Design and synthesis of a fluorinated quinazoline-based type-II Trk inhibitor as a scaffold for PET radiotracer development

NTRK1/2/3 fusions have recently been characterized as low incidence oncogenic alterations across various tumor histologies. Tyrosine kinase inhibitors (TKIs) of the tropomyosin receptor kinase family TrkA/B/C (encoded by NTRK1/2/3) are showing promises in the clinic for the treatment of cancer patients whose diseases harbor NTRK tumor drivers. We describe herein the development of [¹⁸F]QMICF ([¹⁸F]-(R)-9), a quinazoline-based type-II pan-Trk radiotracer with nanomolar potencies for TrkA/B/C (IC₅₀ = 85–650 nM) and relevant TrkA fusions including TrkA-TPM3 (IC₅₀ = 162 nM). Starting from a racemic FLT3 (fms like tyrosine kinase 3) inhibitor lead with off-target TrkA activity ((±)-6), we developed and synthesized the fluorinated derivative (R)-9 in three steps and 40% overall chemical yield. Compound (R)-9 displays a favorable selectivity profile on a diverse set of kinases including FLT3 (>37-fold selectivity for TrkB/C). The mesylate precursor 16 required for the radiosynthesis of [¹⁸F]QMICF was obtained in six steps and 36% overall yield. The results presented herein support the further exploration of [¹⁸F]QMICF for imaging of Trk fusions in vivo.     

Prognostic Value of Molecular Breast Cancer Subtypes based on Her2, ESR1, PGR and Ki67 mRNA-Expression in Muscle Invasive Bladder Cancer

INTRODUCTION: Gene expression analyses have identified similarities between bladder and breast cancer, where clinical risk stratification is based on Her2, ESR1, PGR and Ki67 expression. The aim of the study was to assess the respective marker gene expression in patients treated with radical cystectomy for muscle-invasive bladder cancer (MIBC) and to evaluate the applicability of breast cancer subtypes for MIBC risk stratification. MATERIALS & METHODS: 102 patients treated with radical cystectomy for MIBC were assessed. Using routine FFPE tissue and an IVD validated kit, mRNA expression was measured by single step RT-qPCR. Partition test were employed to define cut-off values for high or low marker gene expression. Association of expression with outcome was assessed using Kaplan-Meier analysis and multivariate cox regression analysis. Finally, we performed validation of our results in the MD-Anderson cohort (n = 57). RESULTS: Cancer specific survival (CSS) was impaired in patients with high gene expression of Her2 (P = 0.0009) and ESR1 (P = 0.04). In the multivariate regression model Her2 expression remained significant for the prediction of CSS (HR = 2.11, CI 1.11-4.21, P = 0.024). Furthermore, molecular stratification by breast cancer subgroups was significant (P = 0.023) for CSS prediction. Especially the differentiation between Her2-positive and Luminal A (HR = 4.41, CI 1.53-18.71, P = 0.004) and Luminal B (HR = 1.96, CI 0.99-4.08, P = 0.053) respectively was an independent prognostic parameter for CSS. External validation resulted in comparable risk stratification with differences in fractional subgroups distribution. CONCLUSION: Gene expression of Her2, ESR1, PGR, Ki67 and corresponding breast cancer subtypes allow a risk-stratification in MIBC, whereby Her2 overexpressing tumors reveal a particularly poor prognosis.     

Integrated Analysis Identifies Molecular Signatures and Specific Prognostic Factors for Different Gastric Cancer Subtypes

BACKGROUND: Gastric cancer (GC) is the fifth leading cause of cancer-related deaths worldwide. As an effective and easily performed method, microscopy-based Lauren classification has been widely accepted by gastrointestinal surgeons and pathologists for GC subtyping, but molecular characteristics of different Lauren subtypes were poorly revealed. METHODS: GSE62254 was used as a derivation cohort, and GSE15459 was used as a validation cohort. The difference between diffuse and intestinal GC on the gene expression level was measured. Gene ontology (GO) enrichment analysis was performed for both subgroups. Hierarchical clustering and heatmap exhibition were also performed. Kaplan-Meier plot and Cox proportional hazards model were used to evaluate survival grouped by the given genes or hierarchical clusters. RESULTS: A total of 4598 genes were found differentially expressed between diffuse and intestinal GC. Immunity- and cell adhesion–related GOs were enriched for diffuse GC, whereas DNA repair– and cell cycle–related GOs were enriched for intestinal GC. We proposed a 40-gene signature (χ² = 30.71, P < .001) that exhibits better discrimination for prognosis than Lauren classification (χ² = 12.11, P = .002). FRZB [RR (95% CI) = 1.824 (1.115-2.986), P = .017] and EFEMP1 [RR (95% CI) = 1.537 (0.969-2.437), P = .067] were identified as independent prognostic factors only in diffuse GC but not in intestinal GC patients. KRT23 [RR (95% CI) = 1.616 (0.938-2.785), P = .083] was identified as an independent prognostic factor only in intestinal GC patients but not in diffuse GC patients. Similar results were achieved in the validation cohort. CONCLUSION: We found that GCs with different Lauren classifications had different molecular characteristics and identified FRZB, EFEMP1, and KRT23 as subtype-specific prognostic factors for GC patients.     

Synthesis,anticancer, and docking studies of salicyl-hydrazone analogues: A novel series of small potent tropomyosin receptor kinase A inhibitors

A series of novel salicyl-hydrazone analogues were synthesized and evaluated for their in vitro cytotoxic activities in five human cancer cell lines, namely, lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), colon cancer (HCT15) and pancreatic cancer (MIA-PaCa-2) cells, and for their in vitro tropomyosin receptor kinase A (TrkA) inhibitory activities. Each of the compounds showed significant cytotoxicity against all cancer cells. Compound 3i was found to be most potent against all cancer cell lines with IC₅₀ values of 2.46 (A549), 0.87 (SK-OV-3), 1.43 (SK-MEL-2), 0.89 (HCT15), and 0.48 μM (MIA-PaCa-2), followed by compound 3l. Cytotoxicity of 3i was similar to that of doxorubicin (0.87 μM) against HCT15 cells. Compounds 3i and 3l also showed highest TrkA inhibitory activities with IC₅₀ values of 0.231 and 0.380 μM, respectively. A SAR study of the series revealed that compounds with hydroxyl groups showed better cytotoxicity and TrkA inhibitory potency (in the following order 2,4-OH > 2,3,4-OH > 3,4-OH > 4-OH) than compounds possessing electron donating or withdrawing groups on the benzylidenephenyl ring. Docking studies of compounds 3i and 3l conducted on the crystal structure of TrkA receptor (a promising target for anticancer agents) showed both had a high docking score and similar order of experimental TrkA inhibitory activities. The formation of several hydrogen bonds involving N and O containing moieties contributed most significantly to ligand binding and stabilization at the active site of the receptor. In addition, ligand-receptor complexes were further stabilized by π-cation, π-anion, amide-π stacked, and van der Waal’s interactions. Conformational analyses showed ligand molecules adopted similar conformations at the receptor active site during interactions, but that the low energy optimized conformations of compounds 3i and 3l differed.     

Analysis of Chemopredictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients

Introduction: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. Methods: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board–approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. Results: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR = 2.2 (P = .016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR = 2.75 (P = .07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR = 2.36 (P = .036), but a much attenuated remaining bulk tumor association, OR = 1.46 (P = .472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC = 0.989 [sensitivity = 100/specificity = 97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification nonevent net reclassification improvement [NRI] and overall NRI = 0.111, P = .030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months for those with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. Panel results across 14 potential other treatments indicated that 34/41 (83%) potentially more optimal alternative therapies may have been chosen using CSC results, whereas 27/41 (66%) alternative therapies may have been chosen using bulk tumor results. Conclusions: The ChemoID CSC drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. GBM cancer recurrence may occur quickly if the CSC test has a low in vitro cell kill rate even if the bulk tumor test cell kill rate is high.     

Magnetic Resonance Imaging (MRI) of Intratumoral Voxel Heterogeneity as a Potential Response Biomarker: Assessment in a HER2+ Esophageal Adenocarcinoma Xenograft Following Trastuzumab and/or Cisplatin Therapy

We evaluated magnetic resonance imaging (MRI) voxel heterogeneity following trastuzumab and/or cisplatin in a HER2+ esophageal xenograft (OE19) as a potential response biomarker. OE19 xenografts treated with saline (controls), monotherapy, or combined cisplatin and trastuzumab underwent 9.4-T MRI. Tumor MRI parametric maps of T1 relaxation time (pre/post contrast), T2 relaxation time, T2* relaxation rate (R2*), and apparent diffusion coefficient obtained before (TIME0), after 24 hours (TIME1), and after 2 weeks of treatment (TIME2) were analyzed. Voxel histogram and fractal parameters (from the whole tumor, rim and center, and as a ratio of rim‐to‐center) were derived. Tumors were stained for immunohistochemical markers of hypoxia (CA-IX), angiogenesis (CD34), and proliferation (Ki-67). Combination therapy reduced xenograft growth rate (relative change, ? +0.58 ± 0.43 versus controls, ? +4.1 ± 1.0; P = 0.008). More spatially homogeneous voxel distribution between the rim to center was noted after treatment for combination therapy versus controls, respectively, for contrast-enhanced T1 relaxation time (90th percentile: ratio 1.00 versus 0.88, P = 0.009), T2 relaxation time (mean: 1.00 versus 0.92, P = 0.006; median: 0.98 versus 0.91, P = 0.006; 75th percentile: 1.02 versus 0.94, P = 0.007), and R2* (10th percentile: 0.99 versus 1.26, P = 0.003). We found that combination and trastuzumab monotherapy reduced MRI spatial heterogeneity and growth rate compared to the control or cisplatin groups, the former providing adjunctive tumor response information.     

Genetic Variations of GWAS-Identified Genes and Neuroblastoma Susceptibility: a Replication Study in Southern Chinese Children

Neuroblastoma is one of the most commonly diagnosed solid cancers for children, and genetic factors may play a critical role in neuroblastoma development. Previous genome-wide association studies (GWASs) have identified nine genes associated with neuroblastoma susceptibility in Caucasians. To determine whether genetic variations in these genes are also associated with neuroblastoma susceptibility in Southern Chinese children, we genotyped 25 polymorphisms within these genes by the TaqMan method in 256 cases and 531 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the associations. We performed a meta-analysis to further evaluate the associations. Furthermore, we calculated the area under the receiver-operating characteristic curves (AUC) to assess which gene/genes may better predict neuroblastoma risk. We confirmed that CASC15 rs6939340 A > G, rs4712653 T > C, rs9295536 C > A, LIN28B rs221634 A > T, and LMO1 rs110419 A > G were associated with significantly altered neuroblastoma susceptibility. We also confirmed that rs6939340 A > G (G versus A: OR = 1.30, 95% CI = 1.13-1.50) and rs110419 G > A (A versus G: OR = 1.37, 95% CI = 1.19-1.58) were associated with increased neuroblastoma risk for all subjects. We also found that the combination of polymorphisms in CASC15, LIN28B, and LMO1 may be used to predict neuroblastoma risk (AUC = 0.63, 95% CI = 0.59-0.67). Overall, we verified five GWAS-identified polymorphisms that were associated with neuroblastoma susceptibility alteration for Southern Chinese population; however, these results need further validation in studies with larger sample sizes.     

Bifidobacterium primatium sp. nov., Bifidobacterium scaligerum sp. nov., Bifidobacterium felsineum sp. nov. and Bifidobacterium simiarum sp. nov.: Four novel taxa isolated from the faeces of the cotton top tamarin (Saguinus oedipus) and the emperor tamarin (Saguinus imperator)

Four novel Gram-stain-positive, non spore forming and fructose-6-phosphate phosphoketolase-positive strains were isolated from the faeces of a cotton top tamarin (Saguinus oedipus) and an emperor tamarin (Saguinus imperator). Phylogenetic analyses based on 16S rRNA revealed that bifidobacterial strains TRE 1^T exhibit close phylogenetic relatedness to Bifidobacterium catulorum DSM 103154 (96.0%) and Bifidobacterium tissieri DSM 100201 (96.0%); TRE D^T and TRE H^T were closely related to Bifidobacterium longum subsp. longum ATCC 15708^T with similarity values of 97.4% and 97.5%, respectively; TRI 7^T was closely related to Bifidobacterium tissieri DSM 100201 (96.0%). The Average Nucleotide Identity (ANI) and in silico DDH (isDDH) analysis with closest neighbour supported an independent phylogenetic position of all strains with values ranged from 74 to 85% for ANI and from 24 to 28% for isDDH. DNA base composition of the four strains was in the range of 58.3–63.5 mol% G + C. Based on the phylogenetic, genotypic and phenotypic data, the strains TRE 1^T, TRE D^T, TRE H^T and TRI 7^T clearly represent four novel taxa within the genus Bifidobacterium for which the names Bifidobacterium primatium sp. nov. (type strain TRE 1^T = DSM 100687^T = JCM 30945^T), Bifidobacterium scaligerum sp. nov. (type strain TRE D^T = DSM 103140^T = JCM 31792^T), Bifidobacterium felsineum sp. nov. (type strain TRE H^T = DSM 103139^T = JCM 31789^T) and Bifidobacterium simiarum sp. nov. (type strain TRI 7^T = DSM 103153^T = JCM 31793) are proposed.     

The Functional Roles of the MDM2 Splice Variants P2-MDM2-10 and MDM2-∆5 in Breast Cancer Cells

BACKGROUND: MDM2 is a negative regulator of p53 and is upregulated in numerous human cancers. While different MDM2 splice variants have been observed in both normal tissues and malignant cells, their functions are poorly understood. METHODS: We evaluated the effect of MDM2 splice variants by overexpression in MCF-7 cells and analyses of expression of downstream genes (qPCR and Western blot), subcellular localization (immunofluorescence), cell cycle assays (Nucleocounter3000), apoptosis analysis (Annexin V detection), and induction of senescence (β-galactosidase analysis). RESULTS: In a screen for MDM2 splice variants in MCF-7 breast cancer cells, extended with data from healthy leukocytes, we found P2-MDM2-10 and MDM2-Δ5 to be the splice variants expressed at highest levels. Contrasting MDM2 full-length protein, we found normal tissue expression levels of P2-MDM2-10 and MDM2-Δ5 to be highest in individuals harboring the promoter SNP309TT genotype. While we detected no protein product coded for by MDM2-Δ5, the P2-MDM2-10 variant generated a protein markedly more stable than MDM2-FL. Both splice variants were significantly upregulated in stressed cells (P = 4.3 × 10^?4 and P = 7.1 × 10^?4, respectively). Notably, chemotherapy treatment and overexpression of P2-MDM2-10 or MDM2-Δ5 both lead to increased mRNA levels of the endogenous MDM2-FL (P = .039 and P = .070, respectively) but also the proapoptotic gene PUMA (P = .010 and P = .033, respectively), accompanied by induction of apoptosis and repression of senescence. CONCLUSION: We found P2-MDM2-10 and MDM2-Δ5 to have distinct biological functions in breast cancer cells. GENERAL SIGNIFICANCE: Alternative splicing may influence the oncogenic effects of the MDM2 gene.     

MRI Texture Analysis Reflects Histopathology Parameters in Thyroid Cancer – A First Preliminary Study

OBJECT: Thyroid cancer represents the most frequent malignancy of the endocrine system with an increasing incidence worldwide. Novel imaging techniques are able to further characterize tumors and even predict histopathology features. Texture analysis is an emergent imaging technique to extract extensive data from an radiology images. The present study was therefore conducted to identify possible associations between texture analysis and histopathology parameters in thyroid cancer. METHODS: The radiological database was retrospectively reviewed for thyroid carcinoma. Overall, 13 patients (3 females, 23.1%) with a mean age of 61.6 years were identified. The MaZda program was used for texture analysis. The T1-precontrast and T2-weighted images were analyzed and overall 279 texture feature for each sequence was investigated. For every patient cell count, Ki67-index and p53 count were investigated. RESULTS: Several significant correlations between texture features and histopathology were identified. Regarding T1-weighted images, S(0;1)Sum Averg correlated the most with cell count (r = 0.82). An inverse correlations with S(5;0)AngScMom, S(5;0)DifVarnc S(5;0), DiffEntrp and GrNonZeros (r = ?0.69, ?0.66, ?0.69 and ?0.63, respectively) was also identified. For T2-weighted images, Variance with r = 0.63 was the highest coefficient, WavEnLL_S3 correlated inversely with cell count (r = ?0.57). WavEnLL_S2 derived from T1-weighted images was the highest coefficient r = ?0.80, S(0;5)SumVarnc was positively with r = 0.74. Regarding T2-weighted images WavEnHL_s-1 was inverse correlated with Ki67 index (r = ?0.77). S(1;0)Correlat was with r = 0.75 the best correlation with Ki67 index. For T1-weighed images S(5;0)SumofSqs was the best with r = 0.65 with p53 count. For T2-weighted images S(1;?1)SumEntrp was the inverse correlation with r = ?0.72, whereas S(0;4)AngScMom correlated positively with r = 0.63. CONCLUSIONS: MRI texture analysis derived from conventional sequences reflects histopathology features in thyroid cancer. This technique might be a novel noninvasive modality to further characterize thyroid cancer in clinical oncology.     

NFATc1 Expression as a Prognosticator in Urothelial Carcinoma of the Upper Urinary Tract

We recently found that NFATc1, a member of the NFAT family and a key regulator of the immune response, could induce bladder carcinogenesis and cancer progression. In this study, we immunohistochemically stained for NFATc1 in upper urinary tract urothelial carcinoma (UUTUC) specimens and paired nonneoplastic urothelial tissues. NFATc1 was positive in 51 [52%; 40 (40%) weak (1+), 9 (9%) moderate (2+), and 2 (2%) strong (3+)] of 99 UUTUCs, which was significantly higher than in benign urothelium [30 (36%) of 83; 28 (34%) weak and 2 (2%) moderate] (0 vs 1+/2+/3+, P = .038; 0/1+ vs 2+/3+, P = .023). There were no significant associations between NFATc1 expression pattern and tumor grade or pT stage. However, the positive rates of NFATc1 expression tended to be higher in renal pelvic tumors (60%) than in ureteral tumors (42%; P = .080) as well as in pN+ tumors (75%) than in pN0 tumors (49%; P = .089). Kaplan-Meier and log-rank tests revealed that moderate (2+) to strong (3+) NFATc1 expression correlated with lower progression-free survival (P = .032) and cancer-specific survival (P = .005) rates in the 99 cases. Patients with high (2+/3+) NFATc1 muscle-invasive tumor (n = 9) also had a significantly higher risk of cancer-specific mortality (P = .021) compared to those with low (0/1+) NFATc1 muscle-invasive tumor (n = 53). Thus, compared with nonneoplastic urothelium, a significant increase in the expression of NFATc1 in UUTUC was seen, implying the involvement of NFATc1 signals in the development of UUTUC. The current results further suggest that NFATc1 overexpression serves as a predictor of poor prognosis in patients with UUTUC.     

Utility of Genomic Analysis in Differentiating Synchronous and Metachronous Lung Adenocarcinomas from Primary Adenocarcinomas with Intrapulmonary Metastasis

Distinguishing synchronous and metachronous primary lung adenocarcinomas from adenocarcinomas with intrapulmonary metastasis is essential for optimal patient management. In this study, multiple lung adenocarcinomas occurring in the same patient were evaluated using comprehensive histopathologic evaluation supplemented with molecular analysis. The cohort included 18 patients with a total of 52 lung adenocarcinomas. Eleven patients had a new diagnosis of multiple adenocarcinomas in the same lobe (n = 5) or different lobe (n = 6). Seven patients had a history of lung cancer and developed multiple new tumors. The final diagnosis was made in resection specimens (n = 49), fine needle aspiration (n = 2), and biopsy (n = 1). Adenocarcinomas were non‐mucinous, and histopathologic comparison of tumors was performed. All tumors save for one were subjected to ALK gene rearrangement testing and targeted Next Generation Sequencing (NGS). Using clinical, radiologic, and morphologic features, a confident conclusion favoring synchronous/metachronous or metastatic disease was made in 65% of patients. Cases that proved challenging included ones with more than three tumors showing overlapping growth patterns and lacking a predominant lepidic component. Genomic signatures unique to each tumor were helpful in determining the relationship of multiple carcinomas in 72% of patients. Collectively, morphologic and genomic data proved to be of greater value and achieved a conclusive diagnosis in 94% of patients. Assessment of the genomic profiles of multiple lung adenocarcinomas complements the histological findings, enabling a more comprehensive assessment of synchronous, metachronous, and metastatic lesions in most patients, thereby improving staging accuracy. Targeted NGS can identify genetic alterations with therapeutic implications.     

Predicting Treatment Response of Breast Cancer to Neoadjuvant Chemotherapy Using Ultrasound-Guided Diffuse Optical Tomography

PURPOSE: To prospectively investigate ultrasound-guided diffuse optical tomography (US-guided DOT) in predicting breast cancer response to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Eighty-eight breast cancer patients, with a total of 93 lesions, were included in our study. Pre– and post–last chemotherapy, size and total hemoglobin concentration (THC) of each lesion were measured by conventional US and US-guided DOT 1 day before biopsy (time point t0, THC THC0, SIZE S0) and 1 to 2 days before surgery (time point tL, THCL, SL). The relative changes in THC and SIZE of lesions after the first and last NAC cycles were considered as the variables ΔTHC and ΔSIZE. Receiver operating characteristic curve was performed to calculate ΔTHC and ΔSIZE cutoff values to evaluate pathologic response of 93 breast cancers to NAC, which were then prospectively used to predicate response of 61 breast cancers to NAC. RESULTS: The cutoff values of ΔTHC and ΔSIZE for evaluation of breast cancers NAC treatment response were 23.9% and 42.6%. At ΔTHC 23.9%, the predicted treatment response in 61 breast lesions for the time points t1 to t3 was calculated by area under the curve (AUC), which were AUC₁ 0.534 (P = .6668), AUC₂ 0.604 (P = .1893), and AUC₃ 0.674(P =. 0.027), respectively; for ΔSIZE 42.6%, at time points t1 to t3, AUC₁ 0.505 (P = .9121), AUC₂ 0.645 (P = .0115), and AUC₃ 0.719 (P = .0018). CONCLUSION: US-guided DOT ΔTHC 23.9% and US ΔSIZE 42.6% can be used for the response evaluation and earlier prediction of the pathological response after three rounds of chemotherapy.     

Induction Chemotherapy Has No Prognostic Value in Patients with Locoregionally Advanced Nasopharyngeal Carcinoma and Chronic Hepatitis B Infection in the IMRT Era

BACKGROUND: The effectiveness of induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT) over CCRT alone in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and chronic hepatitis B infection in the intensity-modulated radiotherapy (IMRT) era is unknown. PATIENTS AND METHODS: A total of 249 patients with stage T1-2 N2-3 or T3-4 N1-3 NPC and chronic hepatitis B infection treated with IMRT were retrospectively reviewed. Propensity score matching (PSM) was employed to balance covariates; 140 patients were propensity-matched (1:1 basis). Survival outcomes in the IC + CCRT and CCRT groups were compared using the Kaplan–Meier method, log-rank test and Cox proportional hazards model. RESULTS: No significant survival differences were observed between IC + CCRT and CCRT (5-year overall survival, 88.3% vs. 82.2%; P = .484; disease-free survival, 73.9% vs. 75.2%; P = .643; distant metastasis-free survival, 84.1% vs. 85.1%; P = .781; and locoregional failure-free survival, 87.9% vs. 85.1%; P = .834). After adjusting for known prognostic factors in multivariate analysis, IC was not an independent prognostic factor for any outcome (all P > .05); subgroup analysis based on T category (T1-2/T3-4), N category (N0-1/N2-3), and overall stage (III/IV) confirmed these results. The incidence of hepatic function damage in the IC + CCRT and CCRT groups was not significantly different. CONCLUSION: IC + CCRT leads to comparable survival outcomes and hepatic function damage compared to CCRT alone in patients with locoregionally advanced NPC with chronic hepatitis B infection in the IMRT era. Further investigations are warranted.     

Positive Expression of Programmed Death Ligand 1 in Peritumoral Liver Tissue is Associated with Poor Survival after Curative Resection of Hepatocellular Carcinoma

BACKGROUND: Recurrence or metastasis of hepatocellular carcinoma (HCC) is mainly intrahepatic after curative resection, demonstrating that the peritumoral environment is important but often neglected. Programmed death ligand 1 (PD-L1) in intratumoral liver tissues is a poor prognosis factor whose impact is removed after curative resection. However, PD-L1 expression remains in the peritumoral liver tissues and its distribution and prognostic value are still not clear. METHODS: We assessed the expression of PD-L1 by immunohistochemistry in peritumoral liver tissues from 90 HCC patients who underwent curative hepatectomy. The results were validated in an independent cohort of additional 90 HCC patients. RESULTS: We found PD-L1 positive expression in 31.11% (28/90) of peritumoral tissues. Peritumoral PD-L1 expression was associated with a significantly worse overall survival (OS) (P = .000) and disease-free survival (DFS) (P = .001) compared to the negative expression group. Additionally, peritumoral PD-L1 positivity significantly correlated with vascular invasion and a lower albumin level (≤35 g/L). Univariate and multivariate Cox regression models both revealed peritumoral PD-L1 as an independent prognostic factor for OS (HR = 2.853, P = .002) and DFS (HR = 2.362, P = .003). The prognostic value of PD-L1 positivity was validated in the independent data set. CONCLUSIONS: Our data suggest PD-L1 expression in peritumoral hepatocytes is an independent prognostic factor for OS and DFS. This implies that future anti-cancer therapy should target not only residual tumor cells but also the “soil” for promoting tumor growth. Peritumoral PD-L1 could be a good target for adjuvant therapy after hepatectomy.     

Pulmonary Sarcomatoid Carcinoma with ALK Rearrangement: Frequency,Clinical-Pathologic Characteristics,and Response to ALK Inhibitor

PURPOSE: The incidence of anaplastic lymphoma kinase (ALK) rearrangement in pulmonary sarcomatoid carcinoma (PSC) is controversial. In this study, we aimed to reveal the reliable frequency and the clinical-pathologic characteristics of pulmonary sarcomatoid carcinoma (PSC) with ALK rearrangement in Chinese population, and to provide insight into the translatability of anti-ALK treatment in this treatment-refractory disease. METHODS: Immunohistochemistry (IHC) using a Ventana anti-ALK (D5F3) rabbit monoclonal antibody was performed in 141 PSC specimens collected from multiple medical centers. IHC-positive cases were then confirmed using ALK fluorescent in situ hybridization (FISH). The incidence rates and clinical-pathologic characteristics of ALK-rearranged PSC were then analyzed. Response to ALK inhibitor crizotinib in a patient with ALK-rearranged PSC was evaluated according to the response evaluation criteria for solid tumors (RECIST) version 1.1. RESULTS: Five of 141 (3.5%) of PSCs showed ALK rearrangement-positive by IHC and then were confirmed by FISH. Two were carcinosarcomas and the other three were pulmonary pleomorphic carcinoma (PPC). Strong positive ALK rearrangement was observed in both the epithelioid and sarcomatoid components. The median age of ALK-positive patients was younger than that of ALK-negative patients. PSCs in never-smokers were more likely to harbor ALK rearrangement than those in former or current smokers (P < .05). A 40-year-old woman diagnosed with ALK-rearranged PPC experienced a partial response (?32%) to the ALK inhibitor crizotinib. CONCLUSIONS: The incidence rates of ALK rearrangement in PSC in the Chinese population are similar to those of other subtypes of NSCLC. PSCs in younger never-smokers are more often to harbor ALK rearrangement. ALK inhibitors may serve as an effective treatment for ALK-rearranged PSC.     

Association Between Background Parenchymal Enhancement and Pathologic Complete Remission Throughout the Neoadjuvant Chemotherapy in Breast Cancer Patients

PURPOSE: To retrospectively investigate the quantitative background parenchymal enhancement (BPE) of the contralateral normal breast in patients with unilateral invasive breast cancer throughout multiple monitoring points of neoadjuvant chemotherapy (NAC) and to further determine whether BPE is associated with tumor response, especially at the early stage of NAC. MATERIALS AND METHODS: A total of 90 patients with unilateral breast cancer who then received six or eight cycles of NAC before surgery were analyzed retrospectively. BPE was measured in dynamic contrast-enhanced MRI at baseline and after 2nd, 4th, and 6th NAC, respectively. Correlation between BPE and tumor size was analyzed, and the association between pathologic complete remission (pCR) and BPE was also analyzed. RESULTS: The BPE of contralateral normal breast showed a constant reduction throughout NAC therapy regardless of the menopausal status (P < .001 in all). Both the BPEs and the changes of BPE in each of the three monitoring points were significantly correlated with those in tumor size (P < .05 in all), and the reduction of BPE after 2nd NAC had the largest diagnostic value for pCR (AUC = 0.726, P < .001), particularly in hormonal receptor (HR)-negative patients (OR = 0.243, 95%CI = 0.083 to 0.706, P = .009). CONCLUSION: The BPE of contralateral normal breast had a constant decreased tendency similar to the change of tumor size in NAC. Reduction of BPE at the early stage of NAC was positively associated with pCR, especially in HR-negative status.     

Proving of a Mathematical Model of Cell Calculation Based on Apparent Diffusion Coefficient

OBJECTIVES: Recently, Atuegwu et al. proposed a mathematical model based on ADC_mean and ADC_min to calculation of cellularity. Our purpose was to compare the calculated cellularity according to the formula with the estimated cell count by histopathology in different tumors. METHODS: For this study, we re-analyzed our previous data regarding associations between ADC parameters and histopathological findings. Overall, 134 patients with different tumors were acquired for the analysis. For all tumors, the number of tumor cells was calculated according to Atuegwu et al. 2013. We performed a correlation analysis between the calculated and estimated cellularity. Thereby, Pearson's correlation coefficient was used and P < .05 was taken to indicate statistical significance in all instances. RESULTS: The estimated and calculated cellularity correlated well together in HNSCC (r = 0.701, P = .016) and lymphomas (r = 0.661, P = .001), and moderately in rectal cancer (r = 0.510, P = .036). There were no statistically significant correlations between the estimated and calculated cellularity in uterine cervical cancer, meningiomas, and in thyroid cancer. CONCLUSION: The proposed formula for cellularity calculation does not apply for all tumors. It may be used for HNSCC, cerebral lymphomas and rectal cancer, but not for uterine cervical cancer, meningioma, and thyroid cancer. Furthermore, its usefulness should be proved for other tumors.