Removal Of Primary Tumor Research Articles

Systemic administration of a viral nanoparticle neoadjuvant prevents lung metastasis development through emergency myelopoiesis

ABSTRACT Cancer presents a significant public health concern, particularly in the context of metastatic disease. Surgical removal of primary tumors, while essential, can inadvertently heighten the risk of metastasis. Thus, there is a critical need for innovative neoadjuvant therapies capable of curtailing metastatic progression before or immediately following tumor resection. Addressing this imperative, the papaya mosaic virus nanoparticle (PapMV) has demonstrated potent immunostimulatory capabilities against both viruses and tumors, effectively hindering their proliferation. Our study reveals that PapMV exerts a protective effect against lung metastasis when administered systemically prior to tumor implantation or during the early stages of metastasis in various mouse models of cancer. This anti-tumor effect is initiated by the recruitment of myeloid cells in the lungs. These cells adopt a pro-inflammatory profile, secreting cytokines such as IFN-α, thus fostering a tumor microenvironment inhospitable to tumor progression. Crucially, this protective mechanism hinges on the presence of macrophages before treatment. TLR7 and IFN-I signaling pathways also play pivotal roles in this process. Furthermore, our findings demonstrate that PapMV triggers the activation of the bone marrow emergency response, which accounts for the influx of myeloid cells into the lungs. This study unveils a novel aspect of PapMV’s functionality. By bolstering the immune system, PapMV confers robust protection against metastasis at an early stage of disease progression. This discovery holds promise for therapeutic intervention, particularly as a preemptive measure prior to or just after surgical intervention.

Safety outcomes and immunological correlates in a prospective clinical trial of immune checkpoint therapy plus debulking surgery for patients with metastatic renal cell carcinoma.

Surgical removal of primary tumors was shown to reverse tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT)-containing treatments is not understood. Here, we report the first prospective, non-comparative clinical trial to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma (mccRCC). Based upon baseline evaluation and surgical eligibility after 6 weeks of ICT treatment, 43 patients on this trial proceeded with cytoreductive surgery, while 36 patients who had medical comorbidities preventing surgery or did not have a lesion amenable for surgical resection underwent post-ICT biopsy as specified in the clinical trial protocol, and 25 patients who discontinued study participation due to progressive disease or toxicities or withdrawal of consent did not receive either procedure (total N=104). Our data demonstrated that, in the subgroup of patients receiving the combination of ICT with cytoreductive surgery or biopsy, no additional ICT- or procedure-related toxicities were observed as compared to historical data. The median OS (overall survival) was 54.7 months for patients who received ICT-containing regimens plus cytoreductive surgery (n=43). Immune-monitoring studies with co-detection by indexing (CODEX) identified distinct tumor spatial conformation of cellular subsets as a novel and improved predictor of response to ICT. Importantly, single-cell RNA-sequencing (sc-RNA-seq) data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

CNSC-06. NAVIGATING BRAIN CANCER: PATIENT STORIES AND MEDICAL BREAKTHROUGH

Abstract The complex interplay of genetic mutation, dys regulated signalling pathways, Epigenetic modifications and Interaction with tumor microenvironment are the major aggravating factors for Brain Tumors. Neurological complications involve Increased Intracranial pressure, Seizures, Motor and Sensory deficits, Aphasia, Hydrocephaly, Behavioral and personality changes, Cerebellar Symptoms. It is diagnosed in a sequential steps. Collecting good history from patient in primary then examining the patient all through and making some investigations to come to a final diagnosis. On asking history to a patient he complains of recurrent convulsions, Personality changes and some motor activity deficit and loss of few senses. On examination we can reveal defect in cranial nerve functions, Motor or sensory deficits, loss of reflexes and coordination. Then Investigations being the next step for diagnosis, We ask the patient to undergo for a test for Blood Biomarkers and CSF analysis in case of suspection of metastatic Brain tumors. Biopsy to obtain for Histopathological Examination. Histopathological examination is done for analysis of genetic mutations and molecular markers. The other imaging techniques like MRI, MRS, CT, PET, EEG are done. This gives a clear picture of what actually caused tumor and shows a way for treatment. Now the treatment involves both Medical and Surgical treatment. Medical treatment includes Chemotherapy along with radiation therapy where the drugs given are Temozolomide and targeted therapy included EGFR BRAF inhibitors for glioblastoma and low grade gliomas respectively. Tumor treating fields- Optune is given. Surgical treatment involves Craniotomy for removal of primary Brain tumors, Neuro Endoscopy if tumor is present in ventricles or base of Brain, Laser interstitial Thermal therapy for deap seated and recurrent brain tumors. This is all about the treatment and now the patient management is very important for further clinical help. Physical, occupational and speech therapy helps patients recover. Symptomatic approach for inoperable tumors Provide comprehensive support for patients nearing end of life, Emphasise confidence and Quality of life.

Metabolic Acidity/H2O2 Dual-Cascade-Activatable Molecular Imaging Platform Toward Metastatic Breast Tumor Malignancy.

Fluorescence imaging in the second near-infrared window (NIR-II) is crucial for accurate tumor diagnosis, offering superior resolution and penetration capabilities. Current NIR-II probes are limited by either being "always on" or responding to one stimulus, leading to low signal-to-noise ratios and potential false positives. We introduced a dual-lock-controlled probe, HN-PBA, activated by both H2O2 and tumor acidic environment. This dual response ensures bright fluorescence at tumor sites, leading to higher tumor-to-normal tissue ratios (T/NT) compared to conventional "always on" probes and probes activated only by H2O2. This strategy allows precise tumor identification and removal of primary and metastatic tumors, achieving superior T/NT ratios (24.3/6.4 for orthotopic and lung metastasis, respectively). Our probe also effectively detected lung metastatic foci as small as≤0.7 mm and showed the capability for accurate lesion localization in clinical breast cancer specimens. This dual-stimuli-responsive strategy could aid future diagnostic probe design.

Short- and long-term immunosuppressive effects of melanoma influence the prognostic value of the sentinel lymph node status

BackgroundPresence of micrometastases in the sentinel lymph node (SLN) is currently used to assess prognosis of melanoma patients. The immunoactivity within the SLN is known to be influenced by the primary tumor (PT), which may in turn impact the SLNs’ metastatic state. AimWe characterize the temporal dependence and underlying mechanisms of the immunological effects of the PT on the SLN. MethodsThe prognostic value of SLN state as a function of PT removal time was evaluated. To put the results into a functional context, selected PTs and corresponding SLNs were analyzed for gene and protein expression patterns. ResultsIn a cohort of 202 patients with known distant metastasis and similar PT prognostic characteristics, SLNs removed before or within one week after the PT (IM-SLN) had a higher incidence of micrometastases than those removed at least one week after the PT (DEL-SLN).The immunoactivity in IM-SLN was found to be lower than in DEL-SLN. Specifically, in IM-SLNs, T helper 17 / regulatory T-cells were predominant, whereas in DEL-SLNs, cytotoxic γδT-cells were more frequent. The higher immune activity in DEL-SLNs was probably facilitated by CD209+ antigen-presenting cells. Indeed, in PT with high TGFβ expression CD209+ cells appear to be trapped and no increased immunoactivity was observed in DEL-SLN. ConclusionsPresence of micrometastases in DEL-SLNs have a higher negative prognostic value as in IM-SLNs since they indicate not only a melanoma’s propensity to metastasize, but possibly also its capacity to escape immune responses.

The Ratio of Baseline Ventricle Volume to Total Brain Volume Predicts Postoperative Ventriculo-Peritoneal Shunt Dependency after Sporadic Vestibular Schwannoma Surgery.

Background/Objectives: Obstructive hydrocephalus associated with vestibular schwannoma (VS) is the most common in giant VS. Despite tumor removal, some patients may require ongoing ventriculo-peritoneal (VP) surgery. This investigation explores the factors contributing to the requirement for VP surgery following VS surgery in instances of persistent hydrocephalus (HCP). Methods: Volumetric MRI analyses of pre- and postoperative tumor volumes, cerebellum, cerebrum, ventricle system, fourth ventricle, brainstem, and peritumoral edema were conducted using Brainlab Smartbrush and 3D Slicer. The total brain volume was defined as the sum of the cerebrum, cerebellum, and brainstem. ROC analyses were performed to identify the optimum cut-off values of the volumetric data. Results: Permanent cerebrospinal fluid (CSF) diversion after surgery was indicated in 12 patients (12/71; 16.9%). The ratio of baseline volume fraction of brain ventricles to total brain ventricle volume (VTB ratio) was found to predict postoperative VP shunt dependency. The AUC was 0.71 (95% CI: 0.51-0.91), and the optimum threshold value (</≥0.449) yielded a sensitivity and specificity of 67% and 81%, respectively. Multivariable logistic regression analyses of imaging data (pre- and postoperative VS volume, VTB ratio, and extent of resection (%) (EoR)) and patient-specific factors revealed that an increased VTB ratio (≥0.049, OR: 6.2, 95% CI: 1.0-38.0, p = 0.047) and an EoR < 96.4% (OR: 9.1, 95% CI: 1.2-69.3, p = 0.032) were independently associated with postoperative VP shunt dependency. Conclusions: Primary tumor removal remains the best treatment to reduce the risk of postoperative persistent hydrocephalus. However, patients with an increased preoperative VTB ratio are prone to needing postoperative VP shunt surgery and may benefit from perioperative EVD placement.

Choice of surgical treatment approach in patients with metastatic colorectal cancer complicated by intestinal obstruction

BACKGROUND: Every year more than 1 million new cases of colorectal cancer are diagnosed worldwide, with approximately 30% patients already having distant metastases. Colorectal cancer is often complicated, which makes chemotherapy challenging or, in some cases, impossible, therefore worsening the prognosis. As the first step, such patients need to undergo surgical treatment, in order to eliminate existing complications. However, what volume of surgery remains a discussion point among ongologists: a colostomy or a cytoreductive r2 resection to remove the primary tumor. AIM: To analyze the results of complex treatment in patients with metastatic colorectal cancer and to optimize surgical treatment approaches. MATERIALS AND METHODS: We conducted a study in Samara regional clinical Oncology dispensary (Samara, Russia), which included patients with metastatic colorectal cancer complicated by intestinal obstruction. Before treatment, all patients were examined according with current clinical standards. Subsequently, the patients were divided into two groups: the first group included patients who underwent cytoreductive surgery (r2 resection to remove the primary lesion due to the presence of colonic obstruction), and the second group included patients who underwent palliative surgery (colostomy or a bypass anastomosis in order to eliminate intestinal obstruction without removing the primary tumor). RESULTS: We found that postoperative complications in patients who had undergone primary tumor removal were significantly more prevalent. At the same time, however, the number of complications at the stage of chemotherapy, combined with angiogenesis inhibitor therapy, was significantly greater than in the group of patients in whom primary lesion was not removed. Complications that arose during chemotherapy affected the number of chemotherapy cycles performed. Discontinuation of chemotherapy affected event-free and overall survival. CONCLUSION: Timely identification and elimination of existing complications by removing the primary tumor focus before chemotherapy is an important component of an individual approach in order to develop treatment optimal tactics for patients with metastatic colorectal cancer.

Mesenchymal Stem Cell-Secreted Exosomes and Soluble Signals Regulate Breast Cancer Metastatic Dormancy: Current Progress and Future Outlook.

Breast cancer is most common in women, and in most cases there is no evidence of spread and the primary tumor is removed, resulting in a 'cure'. However, in 10% to 30% of these women, distant metastases recur after years to decades. This is due to breast cancer cells disseminating to distant organs and lying quiescent. This is called metastatic dormancy. Dormant cells are generally resistant to chemotherapy, hormone therapy and immunotherapy as they are non-cycling and receive survival signals from their microenvironment. In this state, they are clinically irrelevant. However, risk factors, including aging and inflammation can awaken dormant cells and cause breast cancer recurrences, which may happen even more than ten years after the primary tumor removal. How these breast cancer cells remain in dormancy is being unraveled. A key element appears to be the mesenchymal stem cells in the bone marrow that have been shown to promote breast cancer metastatic dormancy in recent studies. Indirect co-culture, direct co-culture and exosome extraction were conducted to investigate the modes of signal operation. Multiple signaling molecules act in this process including both protein factors and microRNAs. We integrate these studies to summarize current findings and gaps in the field and suggest future research directions for this field.

COMORBIDITY IN ONCOLOGY: MODERN CHALLENGES AND THE SEARCH FOR WAYS TO SOLVE THE PROBLEM

Introduction. The article is devoted to the current problem of modern oncology – increasing the treatment effectiveness of cancer patients with comorbidities. Comorbidity is accompanied by higher rates of mortality, disability, side effects of treatment, increased use of the patient's body resources, and lower quality of life. The aim of the study. To develop a method of recurrence prevention after bone lesions resection and bone replacement surgery for malignant primary bone tumors, which would ensure a longer duration of the 1st recurrence-free period in patients with comorbidities. Materials and methods. The study included a control group consisting of 27 patients who underwent bone replacement surgery after removal of primary malignant tumors of the pelvis and lower extremities. The study group included 25 patients who underwent biomin bone replacement surgery after removal of malignant primary tumors of the pelvic bones and lower limbs, as well as neuropeptide therapy with the drug dalargin. Results. The obtained data testify to the effectiveness of the proposed method of treatment with the use of dalargin: compaction of the structure of compact and spongy tissues and an increase in their heterogeneity have been established. Under the influence of dalargin, the structure of the interface, characteristic of intact bone tissue, is reorganized, accordingly, the restoration of strength is observed. 12 months after the operation, the bone density in the patients of the main group practically recovered to the values typical for the intact limb (p&lt;0.01). No such recovery was observed in patients of the control group. Within 11 to 23 months, 10 patients of the control group had tumor recurrences. Instead, in the study group, the analysis of the results revealed the following: within 21 months, only 1 patient had a recurrence of the tumor. Conclusions. Neuropeptide Dalargin helps to increase the duration of the 1st relapse-free period in patients with primary malignant bone tumors with polymorbidity. The proposed treatment method with integration into the therapeutic protocol of the neuropeptide dalargin allows to increase the complex therapy effectiveness and improve the prognosis of the course of the disease.

Time to full weight-bearing with the use of a calcium sulfate-calcium phosphate bone substitute as a bone void filler following extended curettage in the treatment of primary benign bone tumours.

The primary objective of this study was to determine time to full weight-bearing after the use of a calcium-sulfate-calcium phosphate bone substitute (CaSO4/CaPO4) as a bone void filler in the treatment of primary benign bone tumours following intralesional curettage. The secondary objectives were to determine surgical complications and recurrence rates. Retrospective review of patients identified from a surgeon-specific orthopaedic oncology database, who underwent curettage of benign bone tumours and subsequent bone void filling with CaSO4/CaPO4. A total of 39 patients (20 males, 19 females) met inclusion criteria with an average age of 31years (range: 13 to 62years), a median follow-up of 3.7years, and a maximum follow-up of 11years. The most common tumour diagnosis was giant cell tumour of bone (GCT) (n = 19), and the most common location was the proximal tibia (n = 9). The mean volume of tumour excised was 74.1cm3 including extraosseous bone expansion due to tumour growth, with a mean of volume of 21.4mL of CaSO4/CaPO4 used to fill the intraosseous cavitary defects to restore normal bone anatomy. None of the lesions required additional internal fixation. The primary outcome measure, average time to full weight-bearing/full range of motion, was 11weeks and 6weeks for upper and lower extremity lesions, respectively. Secondary outcomes included tumour recurrence requiring reoperation in five patients and infection requiring reoperation in two patients. This study demonstrates that CaSO4/CaPO4 is a viable option as a bone void filler in the reconstruction of cavitary defects following removal of primary benign bone tumours. CaSO4/CaPO4 provides sufficient bone regeneration early in the post-operative period to allow progression to full weight-bearing within weeks without the need for internal fixation. There were no graft-specific complications noted.

Albumin-mediated molecular competition of supramolecular photosensitizers for NIR-II imaging-guided phototherapy

Heptamethine cyanines (Cy7) typically exhibit strong near-infrared (NIR) fluorescence signals when in monodisperse states, but their distinctive π-conjugated structure leads to limited solubility in aqueous solutions, ultimately resulting in inherent fluorescence self-quenching. Enhancing the fluorescence quantum yield of these agents within aqueous environments, in order to achieve high-resolution biological imaging, presents a significant challenge. Herein, a benzothiazole-based Cy7-derivative (Cy7-BTH) is developed, exhibiting unique H-aggregation properties in aqueous solutions. Bovine serum albumin (BSA) binds to Cy7-BTH (BSA@Cy7-BTH) to modulate its molecular stacking and energy transfer, boosting its fluorescence accompanied by bright NIR-II tail emission. The competitive binding alters the planarity of Cy7-BTH, restricting its intramolecular rotation, and simutaneously changes the conformation of BSA, leading to BSA@Cy7-BTH aggregation to form hierarchical-structured nanoparticles. Notably, the BSA@Cy7-BTH nanoparticles significantly enhanced photothermal response of Cy7-BTH while maintaining its controlled reactive oxygen species (ROS) generation, offering NIR-II imaging-guided surgical removal of primary tumors, and simultaneously inhibiting cancer cell metastasis by synergistic PDT/PTT dissection of metastatic tumor cells in sentinel lymph nodes (SLNs). This study provides an innovative but facile strategy for their potential clinical applications by precisely regulating the intermolecular competitive interactions of NIR theranostic agents.

Histopathological diagnosis and surgical complications following bilateral anal sacculectomy for the treatment of unilateral canine apocrine gland anal sac adenocarcinoma: 35 cases (2019-2023).

To report the histopathological diagnosis of both anal sacs in dogs undergoing bilateral anal sacculectomy for the treatment of unilateral apocrine gland anal sac adenocarcinoma and to compare the surgical complication rate associated with this procedure in this population with previously published literature. Records were retrospectively reviewed for dogs that underwent bilateral anal sacculectomy for the treatment of apparently unilateral apocrine gland anal sac adenocarcinoma, at a single institute between 2019 and 2023. Clinical staging, surgical treatment, histological findings, intra- and postoperative complications were evaluated. Thirty-five dogs were included. Only five of 35 (14%) dogs were found to have histologically normal contralateral anal sacs. Non-neoplastic anal sac disease was found in 23 of 35 (66%) dogs and bilateral apocrine gland anal sac adenocarcinoma was seen in seven of 35 (20%) dogs. None of the dogs diagnosed with bilateral neoplasia had evidence of bilateral neoplasia before surgery despite a thorough work-up. Complications attributable to the primary tumour removal were seen in 9% of dogs intraoperatively and 14% of dogs postoperatively, commonly tumour capsule disruption and surgical site infection, respectively. Bilateral anal sac disease was diagnosed histologically in the majority of presumed normal anal sacs, with 20% of cases being found to have bilateral apocrine gland anal sac adenocarcinoma. The surgical complication rates of this cohort were comparable to those reported for unilateral anal sacculectomy alone. These findings promote and encourage the use of bilateral anal sacculectomy in cases of suspected unilateral anal sac neoplasia.

FSP1 is a predictive biomarker of osteosarcoma cells’ susceptibility to ferroptotic cell death and a potential therapeutic target

Human osteosarcoma (OS) is a relatively rare malignancy preferentially affecting long body bones which prognosis is often poor also due to the lack of effective therapies. Clinical management of this cancer basically relies on surgical removal of primary tumor coupled with radio/chemotherapy. Unfortunately, most osteosarcoma cells are resistant to conventional therapy, with the undergoing epithelial-mesenchymal transition (EMT) giving rise to gene expression reprogramming, thus increasing cancer cell invasiveness and metastatic potential. Alternative clinical approaches are thus urgently needed. In this context, the recently described ferroptotic cell death represents an attractive new strategy to efficiently kill cancer cells, since most chemoresistant and mesenchymal-shaped tumors display high susceptibility to pro-ferroptotic compounds. However, cancer cells have also evolved anti-ferroptotic strategies, which somehow sustain their survival upon ferroptosis induction. Indeed, here we show that osteosarcoma cell lines display heterogeneous sensitivity to ferroptosis execution, correlating with the mesenchymal phenotype, which is consistently affected by the expression of the well-known anti-ferroptotic factor ferroptosis suppressor protein 1 (FSP1). Interestingly, inhibiting the activity or expression of FSP1 restores cancer cell sensitivity to ferroptosis. Moreover, we also found that: i) AKRs might also contribute to resistance; ii) NRF2 enhances FSP1 expression upon ferroptosis induction; while iii) p53 contributes to the regulation of FSP1 basal expression in OS cells.In conclusion, FSP1 expression can potentially be used as a valuable predictive marker of OS sensitivity to ferroptosis and as a new potential therapeutic target.

Treatment of metastatic paraganglioma: experience of a single center.

Data regarding treatment options and their efficacy for metastatic paragangliomas (mPPGL) is limited. This study aims to report a single center experience in treating mPPGL, comparing the efficacy and safety of various treatment approaches. Retrospective analysis of patients with mPPGL treated at an Endocrinology Department of a cancer institute between January 2000 and October 2022. We analyzed 25 patients with mPPGL, 8 pheochromocytomas and 20 paragangliomas (12% multifocal), followed for a median of 9 [4; 14] years. Surgical approach, aimed at the primary tumor or at debulking of metastases, was the only treatment achieving complete response: 87% in primary tumor and 87.5% with debulking of metastases. These were long-lasting results with a duration of 69 (23.8; 136.8) months in primary tumor removal and 35.1 (15.3; 41) months in metastases debulking. As for other therapeutic approaches, such as radioactive isotopes, tyrosine kinase inhibitors, chemotherapy and external beam radiotherapy, the main outcome was stable disease, with few partial responses. At the last follow-up, 66% of the patients were alive, 15.4% were in remission and 84.6% had stable disease. Median overall survival was 14 years. The 5-year and 10-year survival rates from primary tumor diagnosis were 77.9% and 66.9% respectively, and from metastasis diagnosis were 67.4% and 55.6%, respectively. This is the only European single center analysis addressing outcomes of different therapies in mPGL. The results support surgery as a first-line treatment, being the only approach that may achieve complete response with satisfactory and long-lasting results.

The Function of the Immune System, Beyond Strategies Based on Cell-Autonomous Mechanisms, Determines Cancer Development: Immune Response and Cancer Development.

Although cancer remains a challenging disease to treat, early detection and removal of primary tumors through surgery or chemotherapy/radiotherapy can offer hope for patients. The privilege paradigm in cancer biology suggests that cell-autonomous mechanisms play a central role in tumorigenesis. According to this paradigm, these cellular mechanisms are the primary focus for the prevention and treatment of cancers. However, this point of view does not present a comprehensive theory for the initiation of cancer and an effective therapeutic strategy. Having an incomplete understanding of the etiology of cancer, it is essential to re-examine previous assumptions about carcinogenesis and develop new, practical theories that can account for all available clinical and experimental evidence. This will not only help to gain a better understanding of the disease, but also offer new avenues for treatment. This review provides evidence suggesting a shift in focus from a cell-autonomous mechanism to systemic mechanisms, particularly the immune system, that are involved in cancer formation.

Significant perioperative parameters affecting postoperative complications within 30 days following craniotomy for primary malignant brain tumors

BackgroundThe occurrence of postoperative complications within 30 days (PC1M) of a craniotomy for the removal of a primary malignant brain tumor has been associated with a poor prognosis. However, it is still unclear to early predict the occurrence of PC1M. This study aimed to identify the potential perioperative predictors of PC1M from its preoperative, intraoperative, and 24-h postoperative parameters.MethodsPatients who had undergone craniotomy for primary malignant brain tumor (World Health Organization grades III and IV) from January 2011 to December 2020 were enrolled from a databank of Kaohsiung Veterans General Hospital, Taiwan. The patients were classified into PC1M and nonPC1M groups. PC1M was defined according to the classification by Landriel et al. as any deviation from an uneventful 30-day postoperative course. In both groups, data regarding the baseline characteristics and perioperative parameters of the patients, including a new marker-kinetic estimated glomerular filtration rate, were collected. Logistic regression was used to analyze the predictability of the perioperative parameters.ResultsThe PC1M group included 41 of 95 patients. An American Society of Anesthesiologists score of > 2 (aOR, 3.17; 95% confidence interval [CI], 1.19–8.45; p = 0.021), longer anesthesia duration (aOR, 1.16; 95% CI, 0.69–0.88; p < 0.001), 24-h postoperative change in hematocrit by > − 4.8% (aOR, 3.45; 95% CI, 1.22–9.73; p = 0.0019), and 24-h postoperative change in kinetic estimated glomerular filtration rate of < 0 mL/min (aOR, 3.99; 95% CI, 1.52–10.53; p = 0.005) were identified as independent risk factors for PC1M via stepwise logistic regression analysis. When stratified according to the age of ≥ 65 years (OR, 11.55; 95% CI, 1.30–102.79; p = 0.028), the reduction of kinetic estimated glomerular filtration rate was more robustly associated with a higher risk of PC1M.ConclusionsFour parameters were demonstrated to significantly influence the risk of PC1M in patients undergoing primary malignant brain tumor removal. Measuring and verifying these markers, especially kinetic estimated glomerular filtration rate, would help early recognition of PC1M risk in clinical care.

Tumor removal limits prostate cancer cell dissemination in bone and osteoblasts induce cancer cell dormancy through focal adhesion kinase

BackgroundDisseminated tumor cells (DTCs) can enter a dormant state and cause no symptoms in cancer patients. On the other hand, the dormant DTCs can reactivate and cause metastases progression and lethal relapses. In prostate cancer (PCa), relapse can happen after curative treatments such as primary tumor removal. The impact of surgical removal on PCa dissemination and dormancy remains elusive. Furthermore, as dormant DTCs are asymptomatic, dormancy-induction can be an operational cure for preventing metastases and relapse of PCa patients.MethodsWe used a PCa subcutaneous xenograft model and species-specific PCR to survey the DTCs in various organs at different time points of tumor growth and in response to tumor removal. We developed in vitro 2D and 3D co-culture models to recapitulate the dormant DTCs in the bone microenvironment. Proliferation assays, fluorescent cell cycle reporter, qRT-PCR, and Western Blot were used to characterize the dormancy phenotype. We performed RNA sequencing to determine the dormancy signature of PCa. A drug repurposing algorithm was applied to predict dormancy-inducing drugs and a top candidate was validated for the efficacy and the mechanism of dormancy induction.ResultsWe found DTCs in almost all mouse organs examined, including bones, at week 2 post-tumor cell injections. Surgical removal of the primary tumor reduced the overall DTC abundance, but the DTCs were enriched only in the bones. We found that osteoblasts, but not other cells of the bones, induced PCa cell dormancy. RNA-Seq revealed the suppression of mitochondrial-related biological processes in osteoblast-induced dormant PCa cells. Importantly, the mitochondrial-related biological processes were found up-regulated in both circulating tumor cells and bone metastases from PCa patients’ data. We predicted and validated the dormancy-mimicking effect of PF-562,271 (PF-271), an inhibitor of focal adhesion kinase (FAK) in vitro. Decreased FAK phosphorylation and increased nuclear translocation were found in both co-cultured and PF-271-treated C4-2B cells, suggesting that FAK plays a key role in osteoblast-induced PCa dormancy.ConclusionsOur study provides the first insights into how primary tumor removal enriches PCa cell dissemination in the bones, defines a unique osteoblast-induced PCa dormancy signature, and identifies FAK as a PCa cell dormancy gatekeeper.

A surgically optimized intraoperative poly(I:C)-releasing hydrogel prevents cancer recurrence

Recurrences frequently occur following surgical removal of primary tumors. In many cancers, adjuvant therapies have limited efficacy. Surgery provides access to the tumor microenvironment, creating an opportunity for local therapy, in particular immunotherapy, which can induce local and systemic anti-cancer effects. Here, we develop a surgically optimized biodegradable hyaluronic acid-based hydrogel for sustained intraoperative delivery of Toll-like receptor 3 agonist poly(I:C) and demonstrate that it significantly reduces tumor recurrence after surgery in multiple mouse models. Mechanistically, poly(I:C) induces a transient interferon alpha (IFNα) response, reshaping the tumor/wound microenvironment by attracting inflammatory monocytes and depleting regulatory Tcells. We demonstrate that a pre-existing IFN signature predicts response to the poly(I:C) hydrogel, which sensitizes tumors to immune checkpoint therapy. The safety, immunogenicity, and surgical feasibility are confirmed in a veterinary trial in canine soft tissue tumors. The surgically optimized poly(I:C)-loaded hydrogel provides a safe and effective approach to prevent cancer recurrence.

Relationships between reading performance and regional spontaneous brain activity following surgical removal of primary left-hemisphere tumors: A resting-state fMRI study

Left-hemisphere intraparenchymal primary brain tumor patients are at risk of developing reading difficulties that may be stable, improve or deteriorate after surgery. Previous studies examining language organization in brain tumor patients have provided insights into neural plasticity supporting recovery. Only a single study, however, has examined the role of white matter tracts in preserving reading ability post-surgery and none have examined the functional reading network. The current study aimed to investigate the regional spontaneous brain activity associated with reading performance in a group of 36 adult patients 6–24 months following left-hemisphere tumor resection. Spontaneous brain activity was assessed using resting-state fMRI (rs-fMRI) regional homogeneity (ReHo) and fractional amplitude low frequency fluctuation (fALFF) metrics, which measure local functional connectivity and activity, respectively. ReHo in the left occipito-temporal and right superior parietal regions was negatively correlated with reading performance. fALFF in the putamen bilaterally and the left cerebellum was negatively correlated with reading performance, and positively correlated in the right superior parietal gyrus. These findings are broadly consistent with reading networks reported in healthy participants, indicating that reading ability following brain tumor surgery might not involve substantial functional re-organization.

Abstract B038: Prostate cancer (PCa) cell dormancy in bone depends on physical contacts between PCa cells and osteoblasts and can be induced via FAK inhibition

Abstract Advanced prostate cancer (PCa) in patients still progresses to metastatic relapse after curative treatment such as primary tumor removal. This is likely due to the early disseminated PCa cells that stayed dormant initially and got reactivated to proliferate into overt metastases. However, we don’t know when and to which organs PCa cells disseminate, whether and how primary tumor removal affects the dissemination and dormancy. To answer these, we injected C4-2B cells subcutaneously into immunodeficient NSG mice and randomized the mice for either having the tumors removed at week 2 or keeping the tumors till the endpoints. We then euthanized the mice and semi-quantified the disseminated C4-2B cells in various mouse organs via human-specific genomic PCR at weeks 2/6/8. We serendipitously found PCa metastatic recurrence at a distant site in one mouse at 5 weeks post removal of the C4-2B PCa subcutaneous tumor, suggesting that the mice without observed recurrence may have dormant disseminated tumor cells (DTC). We further observed that tumor removal limited DTC in the bones, specifically, in the bone cortex. In clinic, metastatic PCa tumors were found in patient bone marrows and bone marrow DTC presence was associated with poor prognosis. Therefore, we hypothesized that cells in the bone cortex induce and maintain DTC dormancy. We first explored the dormancy-inducing effects of various types of cells in bone. We co-cultured C4-2B cells in direct contact with osteoblasts MC3T3-E1, macrophages Raw264.7, mesenchymal progenitors OP-9, fibroblasts NIH3T3, or endothelial cells HUVEC. The dormancy phenotypes such as proliferation and marker gene changes of the co-cultured C4-2B cells were compared to C4-2B cells cultured alone. We found that only MC3T3-E1 cells, but not other cells, inhibited C4-2B proliferation, increased the expression of dormancy markers such as NR2F1, and decreased the expressions of proliferation markers such as Ki67 and Cyclin D1, suggesting that osteoblasts induced C4-2B dormancy. Direct physical contacts were necessary as dormancy phenotypes were not observed in C4-2B cells treated with the conditioned media of MC3T3-E1 cells cultured alone, nor in C4-2B cells in transwell co-culture with MC3T3-E1 cells. We then performed RNA-Seq in C4-2B/MC3T3-E1 co-culture to profile the dormancy signature, which was loaded into a novel artificial intelligence (AI) platform to screen for drugs mimicking this signature. One candidate from the AI pipeline, PF-562271, a focal adhesion kinase (FAK) inhibitor, was validated with dormancy-mimicking effect for C4-2B cells in vitro. Further studies are focusing on the in vivo effects and the mechanisms of action of PF-562271. Our study profiled the C4-2B PCa cell disseminations post primary tumor removal. We defined a unique osteoblast-induced dormancy signature and revealed physical contact requirement in dormancy. We also recapitulated osteoblast-induced PCa cell dormancy in vitro using an FAK inhibitor, which could potentially inhibit PCa bone metastatic progression and recurrence clinically. Citation Format: Ruihua Liu, Shang Su, Ke Liu, Jing Xing, Mary Stangis, Diego P. Jacho, Eda D. Yildirim-Ayan, Cara M. Gatto-Weis, Haiquan Yu, Bin Chen, Xiaohong Li. Prostate cancer (PCa) cell dormancy in bone depends on physical contacts between PCa cells and osteoblasts and can be induced via FAK inhibition [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B038.