Hyperprogressive disease during PD-1/PD-L1 blockade in patients with non-small-cell lung cancer.

BACKGROUND: Immune checkpoint blockade with Programmed cell death 1 (PD-1)/PD-L1 inhibitors has been effective in various malignancies and is considered as a standard treatment modality for patients with non-small-cell lung cancer (NSCLC). However, emerging evidence show that PD-1/PD-L1 blockade can lead to hyperprogressive disease (HPD), a flair-up of tumor growth linked to dismal prognosis. This study aimed to evaluate the incidence of HPD and identify the determinants associated with HPD in patients with NSCLC treated with PD-1/PD-L1 blockade. PATIENTS AND METHODS: We enrolled patients with recurrent and/or metastatic NSCLC treated with PD-1/PD-L1 inhibitors between April 2014 and November 2018. Clinicopathologic variables, dynamics of tumor growth, and treatment outcomes were analyzed in patients with NSCLC who received PD-1/PD-L1 blockade. HPD was defined according to tumor growth kinetics (TGK), tumor growth rate (TGR), and time to treatment failure (TTF). Immunophenotyping of peripheral blood CD8+ T lymphocytes was conducted to explore the potential predictive biomarkers of HPD. RESULTS: A total of 263 patients were analyzed. HPD was observed in 55 (20.9%), 54 (20.5%), and 98 (37.3%) patients according to the TGK, TGR, and TTF. HPD meeting both TGK and TGR criteria was associated with worse progression-free survival [hazard ratio (HR) 4.619; 95% confidence interval (CI) 2.868-7.440] and overall survival (HR, 5.079; 95% CI, 3.136-8.226) than progressive disease without HPD. There were no clinicopathologic variables specific for HPD. In the exploratory biomarker analysis with peripheral blood CD8+ T lymphocytes, a lower frequency of effector/memory subsets (CCR7-CD45RA- T cells among the total CD8+ T cells) and a higher frequency of severely exhausted populations (TIGIT+ T cells among PD-1+CD8+ T cells) were associated with HPD and inferior survival rate. CONCLUSION: HPD is common in NSCLC patients treated with PD-1/PD-L1 inhibitors. Biomarkers derived from rationally designed analysis may successfully predict HPD and worse outcomes, meriting further investigation of HPD.

Distant metastatic lesions in patients with differentiated thyroid carcinoma. Clinical implications of radioiodine and FDG uptake.

AIM: Many investigators have reported an inverse relationship between iodine and glucose utilization of differentiated thyroid carcinoma (DTC) according to its degree of differentiation; however, not every DTC is compatible with this phenomenon. This study was conducted to evaluate the clinical implication of iodine and glucose uptake at distant metastatic lesions in DTC patients. PATIENTS, METHODS: 64 DTC patients (women 47; mean age 49.9 ± 16.4 years) with distant metastasis who underwent post (131)I treatment whole-body scan (RxWBS) and FDG PET/CT were included in the study. Radioiodine (RAI) and FDG uptake of metastatic lesions were evaluated. TSH stimulated serum thyroglobulin (s-Tg) were obtained. RESULTS: 53 of 64 patients (82.8%) were RAI(+) group, and 37 patients (57.8%) were FDG(+) group. Patients in the RAI(-) group showed a higher rate of FDG uptake than RAI(+) group (100.0% vs. 49.1%, p = 0.002). Patients in the FDG(-) group showed a higher rate of RAI uptake than FDG(+) group (100.0% vs. 70.3%, p = 0.002). Patients with s-Tg < 100 ng/ml were frequently observed in the FDG(-)/RAI(+) group and the FDG(+)/RAI(-) group (p = 0.023). And patients with s-Tg ≥ 500 ng/ml were more frequently observed in the FDG(+)/RAI(+) group, compared with the FDG(+)/RAI(-) group (p = 0.036). Reduced disease-specific survival (DSS) was observed in patients with RAI(-) (p = 0.003), FDG(+) (p = 0.006), SUVmax > 3.6 (p<0.001), and s-Tg > 75.8 ng/ml (p = 0.009). In multivariate analysis, only a SUVmax > 3.6 was significantly predictive of DSS (p = 0.006). CONCLUSION: An inverse relationship between RAI and FDG uptake, flip-flop phenomenon, was observed in patients with metastatic lesions of DTC. Reduced disease-specific survival was observed in patients with FDG(+), RAI(-) in metastatic lesions, or high s-Tg value.

Preoperative risk stratification using (18)F-FDG PET/CT in women with endometrial cancer.

UNLABELLED: The aim of this study is to evaluate the usefulness of (18)F-FDG PET/CT for preoperative stratification of high-risk and low-risk carcinomas in patients with endometrial cancer. PATIENTS, METHODS: 60 women (mean age 53.8±9.9 years) with endometrial cancer, who underwent (18)F-FDG PET/CT for preoperative staging work-up, followed by primary cytoreductive surgery, were enrolled in this study. Maximum and mean standardized uptake values (SUVmax, SUVmean) of endometrial tumors were measured, and compared with the various clinicopathologic findings obtained after surgery. Tumour aggressiveness was classified as high-risk and low-risk carcinomas. Patients with stage I or II, endometrioid adenocarcinoma, histologic grade 1 or 2, invasion of less than half of the myometrium, maximum tumor size less than 2.0 cm, and absence of cervical invasion and lymphovascular space involvement (LVSI) were classified as the low-risk carcinoma group. The remaining patients were classified as the high-risk carcinoma group. RESULTS: In univariate analysis, SUVmax of the primary endometrial tumor was significantly higher in patients who were in a postmenopausal state (p=0.047), large (>2 cm) primary tumor (p<0.001), nonendometrioid subtype (p=0.024), invasion of more than half of the myometrium (p=0.020), or LVSI (p=0.004). SUVmax differed significantly according to FIGO stage (p=0.013) and histologic grade (p<0.001). In multivariate analysis, FIGO stage, histologic grade, LVSI, and maximum tumor size demonstrated a significant association with SUVmax (p<0.001; r=0.843, r(2)=0.711). SUVmean showed similar results. Forty-one (68.3%) patients were diagnosed postoperatively as high-risk and 19 patients (31.7%) as low-risk carcinoma. Patients with high-risk carcinoma (12.1±6.1) showed significantly higher SUVmax than patients with low-risk carcinoma (5.8±2.8, p<0.001). The optimal SUVmax cut-off value of 8.7, determined by ROC analysis, revealed 75.6% sensitivity, 89.5% specificity, and 81.7% accuracy for risk stratification. CONCLUSION: High-risk endometrial cancer might be differentiated by means of higher SUVmax from low-risk endometrial cancer. (18)F-FDG FDG PET/CT can be applied preoperatively for stratification of risk in patients with endometrial cancer.

Potent, tumor-specific gene expression in an orthotopic hepatoma rat model using a Survivin-targeted, amplifiable adenoviral vector.

Ideal cancer gene therapies should have high tumor specificity and efficacy, and allow systemic administration to target metastases. We recently developed a bi-directional, two-step transcriptional amplification (TSTA) system driven by the tumor-specific Survivin promoter (pSurv) to amplify the correlated expression of both the reporter gene firefly luciferase (FL) and therapeutic gene tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we compare the specificity and potency of an adenovirus carrying this system (Ad-pSurv-TSTA-TRAIL-FL) to a nonspecific vector (Ad-pCMV-FL) in an orthotopic hepatocellular carcinoma (HCC) rat model after systemic administration. At 24 h after injection of Ad-pCMV-FL, bioluminescence imaging revealed a trend (P=0.30) towards greater FL expression in liver versus tumor. In striking contrast, Ad-pSurv-TSTA-TRAIL-FL showed increased FL activity within the tumor compared with the liver (P<0.01), a strong trend towards reduced liver expression compared with Ad-pCMV-FL (P=0.07), and importantly, similar FL levels within tumor compared with Ad-pCMV-FL (P=0.32). Hence, this vector shows potent, tumor-specific transgene expression even after extensive liver transduction and may be of significant value in avoiding hepatotoxicity in HCC patients. Future studies will explore the benefits of tumor-specific TRAIL expression in this model, the potential to target metastases and the extension of this vector for the treatment of other Survivin-positive tumors is warranted.

Can (18)F-FDG PET/CT predict recurrence in patients with cutaneous malignant melanoma?

UNLABELLED: The AIM of this study was to evaluate the prognostic significance of maximum standardized uptake value (SUVmax) of primary cutaneous malignant melanoma (CMM) lesions by (18)F-FDG positron emission tomography/computerized tomography (PET/CT) in terms of recurrence. PATIENTS, METHODS: 37 CMM patients (17 men, mean age: 61.7 ± 13.6 years) that underwent PET/CT at presentation were enrolled in this study. Recurrence was determined by histological confirmation or by radiological and clinical follow-up for at least 8 months after curative surgery. Clinical variables such as age, sex, clinical stage, and primary lesion location, thickness, and ulceration, and SUVmax values were analyzed with respect to their usefulness for predicting recurrence. RESULTS: SUVmax was found to be significantly higher in patients with ulceration of primary lesion of CMM (p = 0.004) and in patients with a stage ≥ III (p < 0.000). Patients that experience recurrence had a significantly higher mean SUVmax value (4.9 ± 2.9) than patients who did not (2.1 ± 1.5, p = 0.024). ROC analysis showed that a SUVmax cut-off value 2.2 had high sensitivity (88.9%) and specificity (67.9%) for predicting recurrence. Kaplan-Meier analysis identified ulceration of primary lesion (p = 0.034), stage ≥ III (p = 0.019) and SUVmax ≥ 2.2 (p = 0.002) as predictors of recurrence. However, Cox proportional-hazards analysis showed that only SUVmax (p = 0.025, relative risk 11.063) significantly predicted recurrence. CONCLUSION: Preoperative SUVmax of primary lesion was found to be the most potent predictor of recurrence in CMM patient. Patients with high SUV max of primary lesion should be followed meticulously for recurrence.

Enhanced anti-tumor effects of combined MDR1 RNA interference and human sodium/iodide symporter (NIS) radioiodine gene therapy using an adenoviral system in a colon cancer model.

Using an adenoviral system as a delivery mediator of therapeutic gene, we investigated the therapeutic effects of the use of combined MDR1 shRNA and human NIS (hNIS) radioiodine gene therapy in a mouse colon xenograft model. In vitro uptake of Tc-99m sestamibi was increased approximately two-fold in cells infected with an adenovirus vector that expressed MDR1 shRNA (Ad-shMDR1) and I-125 uptake was 25-fold higher in cells infected with an adenovirus vector that expressed human NIS (Ad-hNIS) as compared with control cells. As compared with doxorubicin or I-131 treatment alone, the combination of doxorubicin and I-131 resulted in enhanced cytotoxicity for both Ad-shMDR1- and Ad-hNIS-infected cells, but not for control cells. In vivo uptake of Tc-99m sestamibi and Tc-99m pertechnetate was twofold and 10-fold higher for Ad-shMDR1 and Ad-hNIS-infected tumors as compared with tumors infected with a control adenovirus construct that expressed beta-galactosidase (Ad-LacZ), respectively. In mice treated with either doxorubicin or I-131 alone, there was a slight delay in tumor growth as compared to mice treated with Ad-LacZ. However, combination therapy with doxorubicin and I-131 induced further significant inhibition of tumor growth as compared with mice treated with Ad-LacZ. We have shown successful therapeutic efficacy of combined MDR shRNA and hNIS radioiodine gene therapy using an adenoviral vector system in a mouse colon cancer model. Adenovirus-mediated cancer gene therapy using MDR1 shRNA and hNIS would be a useful tool for the treatment of cancer cells expressing multi-drug resistant genes.

Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion.

Angiopoietin-1 (Ang1) is a strong inducer of endothelial cell sprouting, which is a first step in both angiogenesis and neovascularization. We examined the mechanisms underlying Ang1-induced cell sprouting using porcine pulmonary artery endothelial cells. Ang1 induced the nondirectional and directional migration of endothelial cells mediated through the Tie2 but not the Tie1 receptor. Ang1 induced tyrosine phosphorylation of p125(FAK), and this phosphorylation was dependent on phosphatidylinositol (PI) 3'-kinase activity. Ang1 induced the secretion of plasmin and matrix metalloproteinase-2 (MMP-2), which is inhibited by PI 3'-kinase inhibitors. Ang1 also induced the secretion of small amounts of proMMP-3 and proMMP-9 but not proMMP-1. Ang1 suppressed the secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), but not of TIMP-1. Addition of alpha(2)-antiplasmin, a combination of TIMP-1 and TIMP-2, or PI 3'-kinase inhibitors inhibited Ang1-induced sprouting activity. Therefore, Ang1-induced sprouting activity in endothelial cells may be accomplished by cytoskeletal changes and secretion of proteinases and may be largely mediated through intracellular PI 3'-kinase activation.

Intramedullary fat necrosis of multiple bones associated with pancreatitis.

We describe findings of intramedullary fat necrosis on five imaging studies in a patient with alcoholic pancreatitis. Radiography and CT of extremities showed multiple osteolytic lesions that were initially considered to be metastases. However, a 99mTc-methylene diphosphonate whole-body bone scan revealed abnormal areas of increased uptake in only the bones of extremities without involvement of the axial skeleton, a distribution quite unusual for metastatic disease. Furthermore, 99mTc-sestamibi scintigraphy was essentially normal. MRI revealed findings compatible with the diagnosis of fat necrosis/infarct. Findings from bone biopsy demonstrated necrotic bone marrow without malignant cells. It may not be necessary to perform all the imaging studies described in this report when clinical features suggesting metastatic fat necrosis are present. Appearance and distribution of abnormalities on the whole-body bone scan and MR images show that necrosis/infarct of the marrow may obviate bone biopsy, which is often needed to confirm the diagnosis of intramedullary fat necrosis and to exclude neoplastic processes.

Sarcomatous transformation of neurofibromas. Comparative imaging with Ga-67, Tl-201, Tc-99m pentavalent DMSA and Tc-99m MIBI.

A 29-year-old man, with a history of von Recklinghausen's disease, presented with progressive dyspnea associated with a rapidly growing mass on the right chest wall. Plain radiograph and CT of the chest revealed a huge soft-tissue mass with central low-density area involving the right upper lung and chest wall. SPECT imaging with Ga-67 citrate, Tl-201 chloride, Tc-99m pentavalent DMSA (V-DMSA), and Tc-99m MIBI were performed to characterize the mass. The tumor concentrated Ga-67, Tl-201, and Tc-99m (V) DMSA, but not Tc-99m MIBI. Punch biopsy of the lesion revealed malignant transformation of a thoracic neuroma (neurofibrosarcoma). Subsequently, findings compatible with the presence of a multidrug resistance-1 (MDR1) gene in the tumor was documented, which may explain the poor uptake of Tc-99m MIBI. The patient did not respond to intensive chemotherapeutic regimens, and died 3 months later. This case demonstrates the potential use of combined radionuclide imaging for the detection of malignant transformation of neurofibroma, as well as for predicting tumor response to chemotherapy.

Detection, quantitation, and localization of bovine angiogenin by immunological assays.

Bovine angiogenin (bAng) is a potent blood vessel inducing protein found in bovine serum and milk. Antisera have been raised against bAng. Western blot analysis for bAng indicated that the polyclonal antibody recognized bAng specifically, and no cross-reactivity with bovine RNase A, a protein homologous to bAng, was observed. The sandwich enzyme-linked immunosorbent assay for bAng was sensitive to 10 pg of bAng, and this assay was able to quantitate bAng in bovine serum (100-180 ng/mL) and milk (4-8 micrograms/mL). Strong positive immunohistochemical reactions were detected in alveolar cells, the secretion of alveolar cells and excretory ducts in sections of cow mammary gland, epithelial cells of visceral peritoneum and bile-duct in sections of cow liver, and epithelial cells and mucous glands in sections of cow gallbladder. These results suggest that epithelial cells and secretory cells are major sites of angiogenin synthesis.