Artificial intelligence for breast cancer detection in screening mammography in Sweden: a prospective, population-based, paired-reader, non-inferiority study.

BACKGROUND: Artificial intelligence (AI) as an independent reader of screening mammograms has shown promise, but there are few prospective studies. Our aim was to conduct a prospective clinical trial to examine how AI affects cancer detection and false positive findings in a real-world setting. METHODS: ScreenTrustCAD was a prospective, population-based, paired-reader, non-inferiority study done at the Capio Sankt Göran Hospital in Stockholm, Sweden. Consecutive women without breast implants aged 40-74 years participating in population-based screening in the geographical uptake area of the study hospital were included. The primary outcome was screen-detected breast cancer within 3 months of mammography, and the primary analysis was to assess non-inferiority (non-inferiority margin of 0·15 relative reduction in breast cancer diagnoses) of double reading by one radiologist plus AI compared with standard-of-care double reading by two radiologists. We also assessed single reading by AI alone and triple reading by two radiologists plus AI compared with standard-of-care double reading by two radiologists. This study is registered with ClinicalTrials.gov, NCT04778670. FINDINGS: From April 1, 2021, to June 9, 2022, 58 344 women aged 40-74 years underwent regular mammography screening, of whom 55 581 were included in the study. 269 (0·5%) women were diagnosed with screen-detected breast cancer based on an initial positive read: double reading by one radiologist plus AI was non-inferior for cancer detection compared with double reading by two radiologists (261 [0·5%] vs 250 [0·4%] detected cases; relative proportion 1·04 [95% CI 1·00-1·09]). Single reading by AI (246 [0·4%] vs 250 [0·4%] detected cases; relative proportion 0·98 [0·93-1·04]) and triple reading by two radiologists plus AI (269 [0·5%] vs 250 [0·4%] detected cases; relative proportion 1·08 [1·04-1·11]) were also non-inferior to double reading by two radiologists. INTERPRETATION: Replacing one radiologist with AI for independent reading of screening mammograms resulted in a 4% higher non-inferior cancer detection rate compared with radiologist double reading. Our study suggests that AI in the study setting has potential for controlled implementation, which would include risk management and real-world follow-up of performance. FUNDING: Swedish Research Council, Swedish Cancer Society, Region Stockholm, and Lunit.

Metastasis of Uterine Leiomyosarcoma to the Breast: Medical and Histopathological Criteria.

It is uncommon for extramammary tumors to metastasize to the breast, and very few cases describing metastasis of primary uterine leiomyosarcoma to the breast have been reported. We present the case of a 51-year-old woman diagnosed with metastasis of uterine leiomyosarcoma to the breast diagnosed 10 years ago after hysterectomy. Ultrasonography, mammography, and cytology were used to establish a preliminary diagnosis that was confirmed upon examination of the excised tumor that show a rare soft tissue tumor composed of atypical spindle cells and increased proliferation rate. We discuss the importance of distinguishing between various primary mesenchymal tumors of the breast because of phenotypic overlap and some guidance of the histological criteria for metastasis of leiomyosarcoma, as well as differential diagnosis and surgical treatment.

Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma.

BACKGROUND: Adoptive natural killer (NK) cell transfer is being increasingly used as cancer treatment. However, clinical responses have so far been limited to patients with hematological malignancies. A potential limiting factor in patients with solid tumors is defective homing of the infused NK cells to the tumor site. Chemokines regulate the migration of leukocytes expressing corresponding chemokine receptors. Various solid tumors, including renal cell carcinoma (RCC), readily secrete ligands for the chemokine receptor CXCR2. We hypothesize that infusion of NK cells expressing high levels of the CXCR2 chemokine receptor will result in increased influx of the transferred NK cells into tumors, and improved clinical outcome in patients with cancer. METHODS: Blood and tumor biopsies from 14 primary RCC patients were assessed by flow cytometry and chemokine analysis. Primary NK cells were transduced with human CXCR2 using a retroviral system. CXCR2 receptor functionality was determined by Calcium flux and NK cell migration was evaluated in transwell assays. RESULTS: We detected higher concentrations of CXCR2 ligands in tumors compared with plasma of RCC patients. In addition, CXCL5 levels correlated with the intratumoral infiltration of CXCR2-positive NK cells. However, tumor-infiltrating NK cells from RCC patients expressed lower CXCR2 compared with peripheral blood NK cells. Moreover, healthy donor NK cells rapidly lost their CXCR2 expression upon in vitro culture and expansion. Genetic modification of human primary NK cells to re-express CXCR2 improved their ability to specifically migrate along a chemokine gradient of recombinant CXCR2 ligands or RCC tumor supernatants compared with controls. The enhanced trafficking resulted in increased killing of target cells. In addition, while their functionality remained unchanged compared with control NK cells, CXCR2-transduced NK cells obtained increased adhesion properties and formed more conjugates with target cells. CONCLUSIONS: To increase the success of NK cell-based therapies of solid tumors, it is of great importance to promote their homing to the tumor site. In this study, we show that stable engineering of human primary NK cells to express a chemokine receptor thereby enhancing their migration is a promising strategy to improve anti-tumor responses following adoptive transfer of NK cells.

Colombian reference growth curves for height, weight, body mass index and head circumference.

AIM: Published Growth studies from Latin America are limited to growth references from Argentina and Venezuela. The aim of this study was to construct reference growth curves for height, weight, body mass index (BMI) and head circumference of Colombian children in a format that is useful for following the growth of the individual child and as a tool for public health. METHODS: Prospective measurements from 27 209 Colombian children from middle and upper socio-economic level families were processed using the generalised additive models for location, scale and shape (GAMLSS). RESULTS: Descriptive statistics for length and height, weight, BMI and head circumference for age are given as raw and smoothed values. Final height was 172.3 cm for boys and 159.4 cm for girls. Weight at 18 years of age was 64.0 kg for boys and 54 kg for girls. Growth curves are presented in a ± 3 SD format using logarithmic axes. CONCLUSION: The constructed reference growth curves are a start for following secular trends in Colombia and are also in the presented layout an optimal clinical tool for health care.

Evaluation of the fallopian tubes after neoadjuvant chemotherapy: persistence of serous tubal intraepithelial carcinoma.

The origin of pelvic serous carcinoma continues to be controversial. Recent studies of patients undergoing primary surgery for ovarian, primary peritoneal, and uterine serous carcinomas have indicated the value of complete fimbrial sampling for detecting occult serous tubal intraepithelial carcinoma (STIC). Evidence suggests that a significant proportion of pelvic serous carcinomas may arise from in situ lesions on the distal fallopian tube. In this study, 14 consecutive cases of interval debulking surgery after neoadjuvant chemotherapy were reviewed, using both hematoxylin and eosin staining and, as needed, immunohistochemistry for p53 and MIB-1. The degree of fimbrial sampling was evaluated, and cases were examined for tumor involvement in the endosalpinx and the presence of STIC. Tumor treatment response was classified using a semiquantitative 4-tier scale. The results indicate that STIC can persist despite chemotherapy and can be readily identified during microscopic examination. These results are expected to improve the quality of the pathology evaluation by providing data-driven recommendations for sampling in interval surgery cases and showing the value of a systematic approach to evaluating the fallopian tube (sectioning and extensively examining the fimbria protocol). These results demonstrate that a tubal primary can still be assigned in these situations. Finally, this study raises interesting biologic questions about the sensitivity of cells originating from serous cancer tumor to chemotherapy. The presence or absence of STIC in specimens from interval surgery after neoadjuvant treatment has not previously, to our knowledge, been addressed.

Male germ cell development in humans.

BACKGROUND: Germ cells are unique cells that possess the ability to transmit genetic information between generations. Detailed knowledge about the molecular and cellular mechanisms determining the fate of human male germ cells still remains sparse. This is partially due to ethical issues limiting the access to research material. Therefore, the mechanisms of proliferation, differentiation and apoptosis of human male germ cells still remain challenging study objectives. METHODS: This review focuses on using English articles accessible in PubMed as well as personal files on the current knowledge of the molecular and cellular mechanisms connected with human testicular germ cell development, maturation failure and the possibility of fertility preservation in patients in whom there is a risk of gonadal failure. However, since rodents, particularly mice, offer the possibility of studying germ cell development by use of genetic modification techniques, some studies using animal models are also discussed. CONCLUSION: This mini review focuses on the current knowledge about male germ cells. However, the reader is referred to two previous mini reviews focusing on testicular somatic cells, i.e. on Sertoli cells and Leydig cells.

Insulin-like growth factor-I is an important antiapoptotic factor for rat leydig cells during postnatal development.

The present investigation examines the influence of IGF-I and the role of IGF-I receptor (IGF-IR) in the apoptosis/survival of Leydig cells. Immunohistochemical analysis of the rat testis at different ages revealed that the level of the phosphorylated IGF-IR increases from birth to d 20 of postnatal life, remaining high in the adult testis. Western blotting revealed that this level is higher in Leydig cells isolated from 40-d-old than from 10- or 60-d-old rats. Application of the terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay revealed that IGF-I decreases the level of apoptosis in Leydig cells at all stages of development, and the selective inhibitor of IGF-IR, picropodophyllin, blocks this antiapoptotic effect. The mechanism underlying the antiapoptotic action of IGF-I involves the phosphatidylinositol 3-kinase/Akt pathway, and in immature Leydig cells, this growth factor enhances the expression of Bcl-2 and cellular inhibitor of apoptosis proteins 2, while preventing activation of caspase-3 by cleavage. Furthermore, IGF-II and high concentrations of insulin also evoke phosphorylation of IGF-IR and, like IGF-I, enhance the expression of the steroidogenic acute regulatory protein by Leydig cells. Inhibition of IGF-IR by picropodophyllin decreases the survival of Leydig cells, both in the presence and absence of IGF-I, demonstrating that signaling via the IGF-IR plays an important role in Leydig cell survival.

Anti-apoptotic factor humanin is expressed in the testis and prevents cell-death in leydig cells during the first wave of spermatogenesis.

Humanin (HN) is a 24 amino acids peptide with potent neuro-survival properties that protects against damage associated with Alzheimer's disease. In the present report, we have demonstrated by immunohistochemical analysis and Western blotting the pattern of expression of rat humanin (HNr) in the testis of 10- to 60-day-old rats. The Leydig cells of 10- and 40- day-old rats expressed this peptide at high levels; and in the testis of 60-day-old rats the expression of HNr expanded to include Leydig, endothelial, peritubular and germ cells. As monitored by Western blotting, HNr was released into the medium of cultures of Leydig cells isolated from 10-, 40-, and 60-days-old rats. HNr stimulated the incorporation of [(3)H]TdR into DNA of Leydig cells from 10-days-old rats, in a manner that indicated promotion of cell survival rather than an increase in the rate of cell multiplication. This peptide also enhanced steroidogenesis by cultured Leydig cells from 10- to 40-day-old rats both alone and synergistically with IGF-I. The expression of HNr in cultured Leydig cells increased in response to GH and IGF-I. In summary, we demonstrated here that HNr was expressed at all stages of maturation in the rat testis. This peptide promoted the survival of Leydig cells in culture and interacted with IGF-I to stimulate DNA synthesis and steroidogenesis. We propose that HNr is a novel testicular anti-apoptotic factor.

Stimulation of steroidogenesis in immature rat Leydig cells evoked by interleukin-1alpha is potentiated by growth hormone and insulin-like growth factors.

The cytokine IL-1alpha is produced constitutively by the intact testis, but its function in this organ remains largely unknown. In this study we examined cooperation between IL-1alpha and GH and IGFs with regard to stimulation of steroidogenesis by Leydig cells from 40-d-old rats in vitro. IL-1alpha alone stimulated testosterone (T) and dihydrotestosterone (DHT) production. GH, IGF-I, or IGF-II alone was without effect on T production, but they were found to elevate DHT release, albeit without an obvious dose-response effect. Costimulation with IL-1alpha and GH or with IL-1alpha and IGF-I or IGF-II elevated the rate of steroidogenesis (both T and DHT) above that observed with IL-1alpha alone. GH was found to increase the level of IGF-I in the cultured Leydig cells, an effect that was potentiated by IL-1alpha. The costimulatory effect of GH on steroidogenesis was abolished by treatment with picropodophyllin, a specific inhibitor of the IGF-I receptor, indicating that the action of GH is mediated via IGF-I. Moreover, cells costimulated with IL-1alpha and GH exhibited a marked decrease in the level of intact IGF-binding protein-3 in the culture medium due to the induction of proteolytic activity toward this binding protein. In contrast, secretion of IGF-binding protein-2 was increased by such costimulation. These findings suggest that the stimulation of steroidogenesis in Leydig cells evoked by GH and IGFs requires cooperation with IL-1alpha. This cooperation may play an important role in connection with postnatal Leydig cell maturation and steroidogenesis.