Dissemination Of Malignant Cells Research Articles

Pulsing Addition to Modulated Electro-Hyperthermia.

Numerous preclinical results have been verified, and clinical results have validated the advantages of modulated electro-hyperthermia (mEHT). This method uses the nonthermal effects of the electric field in addition to thermal energy absorption. Modulation helps with precisely targeting and immunogenically destroying malignant cells, which could have a vaccination-like abscopal effect. A new additional modulation (high-power pulsing) further develops the abilities of the mEHT. My objective is to present the advantages of pulsed treatment and how it fits into the mEHT therapy. Pulsed treatment increases the efficacy of destroying the selected tumor cells; it is active deeper in the body, at least tripling the penetration of the energy delivery. Due to the constant pulse amplitude, the dosing of the absorbed energy is more controllable. The induced blood flow for reoxygenation and drug delivery is high enough but not as high as increasing the risk of the dissemination of malignant cells. The short pulses have reduced surface absorption, making the treatment safer, and the increased power in the pulses allows the reduction of the treatment time needed to provide the necessary dose.

Phloridzin Docosahexaenoate, an Omega-3 Fatty Acid Ester of a Flavonoid Precursor, Inhibits Angiogenesis by Suppressing Endothelial Cell Proliferation, Migration, and Differentiation.

Angiogenesis is a normal physiological process that also contributes to diabetic retinopathy-related complications and facilitates tumor metastasis by promoting the hematogenic dissemination of malignant cells from solid tumors. Here, we investigated the in vitro, ex vivo, and in vivo anti-angiogenic activity of phloridzin docosahexaenoate (PZ-DHA), a novel ω-3 fatty acid ester of a flavonoid precursor. Human umbilical vein endothelial cells (HUVEC) and human dermal microvascular endothelial cells (HMVEC) treated with a sub-cytotoxic concentration of PZ-DHA to assess in vitro anti-angiogenic activity showed impaired tubule formation on a Matrigel matrix. Ex vivo angiogenesis was measured using rat thoracic aortas, which exhibited reduced vessel sprouting and tubule formation in the presence of PZ-DHA. Female BALB/c mice bearing VEGF165- and basic fibroblast growth factor-containing Matrigel plugs showed a significant reduction in blood vessel development following PZ-DHA treatment. PZ-DHA inhibited HUVEC and HMVEC proliferation, as well as the migration of HUVECs in gap closure and trans-well cell migration assays. PZ-DHA inhibited upstream and downstream components of the Akt pathway and vascular endothelial growth factor (VEGF165)-induced overexpression of small molecular Rho GTPases in HUVECs, suggesting a decrease in actin cytoskeletal-mediated stress fiber formation and migration. Taken together, these findings reveal the potential of combined food biomolecules in PZ-DHA to inhibit angiogenesis.

Predominant localization and ways of metastatic dissemination to the brain of malignant tumors of the female reproductive system

Background. Metastases of the female reproductive system cancer to the brain are rare and reach about 5 % of all cases with metastatic lesions of the central nervous system. The most common metastases are ovarian cancer (0.49–6.1 %), endometrial cancer (0.4–1.2 %) and cervical cancer (0.3–0.9 %). The predominant localization and ways of spreading metastases to the brain in this category of tumors may differ from lung cancer, breast cancer, kidney cancer or melanoma.Aim. To analyze the localization of brain metastases of malignant tumors of the female reproductive system and the ways of dissemination of malignant cells from the primary focus to the central nervous system.Materials and methods. From 2013 to 2020, a total number of 448 patients with metastatic brain tumors from different cancers were operated on at the Department of Neuro‑Oncology of the Federal Center of Neurosurgery (Novosibirsk). Metastases of tumors of the female reproductive system were presented in 32 (7.1 %) cases. The average age was 55.1 (27–72) years. Ovarian cancer was the primary focus in 24 (5.3 %) cases, endometrial cancer – in 6 (1.3 %), cervical cancer – in 2 (0.4 %). Occipital lobe was the most often location for the metastases in the brain and occurred in 10 (31.3 %) patients. Subtentorial localization was on the second place and noted in 9 (28.1 %) cases. Of these, metastases to the cerebellum were registered in 8 cases and in 1 case the metastasis was located in the brain stem.Results. Gross total removal of metastasis was achieved in all 32 patients. Of 9 cases with subtentorial localization of metastasis, only 1 patient had lung metastases verified. Regression of neurological symptoms and improvement of the condition were noted in 16 patients after surgery. The Karnovsky performance score at the time of discharge was 85.2.Conclusion. The subtentorial location of metastases in malignant tumors of the female reproductive system occupies one of the leading places. This is because the dissemination of tumor cells from the pelvis can occur through a Batson vertebral venous system directly to the cerebellum or brain stem without the pulmonary blood circulation and lung dissemination. This should be taken into account for the early diagnosis of subtentorial metastatic brain tumors and referral of these patients for neurosurgical treatment.

Modelling Myeloma Dissemination in vitro with hMSC-Interacting Subpopulations of INA-6 Cells and their Aggregation/Detachment Dynamics.

Multiple myeloma involves early dissemination of malignant plasma cells across the bone marrow; however, the initial steps of dissemination remain unclear. Human bone marrow-derived mesenchymal stromal cells (hMSCs) stimulate myeloma cell expansion (e.g., IL-6) and simultaneously retain myeloma cells via chemokines (e.g., CXCL12) and adhesion factors. Hence, we hypothesized that the imbalance between cell division and retention drives dissemination. We present an in vitro model using primary hMSCs co-cultured with INA-6 myeloma cells. Time-lapse microscopy revealed proliferation and attachment/detachment dynamics. Separation techniques (V-well adhesion assay and well plate sandwich centrifugation) were established to isolate MSC-interacting myeloma subpopulations that were characterized by RNAseq, cell viability and apoptosis. Results were correlated with gene expression data (n=837) and survival of myeloma patients (n=536). On dispersed hMSCs, INA-6 saturate hMSC-surface before proliferating into large homotypic aggregates, from which single cells detached completely. On confluent hMSCs, aggregates were replaced by strong heterotypic hMSC-INA-6 interactions, which modulated apoptosis time-dependently. Only INA-6 daughter cells (nMA-INA6) detached from hMSCs by cell division but sustained adherence to hMSC-adhering mother cells (MA-INA6). Isolated nMA-INA6 indicated hMSC-autonomy through superior viability after IL-6 withdrawal and upregulation of proliferation-related genes. MA-INA6 upregulated adhesion and retention factors (CXCL12), that, intriguingly, were highly expressed in myeloma samples from patients with longer overall and progression-free survival, but their expression decreased in relapsed myeloma samples. Altogether, in vitro dissemination of INA-6 is driven by detaching daughter cells after a cycle of hMSC-(re)attachment and proliferation, involving adhesion factors that represent a bone marrow-retentive phenotype with potential clinical relevance.

Activated platelets facilitate hematogenous metastasis of breast cancer by modulating the PDGFR-β/COX-2 axis

Platelets have been widely recognized as a bona fide mediator of malignant diseases, and they play significant roles in influencing various aspects of tumor progression. Paracrine interactions between platelets and tumor cells have been implicated in promoting the dissemination of malignant cells to distant sites. However, the underlying mechanisms of the platelet-tumor cell interactions for promoting hematogenous metastasis are not yet fully understood. We found that activated platelets with high expression of CD36 were prone to release a plethora of growth factors and cytokines, including high levels of PDGF-B, compared to resting platelets. PDGF-B activated the PDGFR-β/COX-2 signaling cascade, which elevated an array of pro-inflammatory factors levels, thereby aggravating tumor metastasis. The collective administration of CD36 inhibitor and COX-2 inhibitor resolved the interactions between platelets and tumor cells. Collectively, our findings demonstrated that targeting the crosstalk between platelets and tumor cells offers potential therapeutic strategies for inhibiting tumor metastasis.

Circulating Tumor Cells in Breast Cancer: A Step Toward Precision Medicine for Real-Time Monitoring of Metastasis

Tumor metastasis involves the dissemination of malignant cells into the basement membrane and vascular system contributes to the circulating pool of these markers. In this context our aim has been focused on development of a non-invasive score based on degradation of glycosaminoglycans in the extracellular matrix for assessment of metastasis in patients with breast cancer. Circulating tumor cells (CTCs) represent a unique liquid biopsy carrying comprehensive biological information of the primary tumor. Herein, we sought to develop a novel score based on the combination of the most significant CTCs biomarkers with and routine laboratory tests for accurate detection of Metastases in patients with breast cancer. Cytokeratin 18 (CK18), Cytokeratin 19 (CK19) and CA15.3 were assayed in metastatic breast cancer patients (88), non-metastatic breast cancer patients (129) and healthy control (32). Areas under receiving operating curve (AUCs) were calculated and used for construction on novel score. A novel score named CTC-MBS = CA15.3 (U/L) × 0.08 + CK 18 % × 2.9 + CK19 × 3.1. CTC-MBS score produces AUC of 1 for differentiate patients with metastatic breast cancer from those with non-metastatic breast cancer with sensitivity and specificity of a cut-off 0 (i.e., less than 0 the case is considered metastatic, whereas above 0 it is considered non-metastatic. CTC-MBS score is a novel, non-invasive and simple can applied to discriminate patients with metastatic breast cancer and could replace CA15.3 during screening and follow-up of breast cancer patients.

The Impact of Molecular Biology in the Seeding, Treatment Choices and Follow-Up of Colorectal Cancer Liver Metastases-A Narrative Review.

There is a clear association between the molecular profile of colorectal cancer liver metastases (CRCLM) and the degree to which aggressive progression of the disease impacts patient survival. However, much of our knowledge of the molecular behaviour of colorectal cancer cells comes from experimental studies with, as yet, limited application in clinical practice. In this article, we review the current advances in the understanding of the molecular behaviour of CRCLM and present possible future therapeutic applications. This review focuses on three important steps in CRCLM development, progression and treatment: (1) the dissemination of malignant cells from primary tumours and the seeding to metastatic sites; (2) the response to modern regimens of chemotherapy; and (3) the possibility of predicting early progression and recurrence patterns by molecular analysis in liquid biopsy.

Does gas insufflation during oncologic laparoscopic surgery cause dissemination of malignant cells?

To investigate whether benign or malignant cells are present in gas evacuated from the abdominal cavity during oncologic laparoscopic surgery. Thirty patients were included in this prospective observational study conducted at an academic, tertiary medical center. Fifteen patients underwent a laparoscopic staging procedure for high-grade uterine adenocarcinoma and 15 patients underwent laparoscopic nephrectomy for suspected renal cell carcinoma. The gas evacuated during laparoscopy was passed through a filter in order to capture any aerosolized cells formed during surgery. After surgery, the filter was rinsed backwards with 50 mL of saline, and the fluid was centrifuged and sent for cytological evaluation. The primary outcome was presence of benign or malignant cells in the rinsed fluid. Neither benign nor malignant cells were identified in evacuated gas in 29 cases (96.7%). In one endometrial cancer case, where macroscopic extra-uterine pelvic metastases were encountered intra-operatively, atypical epithelial cells were found in collected fluid of rinsed gas filter. Gas insufflation during laparoscopy for gynecologic and urologic malignancies apparently does not cause aerosolization and dissemination of malignant cells. However, laparoscopic surgery itself may cause cell spread possibly via surgical instruments when macroscopic, extra-organ tumor spread is encountered, the clinical significance of which remains undetermined.

Clonal Hematopoiesis Evolves into Dendritic Cell Neoplasm through the Acquisition of UV Mutations in the Skin

Background Expansion of blood cells derived from a single mutated blood stem cell - clonal hematopoiesis - often precedes leukemic transformation. However, the circumstances that promote or prevent transformation are poorly understood. Here, we investigate the evolution of clonal hematopoiesis into blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive blood cancer that often presents with malignant cells isolated to the skin (referred to as skin-only disease). We gain a better understanding of the influence of site-specific selective pressures and the role of TET2 mutations, which may inform interventions to prevent disease progression. Methods We analyzed bone marrow and skin from 13 BPDCN patients using targeted, exome, and whole-genome sequencing, with germline controls. We performed multimodal single-cell sequencing (10x 3' v3.1 single-cell RNA-seq with genotyping of expressed variants) on bone marrow from 6 healthy donors (20,411 cells), 5 skin-only BPDCN patients with malignant cells in the skin but not conventionally detectable in marrow (36,018 cells), and 6 BPDCN patients with overt bone marrow involvement (30,582 cells). For functional studies, we targeted Tet2 using CRISPR/Cas9 in mouse blood progenitor cells immortalized by an estrogen receptor hormone binding domain fused to HoxB8, which undergo synchronized differentiation to myeloid and dendritic cells upon estrogen withdrawal. We used CellRanger, Seurat, RandomForest machine learning, and the R tidyverse package collection for bioinformatics. Results Genetics allowed us to reconstruct the evolution of BPDCN across bone marrow and skin (representative patient, panel a). Invariably, we detected founder mutations in marrow, including TET2 inactivation in 9/13 patients (two mutations, likely bi-allelic, in 5/9). Single-cell sequencing of marrow from 5 skin-only patients showed that pre-malignant mutant stem cells contributed to multiple lineages, and that TET2 mutated clones were myeloerythroid-biased. We generated a gene expression signature to identify rare malignant BPDCN cells in marrow of skin-only patients. In 3/5 patients, we identified rare cells (0.03-0.19%) with the transcriptional profile of fully transformed cells, and concurrent single-cell genetic analysis suggested that these cells originated from the skin tumor (panel b). To assess whether disseminated skin tumor cells establish bone marrow disease, we quantified mutational signatures: skin tumors and malignant BPDCN marrow cells in 5/5 patients harbored UV-induced mutations, likely acquired in a single skin-resident plasmacytoid dendritic cell (pDC) during malignant transformation. Finally, we edited Tet2 in mouse myelo-dendritic progenitors and tested the response to UV irradiation in vitro. In addition to observing that Tet2 inactivation increases dendritic cell commitment, the more striking result was a survival advantage of Tet2-mutated cells in the presence of UV (n = 6, fold change 1.803, P = 0.0012). These results highlight an unexpected function of TET2 that may predispose mutated pDCs to survive UV-induced DNA damage in the skin, leading to disease progression. Conclusion The complex evolution of BPDCN traverses multiple anatomic sites prior to full transformation. This allows for accurate sequencing of oncogenic events. Disease evolution frequently starts with acquisition of a leukemia-associated mutation in a multipotent blood stem cell, leading to clonal expansion. In the most frequently observed scenario, bi-allelic TET2 inactivation promotes myeloerythroid bias, increases dendritic cell commitment, and confers resistance to UV-mediated cell death. Subsequent evolution of skin-resident mutant pDCs leads to a high burden of UV-induced mutations and ultimate transformation. Dissemination of malignant cells, which can be detected by integrating single-cell gene expression and mutation profiles, initiates "retrograde" bone marrow disease. Our discovery that multiple anatomic sites - and local selective pressures - play a role in disease progression provides a template to study multi-site evolution of clonal hematopoiesis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sequencing of cerebrospinal fluid in non-small-cell lung cancer patients with leptomeningeal metastasis: A systematic review.

Leptomeningeal metastasis (LM) refers to the dissemination of malignant cells in the subarachnoid space, pia, and arachnoid mater and is a severe condition associated with metastatic solid tumors. The most common solid tumor that develops into LM is lung cancer and the incidence increased in patients with advanced non-small-cell lung cancer (NSCLC) with targetable mutations. However, tissue biopsy of LM is inaccessible, leading to the paucity of genomic profiles of LM to guide targeted treatments and explore biological mechanisms. In recent years, liquid biopsy is considered a minimally invasive and dynamic method to trace the genomic alterations of cancer cells and some studies started to perform sequencing of cerebrospinal fluid (CSF) in patients with LM to reveal the targeted mutations and genomic profiles. In this review, we focused on studies performed sequencing of CSF in NSCLC patients with LM and summarized the sequencing results and their commonality. As the only way to reveal the genomic landscapes of LM, our review provided evidence that sequencing of CSF is a promising management method in LM patients to dynamically guide target therapy and monitor intracranial tumor response. Furthermore, it reveals a unique genomic profile of LM including driver genes, drug-resistant mutations, and a number of copy number variations. Sequencing of CSF in LM patients seems to provide more comprehensive genomic information than we expected and the biological significance behind the genomic alternations needs further study.

Does Gas Insufflation during Gynecologic or Urologic Oncologic Laparoscopy Cause Dissemination of Malignant Cells

<h3>Study Objective</h3> To investigate whether benign or malignant cells are found in evacuated gas during laparoscopy for gynecological or urological malignancies. <h3>Design</h3> Observational prospective study. <h3>Setting</h3> Academic, tertiary medical center. <h3>Patients or Participants</h3> A total of 30 patients were included; 15 underwent laparoscopic staging due to uterine adenocarcinoma and 15 had laparoscopic nephrectomy due to suspected renal cell carcinoma. <h3>Interventions</h3> All gas evacuated during laparoscopy was passed through a filter in order to capture any aerosolized cells formed during surgery. After surgery, the filter was rinsed backwards with 50 CC of normal saline. The fluid was collected, centrifuged and sent for cytological evaluation. Filter ability to capture malignant cells was proved by filtering ascites fluid of an ovarian cancer patient through the filter. The primary outcome was the rate laparoscopic surgeries in which the filtered sample was positive for malignant or benign cells. <h3>Measurements and Main Results</h3> No benign or malignant cells were identified in evacuated gas during laparoscopic surgeries in all but one case. This case of malignant adenocarcinoma had a clear, macroscopic extra-uterine pelvic spread and malignant adenocarcinoma cells were identified in the cytology examination of the fluid collected. <h3>Conclusion</h3> In contrast to previous concerns, in all cases where the tumor was confined to its' organ, we found no evidence of benign or malignant cell spread in the gas evacuated from the abdominal or retroperitoneal cavity during laparoscopy. The single event of malignant cells from aerosolized gas was in a case with a macroscopic, extra-organ involvement. Our study confirms the safety of performing laparoscopic surgery for gynecologic and urologic malignancies with regard to aerosolized gas. The explanation for malignant cells found in evacuated gas could be both aerosolization of cells or cells that adhered to surgical instruments. The clinical significance of this finding in the setting of macroscopic, extra-organ tumor spread is unclear.

Mechanisms and Clinical Significance of Tumor Lymphatic Invasion.

Tumor-associated lymphatic vessels play an important role in tumor progression, mediating lymphatic dissemination of malignant cells to tumor-draining lymph nodes and regulating tumor immunity. An early, necessary step in the lymphatic metastasis cascade is the invasion of lymphatic vessels by tumor cell clusters or single tumor cells. In this review, we discuss our current understanding of the underlying cellular and molecular mechanisms, which include tumor-specific as well as normal, developmental and immunological processes “hijacked” by tumor cells to gain access to the lymphatic system. Furthermore, we summarize the prognostic value of lymphatic invasion, discuss its relationship with local recurrence, lymph node and distant metastasis, and highlight potential therapeutic options and challenges.

Whether preoperative hysteroscopy increases the dissemination of endometrial cancer cells: A systematic review and meta-analysis.

To determine whether hysteroscopy (HSC) increases the risk of intraperitoneal dissemination in endometrial cancer patients. We conducted a comprehensive review of multiple databases. Quality assessments of eligible studies were performed using the Newcastle-Ottawa and Jadad scales. Positive peritoneal cytology (PPC) as the outcome of interest was compared between endometrial cancer patients with and without HSC. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated as a measure of effects. Three case-control studies and eight retrospective cohort studies included 3364 patients, of whom 1116 underwent preoperative HSC, which resulted in a significantly higher PPC rate (OR, 1.82; 95% CI, 1.31-2.54; p=0.0004). I2 was 11%, and the heterogeneity was acceptable. The difference between the groups with stages I-II was statistically insignificant (OR, 1.50; 95% CI, 0.75-2.99; p=0.25). When liquid was used as the uterine distension medium during HSC and the intrauterine pressure was controlled under 80 mmHg, the difference between the two groups was also insignificant (OR, 1.18; 95% CI, 0.50-2.79; p=0.71). However, when the intrauterine pressure exceeded 80 mmHg, the difference between the two groups was statistically significant (OR, 2.18; 95% CI, 1.28-3.73; p=0.004). This meta-analysis indicates that preoperative HSC in patients with endometrial cancer may increase the risk of intraperitoneal dissemination of malignant cells, which may be associated with intrauterine pressure >80 mmHg but not with stages I-II. There is no reason to avoid HSC for the diagnosis of endometrial cancer, especially in early stages, but intrauterine pressure should possibly be controlled below 80 mmHg.

Port site metastases a year after initial laparoscopic cholecystectomy. Should the use of retrieval bags during laparoscopic cholecystectomy be the new gold standard?

Port site metastases a year after initial laparoscopic cholecystectomy. Should the use of retrieval bags during laparoscopic cholecystectomy be the new gold standard?

Pathophysiological and anatomical basis of lymphatic transit of cancer cells and role of the lymphatic system: a review of published literature

Cancer metastasis involves dissemination of malignant cells from the primary tumor, via local lymphatic vessels to gain access to systemic circulation, while evading the destruction by immune cells, followed by successful extravasation and initiation of malignant growth in the distant organ. Despite the obvious contribution of the lymphatic system to the metastatic spread of cancer, basic research regarding the mechanisms leading to tumor dissemination via lymphatic vessels has been limited for years. Recent identification of molecular growth factors of lymphangiogenesis have led to new advances in our understanding of the underlying mechanisms of tumor metastasis. These growth factors have enabled scientists to better identify peritumoral lymphatics and to visualize precisely the ingrowth of tumor cells into the lumen of lymphatic capillaries. Moreover, it has been shown that these molecular markers secreted from a primary tumor can induce lymphangiogenesis in close regional lymph nodes, even prior to tumor cells arrival, which may facilitate metastasis spread. Comprehensive research of the multiplex interactions between tumor cells, lymphatics and the immune system will be crucial to further enhance the development of therapeutic and prognostic approaches to cancer. This review presents the ontogeny and anatomy of the lymphatic vasculature, discuss the immunological, molecular and physiological control of lymphatic vessel function, and explore the contribution of the lymphatic system to the development of metastases.

Spotlight on… heavy menstrual bleeding and uterine fibroids

Heavy menstrual bleeding (HMB) is a common condition affecting 20–30% of women of reproductive age.1 In England and Wales, nearly 80 000 women a year are referred to secondary care, with one-third of those subsequently undergoing surgical interventions.1 It is not uncommon for HMB to be associated with fibroid uterus, endometriosis and adenomyosis, and in a minority of cases, it may be an early sign of endometrial hyperplasia or cancer. The national HMB audit also highlighted that almost one-third of women affected by HMB had not received treatment in primary care before referral to secondary care.1 This figure could be quite different during the current COVID-19 pandemic. The audit also pointed out that women from ethnic minority groups and those from more socio-economically deprived areas made more visits to their GP regarding their HMB and saw less improvement in their condition.1 Women from more deprived areas also reported more severe HMB symptoms and poorer quality of life.2 It is therefore important to recognise any intervention should aim to improve quality of life rather than focusing on blood loss.3 Heavy menstrual bleeding is also the most common cause of iron deficiency and iron-deficiency anaemia in premenopausal women, which is frequently overlooked in routine practice (TOG 2017;19:155–61). In the last 10 years, The Obstetrician & Gynaecologist (TOG) has featured a number of articles covering HMB-related topics. A well-established National Institute for Health and Care Excellence (NICE) guideline on assessment and management of HMB was updated in 2018 and 2020.3 Since the first edition published in 2007, there have been very few changes in the medical management of HMB. Carey and Allen (TOG 2012;14:223–8) described the noncontraceptive uses and benefits of combined oral contraception, while Murdoch and Roberts (TOG 2014;16:46–50) explored the mode of action and the potential use of selective progesterone receptor modulators in treating fibroid uterus, although its use on uterine fibroids has been largely halted in the last couple years due to serious health complications.3 Nearly one-third of women with HMB referred to secondary care will subsequently require surgical interventions.1 Saraswat and Cooper conducted an in-depth review of endometrial ablation (TOG 2017;19:37–45), which covers its development, patient satisfaction rates, safety, the long-term sequelae and the cost-effectiveness of first- and second-generation techniques of endometrial ablation. Overall patient satisfaction rates and amenorrhoea rates were up to 80% and 50%, respectively. Nevertheless, around one in six women would still require further surgical intervention within 5 years. Ultimately, only hysterectomy can ensure long term amenorrhoea. The same authors (TOG 2017;19:101–8) also examined different surgical approaches to hysterectomy (laparoscopic, abdominal and vaginal) as well as myomectomy. A recently published multi-centre randomised controlled trial (the HEALTH study)4 concluded that laparoscopic supracervical hysterectomy is superior to second generation endometrial ablation in terms of clinical effectiveness, although the differences were relatively moderate. A laparoscopic approach may and should become the standard approach in performing hysterectomy. Elnasharty and Moustafa provide useful tips and techniques on dealing with the challenges in laparoscopic hysterectomy (TOG 2020; 22:313–7). HMB is often found to be associated with fibroid uterus, although not all women with fibroid uterus complain of HMB. This poses a significant management dilemma, especially among women with a history of subfertility. Younas et al. summarised the recent evidence on managing uterine fibroids including uterine artery embolisation, magnetic resonance imaging-guided focused ultrasonography as well as a different surgical approach on myomectomy (TOG 2016;18:33–42). A similar review was also published in 2018, when Bryant-Smith and Holland predominately explored the techniques and controversies in laparoscopic myomectomy, although they also examined the potential risk of unintentional dissemination of malignant cells during intracorporeal morcellation of undiagnosed leiomyosarcoma (TOG 2018;20:261–8). In the same issue of TOG, Sampat and Alleemudder reviewed the management and outcomes of fibroids in pregnancy (TOG 2018;20:187–95). As mentioned earlier, HMB can be a sign of endometrial hyperplasia or cancer, particularly in women with history of polycystic ovary syndrome and/or being overweight. Jones et al. discussed the diagnostic tools for detecting endometrial cancer (TOG 2021;23:103–12). All of the above contributing authors emphasised the importance of involving patients in the decision-making process, however, Jeffery, Kayani and Garden reminded us of the difficulties in managing menstrual problems in adolescents with learning disabilities (TOG 2013;15:106–12). This article also evaluated the need for different management options. An online collection of TOG articles on heavy menstrual bleeding and uterine fibroids is available at http://onlinetog.org.

Monitoring radiofrequency therapy-induced tumor cell dissemination by in vivo flow cytometry.

Clinical and experimental findings have disclosed a high recurrence rate after radiofrequency ablation (RFA), which might be due to the dissemination of malignant cells into the vasculature during ablation. Here, we apply in vivo flow cytometry (IVFC) to monitor circulating tumor cells (CTCs) while performing ablation in a real-time and noninvasive way in an orthotopic model of prostate cancer. We report that CTCs are dramatically increased during RFA. The CTCs induced by ablation eventually translate into enhanced distant metastasis and reduced survival as compared to resection. Immunofluorescence analysis reveals that RFA significantly increases the infiltration of tumor-associated macrophages (TAMs) in the lung. Our study thus suggests that the ablative procedure of prostate tumors causes immediate tumor cell dissemination and increases distant metastasis.

Hysteroscopic Morcellation in Endometrial Cancer Diagnosis: Increased Risk?

Operative hysteroscopy requires elevated intrauterine pressures, which could lead to the spread of malignant cells into the peritoneal cavity. Currently, there is a paucity of data analyzing clinical outcomes in endometrial cancer after hysteroscopic morcellation with newer equipment. In this study, we sought to determine whether there are increased rates of positive peritoneal cytology, lymphovascular space invasion, or surgical upstaging in patients undergoing hysteroscopic morcellation compared with alternative endometrial biopsy methods. A retrospective chart review of patients from 2013-2018 was performed. The exclusion criteria included biopsy at outside institution, stage IV endometrial cancer known before biopsy, and missing data regarding biopsy method and histology. Peritoneal cytology results, lymphovascular space invasion, and surgical staging were compared by method of biopsy and histology using chi-square and Kruskal-Wallis tests. The patients included in this study were accrued from the Karmanos Cancer Insittute in Detroit, Michigan. A total of 289 patients met the inclusion criteria: 184 patients were classified as low-grade (Fédération Internationale de Gynécologie et d'Obstétrique grades 1 and 2) and 105 as high-grade (Fédération Internationale de Gynécologie et d'Obstétrique grade 3, serous, clear cell, and carcinosarcoma) endometrial cancer. Fifty-three patients (18%) underwent hysteroscopy with morcellation. Alternative biopsy methods included hysteroscopy without morcellation, n = 81 (28%); endometrial biopsy, n = 112 (38.7%); and dilation and curettage, n = 43 (15%). Positive peritoneal cytology was noted in 34 cases (12%) and negative cytology in 165 (57%). Cytology was not performed in 90 cases (31%). When comparing outcomes by histologic subtypes, no difference was seen in peritoneal cytology (p = .704 and .727 for low grade and high grade, respectively), stage (p = .773 and .053 for low grade and high grade, respectively) or lymphovascular space invasion (p = .400 and .142 for low grade and high grade, respectively). Our study demonstrates that hysteroscopy with morcellation is a safe diagnostic method for low- and high-grade endometrial pathologic conditions and does not lead to increased dissemination of malignant cells, lymphovascular space invasion, or upstaging of patients.

Cytokine profile in multiple myeloma

BackgroundCytokines play a crucial role in the growth, survival and dissemination of malignant plasma cells in patients of multiple myeloma (MM). We estimated concentrations of five key cytokines: Vascular Endothelial Growth Factor (VEGF), Interleukin-6 (IL-6), Tumor Necrosis Factor- alpha (TNF- α), B-cell activating factor (BAFF), and Receptor Activator of Nuclear Factor-κB ligand (RANKL) in newly diagnosed and relapsed/refractory MM (RRMM). MethodsThe study groups include 68 newly diagnosed and 21 relapsed/refractory (RR) MM patients. 32 out of 68 newly diagnosed MM patients were evaluated for serum cytokine concentrations after their treatment. For survival analysis, the various parameters were studied in relation to both progression free survival (PFS) and overall survival (OS). ResultsThe median serum levels of VEGF, IL-6, BAFF and RANKL were higher in RRMM compared with newly diagnosed patients. However, the difference was significant for BAFF levels (p = 0.04). The median serum levels of VEGF, IL-6, TNF-α, BAFF and RANKL were significantly higher in newly diagnosed and RRMM patients, compared to controls. We also observed lower plasma levels of VEGF (p=<0.0001) and BAFF (p=<0.0001) in BM compartment compared to the levels in serum from peripheral blood of newly diagnosed patients. Significant reduction in the median levels of IL-6, TNF-α, BAFF and RANKL was seen after 4–6 cycles of induction treatment in responders but not in non-responders. On survival analysis, RRMM patients had inferior median OS and PFS compared to that in newly diagnosed MM patients and found to be significantly associated with low haemoglobin representing the more aggressive disease biology in recurrent myeloma. The mean levels of IL-6 were significantly different in patients who died as compared to patients who were alive. ConclusionsThe present study demonstrates that the serum levels of VEGF, IL-6, TNF, BAFF and RANKL are significantly elevated and decrease significantly after treatment. The concentrations of circulating cytokines will reflect those of the bone marrow and could be used for subsequent analyses.

Unraveling mucin domains in cancer and metastasis: when protectors become predators.

A dynamic mucosal layer shields the epithelial cells lining the body cavities and is made up of high molecular weight, heavily glycosylated, multidomain proteins called mucins. Mucins, broadly grouped into transmembrane and secreted mucins, are the first responders to any mechanical or chemical insult to the epithelia and help maintain tissue homeostasis. However, their intrinsic properties to protect and repair the epithelia are exploited during oncogenic processes, where mucins are metamorphosed to aid the tumor cells in their malignant journey. Diverse domains, like the variable number tandem repeats (VNTR), sea urchin sperm protein enterokinase and agrin (SEA), adhesion-associated domain (AMOP), nidogen-like domain (NIDO), epidermal growth factor-like domain (EGF), and von Willebrand factor type Ddomain (vWD) on mucins, including MUC1, MUC4, MUC5AC, MUC5B, and MUC16, have been shown to facilitate cell-to-cell and cell-to-matrix interactions, and cell-autonomous signaling to promote tumorigenesis and distant dissemination of tumor cells. Several obstacles have limited the study of mucins, including technical difficulties in working with these huge glycoproteins, the dearth of scientific tools, and lack of animal models; thus, the tissue-dependent and domain-specific roles of mucins during mucosal protection, chronic inflammation, tumorigenesis, and hematological dissemination of malignant cells are still unclear. Future studies should try to integrate information on the rheological, molecular, and biological characteristics of mucins to comprehensively delineate their pathophysiological role and evaluate their suitability as targets in future diagnostic and therapeutic strategies.