The spatial landscape of clonal somatic mutations in benign and malignant tissue

Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. Here, we provide an unsupervised approach to study spatial genome integrity in situ to describe previously unidentified clonal relationships. We employed spatially resolved transcriptomics to infer spatial copy number variations in >120 000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue using an organ-wide approach focused on the prostate. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of capturing the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.

The spatial landscape of clonal somatic mutations in benign and malignant tissue

Defining the transition from benign to malignant tissue is fundamental to improve early diagnosis of cancer. Here, we provide an unsupervised approach to study spatial genome integrity in situ to gain molecular insight into clonal relationships. We employed spatially resolved transcriptomics to infer spatial copy number variations in >120 000 regions across multiple organs, in benign and malignant tissues. We demonstrate that genome-wide copy number variation reveals distinct clonal patterns within tumours and in nearby benign tissue. Our results suggest a model for how genomic instability arises in histologically benign tissue that may represent early events in cancer evolution. We highlight the power of an unsupervised approach to capture the molecular and spatial continuums in a tissue context and challenge the rationale for treatment paradigms, including focal therapy.

Blood oxygenation level-dependent MRI at 3T for differentiating prostate cancer from benign tissue: a preliminary experience

Objective: Blood oxygenation-level dependent (BOLD) MRI may identify or quantify the regional distribution of hypoxia within a tumor. We aimed to evaluate the feasibility of BOLD MRI at 3 T in differentiating prostate cancer from benign tissue. Methods: A total of 145 patients with biopsy-proven prostate cancer underwent BOLD MRI at 3 T. BOLD MRI was performed using a multiple fast field echo sequence to acquire 12 T2*-weighted images. The R2* value (rate of relaxation, s−1) was measured in the index tumor, and benign peripheral (PZ) and transition zone (TZ), and the results were compared. The variability of R2* measurements was evaluated. Results: Tumor R2* values (25.95 s−1) were significantly different from the benign PZ (27.83 s−1) and benign TZ (21.66 s−1) (p < 0.001). For identifying the tumor, the area under the receiver operating characteristic of R2* was 0.606, with an optimal cut-off value of 22.8 s−1 resulting in 73.8% sensitivity and 52% specificity. In the Bland–Altman test, the mean differences in R2* values were 8.5% for tumors, 13.3% for benign PZ, and 6.8% for benign TZ. No associations between tumor R2* value and Gleason score, age, prostate volume, prostate-specific antigen, or tumor size. Conclusion: BOLD MRI at 3 T appears to be a feasible tool for differentiating between prostate cancer and benign tissue. However, further studies are required for a direct clinical application. Advances in knowledge: The R2* values are significantly different among prostate cancer, benign PZ, and benign TZ.

Mitochondria in epithelial ovarian carcinoma exhibit abnormal phenotypes and blunted associations with biobehavioral factors

Malignant tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and mitochondria in malignant tumors remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign tissue and in high-grade epithelial ovarian carcinoma (EOC) in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n = 1435) showed that gene expression of specific mitochondrial proteins in EOC is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in tissue from 51 patients with benign ovarian masses and 128 patients with high-grade EOC revealed that compared to benign tissue, EOCs exhibit 3.3–8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P < 0.001) but similar mitochondrial DNA (mtDNA) levels (− 3.1%), documenting abnormal mitochondrial phenotypes in EOC. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r = − 0.43 to 0.47). In contrast, serous EOCs showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in EOC and warrant further research on the link between biobehavioral factors and mitochondria in cancer.

Contrast-Enhanced Ultrasound Imaging of Uterine Disorders: A Systematic Review

Uterine disorders are often presented with overlapping symptoms. The microvasculature holds specific information important for diagnosing uterine disorders. Conventional sonography is an established diagnostic technique in gynecology, but is limited by its inability to image the microvasculature. Contrast-enhanced ultrasound (CEUS), is capable of imaging the microvasculature by means of intravascular contrast agents; that is, gas-filled microbubbles. We provide a literature overview on the use of CEUS in diagnosing myometrial and endometrial disorders, that is, fibroids, adenomyosis, leiomyosarcomas and endometrial carcinomas, as well as for monitoring and enhancing the effectiveness of minimally invasive therapies. A systematic literature search with quality assessment was performed until December 2020. In total 34 studies were included, published between 2007 and 2020.The results entail a description of contrast-enhancement patterns obtained from healthy tissue and from malignant and benign tissue; providing a first base for potential diagnostic differentiation in gynecology. In addition it is also possible to determine the degree of myometrial invasion in case of endometrial carcinoma using CEUS. The effectiveness of minimally invasive therapies for uterine disorders can safely and accurately be assessed with CEUS. In conclusion, the abovementioned applications of CEUS are promising and it is worth further exploring its full potential for gynecology by designing innovative and methodologically high-quality clinical studies.

Ovarian Tumor Mitochondria Exhibit Abnormal Phenotypes and Blunted Associations with Biobehavioral Factors

Tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and tumor mitochondria remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign and cancerous ovarian tissue in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n=1,435) showed that gene expression of specific mitochondrial proteins in ovarian tumors is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in 51 benign and 128 high-grade epithelial ovarian tumors revealed that compared to benign tissue, tumors exhibit 3.3-8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P<0.001) but similar mitochondrial DNA levels (-3.1%), documenting abnormal mitochondrial phenotypes in tumors. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r=-0.43 to 0.47). In contrast, serous tumors showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in ovarian tumors and warrant further research on the link between biobehavioral factors and mitochondria in cancer.

Targeting Toxins toward Tumors

Many cancer diseases, e.g., prostate cancer and lung cancer, develop very slowly. Common chemotherapeutics like vincristine, vinblastine and taxol target cancer cells in their proliferating states. In slowly developing cancer diseases only a minor part of the malignant cells will be in a proliferative state, and consequently these drugs will exert a concomitant damage on rapidly proliferating benign tissue as well. A number of toxins possess an ability to kill cells in all states independently of whether they are benign or malignant. Such toxins can only be used as chemotherapeutics if they can be targeted selectively against the tumors. Examples of such toxins are mertansine, calicheamicins and thapsigargins, which all kill cells at low micromolar or nanomolar concentrations. Advanced prodrug concepts enabling targeting of these toxins to cancer tissue comprise antibody-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), lectin-directed enzyme-activated prodrug therapy (LEAPT), and antibody-drug conjugated therapy (ADC), which will be discussed in the present review. The review also includes recent examples of protease-targeting chimera (PROTAC) for knockdown of receptors essential for development of tumors. In addition, targeting of toxins relying on tumor-overexpressed enzymes with unique substrate specificity will be mentioned.

Ovarian Tumor Mitochondria Exhibit Abnormal Phenotypes and Blunted Associations with Biobehavioral Factors

Tumor cells exhibit mitochondrial alterations and are also influenced by biobehavioral processes, but the intersection of biobehavioral factors and tumor mitochondria remains unexplored. Here we examined multiple biochemical and molecular markers of mitochondrial content and function in benign and cancerous ovarian tissue in parallel with exploratory analyses of biobehavioral factors. First, analysis of a publicly-available database (n=1,435) showed that gene expression of specific mitochondrial proteins in ovarian tumors is associated with survival. Quantifying multiple biochemical and molecular markers of mitochondrial content and function in 51 benign and 128 high-grade epithelial ovarian tumors revealed that compared to benign tissue, tumors exhibit 3.3-8.4-fold higher mitochondrial content and respiratory chain enzymatic activities (P<0.001) but similar mitochondrial DNA levels (−3.1%), documenting abnormal mitochondrial phenotypes in tumors. Mitochondrial respiratory chain activity was also associated with interleukin-6 (IL-6) levels in ascites. In benign tissue, negative biobehavioral factors were inversely correlated with mitochondrial content and respiratory chain activities, whereas positive biobehavioral factors tended to be positively correlated with mitochondrial measures, although effect sizes were small to medium (r=-0.43 to 0.47). In contrast, serous tumors showed less pronounced biobehavioral-mitochondrial correlations. These results document abnormal mitochondrial functional phenotypes in ovarian tumors and warrant further research on the link between biobehavioral factors and mitochondria in cancer.

Differential levels of serum PSA related to volume of benign, Gleason pattern 3 and pattern 4 prostate tissue.

164 Background: PSA is an essential component of prostate cancer screening, management, and oncologic risk. We evaluated how serum levels of PSA vary by volume of benign tissue, Gleason pattern 3 (GP3), and Gleason pattern 4 (GP4). Methods: Consecutive men undergoing radical prostatectomy at two academic institutions for pT2N0, Gleason grade group 1-4, and undetectable postoperative PSA were reviewed. For each man, estimated volume (cc) of benign, GP3, and GP4 were extracted from the prostatectomy specimen. The primary analysis evaluated the association between pre-operative PSA and volume of each type of prostate tissue using multivariable linear regression with adjustment for age. An assessment of predictiveness (R2) for PSA level was performed with each predictor and associated non-linear terms were removed from the model. Results: Estimated contribution to serum PSA for institutions A and B was 0.04-0.05 ng/ml/cc for benign, 0.08-0.11 ng/ml/cc for GP3, and 0.62-0.83 ng/ml/cc for GP4 (Table). We did not see a difference between PSA levels per cc of GP3 vs. benign tissue (p=0.4). R2decreased only slightly when removing age (0.006-0.010), benign tissue (0.049-0.051) or GP3 (0.011-0.023) from the model. When GP4 was removed, R2 decreased 0.063-0.310. R2 was far higher for GP4 than for Grade Group alone and was equal or superior to Grade Group plus total prostate volume. Conclusions: In early stage Grade Group 1-4 prostate cancer, one cc of Gleason pattern 4 was associated with 6 to 20-fold more serum PSA than one cc of Gleason pattern 3 or benign tissue. No difference in PSA per cc was observed between Gleason pattern 3 and benign tissue which has clinical implications for screening and active surveillance. [Table: see text]