Bone Infarct Associated Osteosarcoma: Epidemiologic and Survival Trends

Background Bone tumors are not a frequent occurrence and bone-infarct-associated sarcomas are even rarer. The prognosis of this disease is poor and its treatment remains a challenge. Nevertheless, hardly any analyses in literature report on secondary osteosarcoma (SO) on bone infarct and most of the data available do not provide sufficient details. We evaluated whether this condition could be further characterized and if prognosis could be influenced by the chemotherapy treatment. In particular, we sought to determine (1) the main features of this rare disease; (2) the overall survival (OS) rate; (3) the OS rate associated to chemotherapy treatment; (4) the correspondence between our results and published data in terms of survival. Methods We retrospectively reviewed patients admitted at Rizzoli Orthopedic Institute of Bologna between 1992 and 2018 (1465 total cases of osteosarcoma). We identified a list of 11 cases of SO on bone infarct (cohort 1). We conferred about the epidemiology, surgical and chemotherapy (ChT) treatment and surveillance of infarct-associated osteosarcoma showing the correlation to data present in literature, corresponding to 15 case reports published within 1962-2018 (cohort 2). Results (1) cohort 1 was made of 11 patients: six females and five males, median age was 55 years. Nine (81%) were grade 4, two (19%) grade 3. Tumor predominantly arise on distal femur (64%). Most of patients had localized osteosarcoma at the diagnosis (81%); resection surgery was the elective treatment (73%) followed by amputation (18%). Of 11 patients, seven received also ChT (64%). (2) Five-years OS was 62% (95% CI: 28-84). Median OS was 74 months (95% CI: 12-not reached). The cumulative incidence of cancer-related deaths (CICRD) was 37.7% (95% CI: 11.4-64.5) at 120 months. (3) In the group treated with only surgery OS was 50% at 5 years. For patients treated with any form of ChT, OS was 71% at 5 years (p=0.4773) and hazard ratio (HR) 0.56. The CICRD was 29% (at 2 years of follow-up. Instead, it was of 50% for patients treated only with surgery. (4) Median survival was 74 months and 19 months for cohort 1 and cohort 2 respectively (p=0.09). Data analysis showed a decreased HR for cohort 1 compared to cohort 2 (HR 0.378). Results confirmed also stratifying for age and ChT administration (HR 0.355). Conclusions Based on this work, our opinion is that the choice to undergo the patients to ChT combined to surgery could improve their prognosis.

DNA Methylation and Transcriptomic Features are Preserved Throughout Disease Recurrence and Chemoresistance in High Grade Serous Ovarian Cancers

Background Little is known about the role of global DNA methylation in recurrence and chemoresistance of high grade serous ovarian cancer (HGSOC). We performed whole genome bisulfite sequencing and transcriptome sequencing in 62 primary and recurrent tumors from 28 patients with stage III/IV HGSOC, of which 11 patients carried germline, pathogenic BRCA1 and/or BRCA2 mutations. Results Landscapes of genome-wide methylation (on average 24.2 million CpGs per tumor) and transcriptomes in primary and recurrent tumors showed extensive heterogeneity between patients but were highly preserved in tumors from the same patient. We identified significant differences in the burden of differentially methylated regions (DMRs) in tumors from BRCA1/2 compared to non-BRCA1/2 carriers (mean 659 DMRs and 388 DMRs in paired comparisons respectively). We identified overexpression of immune pathways in BRCA1/2 carriers compared to non-carriers, implicating an increased immune response in improved survival (P=0.006) in these BRCA1/2 carriers. Conclusions These findings indicate methylome and gene expression programs established in the primary tumor are conserved throughout disease progression, even extensive chemotherapy treatment, and that changes in methylation and gene expression are unlikely to serve as drivers for chemoresistance in HGSOC.

Expression of TIMPs and MMPs in Ovarian Tumors, Ascites, Ascites-Derived Cells, and Cancer Cell Lines: Characteristic Modulatory Response Before and After Chemotherapy Treatment

BackgroundThe tissue inhibitors of metalloproteinase (TIMPs) and their associated metalloproteinase (MMPs) are essential regulators of tissue homeostasis and are essential for cancer progression. This study analyzed the expression of TIMP-1,-2,-3 and the associated MMPs (MMP-2,-9,-11,-14) in different Stages, Grades and World Health Organization (WHO) classifications of serous ovarian tumors, ascites, ascites-derived cells from chemo-naïve (CN) and relapsed (CR) patients, and in ovarian cancer cell lines. The status of TIMPs and associated MMPs in response to chemotherapy treatment was assessed in cancer cell lines; TCGA data was interrogated to gauge TIMPs and associated MMPs as prognostic and platinum-response indicators.MethodsThe levels of TIMP-1, -2 and -3 were assessed by immunohistochemistry. The mRNA expression of TIMPs and MMPs was quantified by real time PCR (qRT-PCR). The chemosensitivity (IC50 values) to Cisplatin or Paclitaxel in cell lines was evaluated by MTT assay. The levels of TIMPs in ascites and cell lysates were analyzed by an ELISA assay.ResultsThe expression of TIMP-2 was significantly upregulated in Type 2 compared to Type 1 tumors and normal/benign ovarian tissues. TIMP-3 expression was significantly enhanced in Stage III, Grade 3 and Type 2 tumors compared to normal/benign ovarian tissues. The mRNA expression of MMP-9,-11 and -14 was significantly upregulated in Stage IV compared to normal/benign ovarian tissues. The expression of TIMP-1 was highest, followed by TIMP-2 and then TIMP-3 in CN ascites. At the cellular level, TIMP-2 mRNA expression was significantly higher in CN compared to CR epithelial cells in patients. The expression of TIMP-1 and -2, MMPs and cancer stem cells (CSCs) were upregulated in response to chemotherapy treatments in cancer cell lines. Interrogation of the TCGA dataset suggests shifts in platinum responses in patients consistent with genetic alterations in TIMP-2, -3 and MMP-2, -11 genes in tumors; and decreased overall survival (OS) and progression-free survival (PFS) in patients with altered MMP-14 genes.ConclusionsTIMPs and related MMPs are differentially expressed in serous ovarian tumors, ascites, ascites-derived cells and ovarian cancer cell lines. Chemotherapy treatment modulates expression of TIMPs and MMPs in association with increased expression of genes related to cancer stem cells.

Cell to cell hijacking: Role of membrane nanotubes

Cell to Cell communications is the pivot for life processes. Any event that disrupts this leads to the loss of physiological function, eventually leading to cell death. Evolutionarily, cells developed an elaborate mechanism to undertake this paramount responsibility through cell surface glycocalyx, receptors, integrins, and other recognition molecules. Cells also exchange through local acting soluble mediators as well as through vesicles and exosomes. Recent development in this field led to the identification of a spectacular network of membrane process that seems to be the supremo of all that was known about cellular communications. These are called membrane nanotubes or tunneling nanotubes (TNT). Cellular communication can be subdivided into contact and contactless. The former provides more rapid and molecule transfer as compared to the latter. Tunneling nanotubes (TNTs) are a novel type of contact-based communication. TNTs are straight, thin membrane extensions connecting cells over long distances first reported in PC12 cells in 2004. TNT is believed to form from actin-based membrane protrusion. There are three different models of TNT formation. a>Protrusions from one cell grow and extend until it reaches the other cell, followed by a membrane fusion. b> Membrane protrusions grow from both cells until they meet and establish a connection c> TNT formation by cell dislodgement when cells migrate further apart from each other, and during this movement, TNT is formed. It is possible that all these three models may be operational depending on cell types and context. Tunneling nanotubes (TNT) are dynamic connections between cells, representing a novel route for cell-to-cell communication. TNT was reported in various cell types, like epithelial cells, neuronal cells, mesenchyma cells, and immune cells engaged in intercellular exchanges of molecules, subcellular organelles, and pathogen and viruses transport routes. TNT can extend up to 200 µm in length and about 50 nm to 1500 nm in diameter in macrophages. TNT can be established between similar cell types (homo-TNT) or between one cell type and another ( hetro TNT) and thus may be involved in the initiation and growth of cancer as well as dissemination of cancer cells. TNTs are also assumed to play a role in treatment resistance, e.g., in chemotherapy treatment of cancer. Recently, TNT has been used to hijack mitochondria from healthy cells by the cancer cells as a source of energy. TNT was also reported to transport miRNA and other RNA to the surrounding stroma creating an environment suitable for cancer growth. More research in this discipline is needed to understand the full function of these wonderful nanostructures.

Local Recurrence of Primary Cardiac Leiomyosarcoma After Resection: A Rare Case

Introduction: Leiomyosarcoma (LMS) is a fatal tumor, though primary cardiac is very rarely encountered. In this report, we evaluated the surgical and medical management of primary cardiac LMS, which is a sporadic tumor.Case Presentation: A 60-year-old female patient was examined for pulmonary edema after penicillin allergy in May 2019, while transthoracic echocardiography (ECHO) revealed an appearance compatible with a 5x3.5 cm mass in the right atrium. In addition, transesophageal ECHO showed a 7x4.6 cm foreground mass compatible with a myxoma in the right atrium (RA). The patient was then operated on emergency. Besides, an adjuvant ifosfamide-mesna-doxorubicine (IMA) protocol was planned to be given to the patient after local radiotherapy.Conclusions: In this report presented, we made RT and chemotherapy treatment plans in the case of recurrence without R0 surgery. Recurrence rates of up to 50% can occur in LMS, and systemic chemotherapy can be applied after relapse

A Case Report of Non-Bacterial Cystitis Caused by Immune Checkpoint Inhibitors

We report a case of non-bacterial cystitis after treatment with programmed death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies, which was considered an immune-related adverse event (irAE). A 48-year-old male patient with intrahepatic cholangiocarcinoma (ICC) was treated with nivolumab after postoperative multi-line treatment. This patient recurred worsening of psoriasis and repeated urinary tract discomfort. The drug was discontinued and surgery was performed due to the recurrence of the tumor suggested by imaging. After receiving three cycles of chemotherapy treatment combined with atezolizumab, urinary tract discomfort reappeared. No bacteria were found in multiple urine cultures, and non-bacterial bladder inflammation was considered after cystoscopy biopsy. This is a report of non-bacterial inflammation of the urinary tract caused by immunotherapy.

Immune Checkpoint Inhibitors Combined With Chemotherapy Compared With Chemotherapy Alone for Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis

BackgroundIt is still controversial whether immune checkpoint inhibitors (ICIs) can improve the curative effect when added to original standard chemotherapy treatment for triple-negative breast cancer (TNBC). We compared their antitumor efficacy and adverse effects (AEs) to make a better clinical decision.MethodsSeven databases were searched for eligible articles. Progression-free survival (PFS), overall survival (OS), and AEs were measured as the primary outcomes.ResultsNine randomized controlled trials (RCTs) involving 4,501 patients were included. ICI+chemotherapy treatment achieved better PFS (hazard ratio [HR]: 0.78, [0.70–0.86], p < 0.00001), OS (HR: 0.86, [0.74–0.99], p = 0.04), and complete response (584/1,106 vs. 341/825, risk ratio [RR]: 1.38, [1.01–1.89], p = 0.04). With the prolongation of survival, the survival advantage of ICI+chemotherapy increased compared with chemotherapy. Subgroup analysis suggested that the addition of ICIs might not have a better effect in Asian patients, patients with locally advanced disease, or patients with brain metastases. In the toxicity analysis, more Grade 3–5 AEs and serious AEs were found in the ICI+chemotherapy group. For Grade 3–5 AEs, more cases of diarrhea, severe skin reactions, pneumonitis, hepatitis, and adrenal insufficiency were related to the ICI+chemotherapy group.ConclusionsICI+chemotherapy appears to be better than chemotherapy alone for TNBC treatment, with better OS and PFS. However, its high rates of serious AEs need to be taken seriously.Systematic Review RegistrationPROSPERO Registration: CRD42021276394.

GPER Agonist G-1 Disrupts Tubulin Dynamics and Potentiates Temozolomide to Impair Glioblastoma Cell Proliferation

Glioblastoma (GBM) is the most common brain tumor in adults, which is very aggressive, with a very poor prognosis that affects men twice as much as women, suggesting that female hormones (estrogen) play a protective role. With an in silico approach, we highlighted that the expression of the membrane G-protein-coupled estrogen receptor (GPER) had an impact on GBM female patient survival. In this context, we explored for the first time the role of the GPER agonist G-1 on GBM cell proliferation. Our results suggested that G-1 exposure had a cytostatic effect, leading to reversible G2/M arrest, due to tubulin polymerization blockade during mitosis. However, the observed effect was independent of GPER. Interestingly, G-1 potentiated the efficacy of temozolomide, the current standard chemotherapy treatment, since the combination of both treatments led to prolonged mitotic arrest, even in a temozolomide less-sensitive cell line. In conclusion, our results suggested that G-1, in combination with standard chemotherapy, might be a promising way to limit the progression and aggressiveness of GBM.

Extracellular HMGB1 interacts with RAGE and promotes chemoresistance in acute leukemia cells

Background Nowadays, acute leukemia (AL) among children has favorable outcome, yet some of them get refractory or relapse mainly due to drug resistance. High-mobility group box 1 (HMGB1) has been proven to have a important role in drug resistance via upregulation of autophagy after chemotherapy treatment in acute leukemia. However, the mechanism how extracellular HMGB1 acts on AL cells and leads to chemoresistance remains elusive. Method CCK8 was used to examine the toxicity of chemotherapeutic drug. Elisa was performed to detect the release of HMGB1. Western blot and mRFP-GFP-LC3 adenoviral particles as well as transmission electron microscopy were used to detect the autophagy flux. Western blot and flow cytometry were applied to evaluate the apoptosis. qPCR and western blot were conducted to detect the expression of drug efflux protein. Lentivirus infection was applied to knock down RAGE. In addition, T-ALL NOD/SCID mice xenograft model was used to observe the effect of inhibiting HMGB1/RAGE axis. Results We found that extracellular HMGB1 do upregulate autophagy and in the meantime downregulate apoptosis, primarily through interaction with receptor for advanced glycation end products (RAGE). Suppression of RAGE by RNA interference alleviated the level of autophagy and enhanced apoptosis. What’s more, HMGB1/RAGE induced autophagy was associated with the activation of ERK1/2 and decreased phosphorylation of mammalian target of rapamycin (mTOR), while HMGB1/RAGE limited apoptosis in a Bcl-2-regulated way mediated by P53. On the other hand, we found that HMGB1/RAGE activated the NF-κB pathway and promoted the expression of P-glycation protein (P-gp) as well as multidrug resistance-associated protein (MRP), both are ATP-binding cassette transporters. In vivo experiment, we found that blocking HMGB1/RAGE axis do have a mild pathological condition and a better survival in T-ALL mice. Conclusion HMGB1/RAGE have a important role in drug resistance after chemotherapy treatment, mainly by regulating autophagy and apoptosis as well as promoting the expression of drug efflux protein such as P-gp and MRP. HMGB1/RAGE might be a promising target to cure AL, especially for those met with relapse and refractory.