]f luorocholine (FCH) PET-CT. PROCEDURES: Twelve prostate cancer patients (nine staging, three re-staging) were included. The mean prostate-specific antigen in the primary staging and re-staging groups was 21.5 ± 12 and 73.6 ± 33 ng/ml, respectively. Gleason score ranged from 5-9. In nine patients imaged for pre-operative staging, the median Gleason score was 8 (range, 7-9). PET acquisition started with dynamic PET images in the pelvic region followed by static whole-body acquisition. The patients were monitored for 5-8 days afterward for adverse events. RESULTS: There were no relevant changes in laboratory values or physical examination. Urinary bladder wall received the largest dose equivalent 0.12 mSv/MBq. The whole-body mean effective dose was 0.015 mSv/MBq. There was a significant correlation between detected prostatic lesions by the two imaging modalities (Kappa = 0.356, P < 0.001) and no significant difference in sensitivity (P = 0.16) and specificity (P = 0.41). The sensitivity and specificity of PET imaging using BAY1075553 for lymph node (LN) staging was 42.9 % and 100 %, while it was 81.2 % and 50 % using FCH. The two modalities were closely correlated regarding detection of LNs and bone metastases, although BAY1075553 failed to detect a bone marrow metastasis. Degenerative bone lesions often displayed intense uptake of BAY1075553. CONCLUSIONS: BAY1075553 PET-CT produced no adverse effects, was well tolerated, and detected primary and metastatic prostate cancer. FCH PET-CT results were superior, however, with respect to detecting LN and bone marrow metastases.

Positioning irrigation of contrast cystography for diagnosis of occult vesicoureteric reflux: association with technetium-99m dimercaptosuccinic acid scans.

OBJECTIVE: Positioning irrigation of contrast (PIC) cystography identifies occult or PIC vesicoureteral reflux (PIC-VUR) in children with recurrent febrile urinary tract infections (UTI) but no vesicoureteric reflux (VUR) on standard voiding cystourethrogram (VCUG). We sought to identify the relationship between PIC-VUR and renal scarring in technetium-99m dimercaptosuccinic acid (DMSA) scans. PATIENTS AND METHODS: We retrospectively analysed PIC cystograms and DMSA scans for 154 kidneys in 81 children (65 girls; 16 boys; median age, 4.7 years; range, 0.9-15.2). Renal scarring was graded on a scale of 0-3. DMSA scans were pathologic in 66 patients (81%). Children had experienced mean 3.8 febrile UTI (range 1-25). Forty-seven (58%) children had a history of reflux, including 15 (19%) with previous anti-reflux operations. Indications for PIC cystography were recurrence of febrile UTI after either bilateral negative VCUG (66 children) or unilateral VUR (15 children) with contralateral/bilateral scarring or reflux that had changed sides in subsequent VCUGs. RESULTS: PIC-VUR was bilateral in 63, unilateral in 12, and absent in 6 children. Statistically significant associations between PIC-VUR grade and severity of renal scarring were identified in inter-individual (n = 77, p = 0.017) and intra-individual (refluxing vs. nonrefluxing kidney; n = 12, p = 0.008) analyses. After excluding patients with history of VUR, statistical significance was maintained in inter-individual analysis (n = 49; p = 0.018). CONCLUSION: The data suggest an association between PIC-VUR and severity of renal scarring, and legitimise the use of PIC cystography in children with renal scarring due to recurrent febrile UTI but negative findings on VCUG.

Impact of 18F-choline PET/CT in prostate cancer patients with biochemical recurrence: influence of androgen deprivation therapy and correlation with PSA kinetics.

UNLABELLED: We evaluated the potential of (18)F-fluoromethyldimethyl-2-hydroxyethyl-ammonium (FCH) PET/CT in the detection of recurrent disease or distant metastases and correlated its diagnostic accuracy with prostate-specific antigen (PSA) levels in prostate cancer patients with biochemical evidence of recurrence. Furthermore, the influences of androgen deprivation therapy (ADT) and its duration on (18)F-FCH PET were assessed in this study. METHODS: This prospective study included 250 prostate cancer patients with PSA relapse who underwent (18)F-FCH PET/CT. At the time of (18)F-FCH PET/CT imaging, the mean PSA level was 46.9 ± 314.7 ng/mL and 55.2% (138/250) of patients were receiving ADT. Overall, ADT was performed on 67.2% (168/250) of patients after initial treatment. Imaging was performed on an integrated PET/CT system. Acquisition started 1 min after intravenous injection of (18)F-FCH (4.07 MBq/kg of body weight) with dynamic PET images in the pelvic region during 8 min (1 min/frame) followed by a static semi-whole-body acquisition. The final diagnosis of positive PET lesions was based on histopathology or a consensus of clinical findings, additional imaging, or follow-up imaging modalities. RESULTS: (18)F-FCH PET/CT was able to correctly detect malignant lesions in 74% (185/250) of patients but was negative in 26% (65/250). In 28% of patients, only 1 lesion was detected (69/250); from these, 65.2% (45 patients) had a local recurrence, 18.8% (13 patients) a single lymph node, and 15.9% (11 patients) a solitary bone metastasis. The sensitivity of the (18)F-FCH PET was significantly higher (P = 0.001) in patients with ongoing ADT (85%; confidence interval, 80%-91%) than in patients without ADT (59.5%; confidence interval, 50%-69%). (18)F-FCH PET sensitivity was 77.5%, 80.7%, 85.2%, and 92.8% for the trigger PSA levels of more than 0.5, 1.0, 2.0, and 4.0 ng/mL, respectively. Scan sensitivity was 33% in patients with a trigger PSA level of less than 0.3 ng/mL and 77% in patients with a trigger PSA level of greater than 0.3 ng/mL, respectively (P = 0.001). Using a binary logistic regression analysis model, we showed trigger PSA and ADT to be the only significant predictors of positive PET findings. CONCLUSION: (18)F-FCH PET/CT proved its potential as a noninvasive 1-stop diagnostic modality enabling us to correctly detect occult disease in 74% of patients and to differentiate localized from systemic disease. In patients with biochemical recurrence, it also guides to an optimal treatment approach after initial treatment. Trigger PSA and ADT are the 2 significant predictors of (18)F-FCH-positive PET lesions. ADT seems not to impair (18)F-FCH uptake in hormone-refractory prostate cancer patients.