Primary Tumor Therapy Research Articles

Where Do We Stand in the Management of Oligometastatic Prostate Cancer? A Comprehensive Review.

Simple SummaryOligometastatic prostate cancer is an intermediate stage between localised and metastatic disease. Today, there are many advances in the diagnosis of this stage of the disease, with the appearance of new imaging techniques and treatments, thanks to the development of new modalities, both local and systemic therapies, the emergence of personalised medicine, and theragnostics.Oligometastatic prostate cancer (OMPC) is an intermediate state between localised disease and widespread metastases that includes a spectrum of disease biology and clinical behaviours. This narrative review will cover the current OMPC scenario. We conducted comprehensive English language literature research for original and review articles using the Medline database and grey literature through December 2021. OMPC is a unique clinical state with inherently more indolent tumour biology susceptible to multidisciplinary treatment (MDT). With the development of new imaging techniques, patients with OMPC are likely to be identified at an earlier stage, and the paradigm for treatment is shifting towards a more aggressive approach to treating potentially curable patients. Multimodal management is necessary to improve patient outcomes due to the combination of available therapies, such as local therapy of primary tumour, metastasis directed therapy or systemic therapy, to reduce tumour load and prevent further disease progression. Additional prospective data are needed to select patients most likely to benefit from a given therapeutic approach.

NIR-Responsive Photodynamic Nanosystem Combined with Antitumor Immune Optogenetics Bacteria for Precise Synergetic Therapy.

Photodynamic therapy (PDT) and immunotherapy are considered promising methods for the treatment of tumors. However, these treatment systems are still suffering from shortcomings such as hypoxia, easy metastasis, and delayed immune response during PDT. Therefore, it is still challenging to establish a programmed and rapid response immune combination therapy platform. Here, we construct a two-step synergetic therapy platform for the treatment of primary tumors and distant tumors using upconversion nanoparticles (UCNPs) and engineered bacteria as therapeutic media. In the first step, erbium ion (Er3+)-doped UCNPs act as a photoswitcher to activate the photosensitizer ZnPc to produce 1O2 for primary tumor therapy. In the second step, thulium ion (Tm3+)-doped UCNPs can emit blue-violet light under the excitation of near-infrared (NIR) light to activate the engineered bacteria to produce interferon (INF-γ) and release them in the intestine, which can not only treat tumors directly but also act with PDT to regulate immune pathways to activate the immune system, resulting in a joint immunotherapy effect to inhibit the growth of distant tumors. As a new type of programmatic combination therapy, we have proved that this platform can jointly activate the body's immune system during PDT and immunization treatment and can effectively inhibit tumor metastasis.

Single-fraction stereotactic ablative body radiation therapy for primary and metastasic lung tumor: A new paradigm?

Stereotactic ablative body radiotherapy (SABR) is an effective technique comparable to surgery in terms of local control and efficacy in early stages of non-small cell lung cancer (NSCLC) and pulmonary metastasis. Several fractionation schemes have proven to be safe and effective, including the single fraction (SF) scheme. SF is an option cost-effectiveness, more convenience and comfortable for the patient and flexible in terms of its management combined with systemic treatments. The outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic has driven this not new but underutilized paradigm, recommending this option to minimize patients’ visits to hospital. SF SABR already has a long experience, strong evidence and sufficient maturity to reliably evaluate outcomes in peripheral primary NSCLC and there are promising outcomes in pulmonary metastases, making it a valid treatment option; although its use in central locations, synchronous and recurrencies tumors requires more prospective safety and efficacy studies. The SABR radiobiology study, together with the combination with systemic therapies, (targeted therapies and immunotherapy) is a direction of research in both advanced disease and early stages whose future includes SF.

Novel humanized monoclonal antibodies for targeting hypoxic human tumors via two distinct extracellular domains of carbonic anhydrase IX

BackgroundHypoxia in the tumor microenvironment (TME) is often the main factor in the cancer progression. Moreover, low levels of oxygen in tumor tissue may signal that the first- or second-line therapy will not be successful. This knowledge triggers the inevitable search for different kinds of treatment that will successfully cure aggressive tumors. Due to its exclusive expression on cancer cells, carbonic anhydrase IX belongs to the group of the most precise targets in hypoxic tumors. CA IX possesses several exceptional qualities that predetermine its crucial role in targeted therapy. Its expression on the cell membrane makes it an easily accessible target, while its absence in healthy corresponding tissues makes the treatment practically harmless. The presence of CA IX in solid tumors causes an acidic environment that may lead to the failure of standard therapy.MethodsParental mouse hybridomas (IV/18 and VII/20) were humanized to antibodies which were subsequently named CA9hu-1 and CA9hu-2. From each hybridoma, we obtained 25 clones. Each clone was tested for antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activity, affinity, extracellular pH measurement, multicellular aggregation analysis, and real-time monitoring of invasion with the xCELLigence system.ResultsBased on the results from in vivo experiments, we have selected mouse monoclonal antibodies VII/20 and IV/18. The first one is directed at the conformational epitope of the catalytic domain, internalizes after binding to the antigen, and halts tumor growth while blocking extracellular acidification. The second targets the sequential epitope of the proteo-glycan domain, does not internalize, and is able to block the attachment of cancer cells to the matrix preventing metastasis formation. In vitro experiments prove that humanized versions of the parental murine antibodies, CA9hu-1 and CA9hu-2, have preserved these characteristics. They can reverse the failure of standard therapy as a result of an acidic environment by modulating the TME, and both are able to induce an immune response and have high affinity, as well as ADCC and CDC activity.ConclusionCA9hu-1 and CA9hu-2 are the very first humanized antibodies against CA IX that are likely to become suitable therapies for hypoxic tumors. These antibodies can be applied in the treatment therapy of primary tumors and suppression of metastases formation.

Uveal melanoma metastatic at initial diagnosis: a case series.

Detectable metastasis at the time of initial diagnosis of uveal melanoma (UM) is rare. The purpose of this investigation was to evaluate the characteristics and outcomes in patients with metastatic UM (MUM) at initial diagnosis. An institutional review board-approved retrospective case series analysis was performed in 21 patients that presented for management of MUM at initial diagnosis. Patient, tumor and treatment parameters were recorded, and ophthalmic symptoms, metastasis response and overall survival were assessed. Among 21 patients, median tumor diameter was 18 mm (range, 9.1-35 mm), with 76% classified as a Collaborative Ocular Melanoma Study (COMS) large size. Sites of metastasis included liver (95%), bone (29%) and lung (29%), among others, and were confirmed by biopsy in 95% of patients studied. Symptomatic primary tumors were present in 81%, causing pain (24%) or vision loss (57%). Primary tumor therapy (PTT) was provided upfront for 52% of patients with enucleation (24%) and brachytherapy (29%). Eye pain developed 3-6 months after diagnosis in four of 10 patients who did not receive upfront PTT, whereas it did not occur in any of the 11 patients who received upfront PTT (P = 0.04). PTT palliated pain in all cases. The median overall survival was 11.9 months (range, 2.5-21.1 months). Patients presenting with MUM at initial diagnosis have high-risk tumors and experience survival like patients who develop metastases metachronously. PTT is not associated with survival but may mitigate ophthalmic symptoms, especially in patients with large tumors at risk for causing symptoms.

Role of Ga-68 DOTANOC Positron Emission Tomography/ Computed Tomography Scan in Clinical Management of Patients with Neuroendocrine Tumors and its Correlation with Conventional Imaging- Experience in a Tertiary Care Center in India.

Purpose of Study:Aim of the study was to evaluate the role of 68Gallium-DOTANOC positron emission tomography/computed tomography (68Ga-DOTANOC PET/CT), a pan somatostatin receptor (SSTR) analog in the clinical management of patients with neuroendocrine tumors (NETs) and its correlation with conventional imaging.Materials and Methods:We retrospectively evaluated 69 patients of known/suspected NETs who underwent 68Ga-DOTANOC PET/CT scan for tumor localization (n = 15), stage modification (primary staging, n = 26 and restaging, n = 25) and therapy monitoring (n = 3). We also compared PET scan with conventional imaging as reference standard and evaluated the impact of PET/CT in the clinical management of patients.Results:The concordant findings on 68Ga-DOTANOC PET/CT and conventional imaging seen in 33 and discordant in 36 patients. Among discordant group, disease was upstaged in 32 patients; down staged in 3 patients; no stage change in one patient. PET/CT localized primary tumor in 4 patients. Among patients with raised tumor markers (39/69), PET was positive in 29 and negative in 10 patients. Patients were followed for mean duration of 27 months to assess management. We found strong agreement between positive PET and raised tumor markers (Kappa value = 0.8). Sensitivity and specificity of PET/CT for primary tumor localization, stage modification, and therapy monitoring was >90% (P < 0.05).Conclusions:Study shows that DOTANOC, a broad spectrum SSTRs binding peptide labeled with Ga-68 in PET/CT scan is an excellent modality in the management of NETs patients.

Efficacy of nivolumab plus ipilimumab as first-line therapy for primary tumors in patients with renal cell carcinoma.

With the emergence of several effective combination therapies, information on their effects at the primary site will be crucial for planning future cytoreductive nephrectomy (CN). The present study focused exclusively on changes in primary tumor sizes following treatment with nivolumab plus ipilimumab and investigated the clinical factors associated with a good response in primary tumors. We retrospectively assessed 27 patients diagnosed with advanced renal cell carcinoma (RCC) who started treatment with nivolumab plus ipilimumab. Changes in tumor sizes at the primary site were described using waterfall and spider plots, respectively. We analyzed the correlation of tumor shrinkage between primary and metastatic site. The parameters analyzed between responders and non-responders according to primary tumor sizes were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, peripheral blood markers, and CRP. The median age and follow-up period were 66 years and 9.3 months, respectively. The median IMDC risk score was 3 (range: 1-6). Nineteen patients were diagnosed with clear-cell RCC (ccRCC) and 8 patients with non-ccRCC. Among ccRCC patients, 9 (47.4%) achieved a significant response with a maximum reduction of 30% or more in the size of the primary tumor from baseline within 4 months, while 3 (37.5%) out of 8 patients with non-ccRCC achieved a significant response. Shrinkage of the primary tumor correlated with the metastatic tumors in both ccRCC and non-ccRCC cases. Of note, 6 patients underwent CN and no viable tumor cells were detected in the surgical specimens of 3 patients whose primary tumors shrank by approximately 50%-60% with a reduction to 4 cm or less. Among ccRCC patients, the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were slightly lower in responders than in non-responders (P = 0.0944 and P = 0.0691). The platelet-to-lymphocyte ratio was significantly lower in responders than in non-responder (P = 0.0391). Significant responses in primary tumors to nivolumab plus ipilimumab were observed in 50% of ccRCC patients, while responses varied among non-ccRCC patients. Inflammation markers may be predictive factors of treatment responses in primary tumors. Although further studies are needed, the present results suggest the importance of considering CN from radiological and pathological viewpoints.

Interventional magnetic-resonance-guided cryotherapy combined with microsurgery for recurrent glioblastoma: An innovative treatment?

BackgroundGlioblastoma invariably recurs after primary Stupp tumor therapy and portends a poor prognosis. Cryoablation is a well-established treatment strategy for extra-cranial tumors. The safety and efficacy of interventional MR-guided cryoablation (iMRgC) has not been explored in recurrent glioblastoma. MethodsA retrospective analysis of data collected over a period of 24 months was performed. The inclusion criteria were: (I) recurrent glioblastoma despite Stupp protocol; (II) MRI followed by histological confirmation of recurrent glioblastoma; (III) location allowing iMRgC followed by microsurgical resection; and (IV) patient's consent. The primary objective was to assess feasibility in terms of complications. The secondary objective was to analyze progression-free survival (PFS), post-iMRgC survival and overall survival (OS). ResultsThe study included 6 patients, with a mean age of 67±7.6 years [range, 54–70 years]. No major complications were observed. Median PFS was 7.5 months [IQR 3.75–9.75] and 6-month PFS was 50%. Median post-iMRgC survival was 9 months [IQR 7.5–15.25] and 6-month post-iMRgC survival was 80%. Median OS was 22.5 months [IQR 21.75–30]. ConclusioniMRgC for recurrent glioblastoma demonstrated a good safety profile, with no major complications. Our data suggest improved PFS and OS. Trial registration numberNo. IRB00011687 retrospectively registred on July 7th 2021.

Stereotactic body radiation therapy for primary liver tumors: An effective liver-directed therapy in the toolbox.

The use of radiation for primary liver cancers has historically been limited because of the risk of radiation-induced liver disease. Treatment fields have become more conformal because of several technical advances, and this has allowed for dose escalation. Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy, is now able to safely treat liver tumors to ablative doses while sparing functional liver parenchyma by using highly conformal therapy. Several retrospective and small prospective studies have examined the use of SBRT for liver cancers; however, there is a lack of well-powered randomized studies to definitively guide management in these settings. Recent advances in systemic therapy for primary liver cancers have improved outcomes; however, the optimal selection criteria for SBRT as a local therapy remain unclear among other liver-directed options such as radiofrequency ablation, transarterial chemoembolization, and radioembolization.

RADT-34. OLFACTORY PERCEPTION DURING PROTON RADIATION AND DIFFERENCES IN FREQUENCY OF OLFACTORY PERCEPTIONS BASED ON PROTON CRANIOSPINAL IRRADIATION TECHNIQUE FOR PEDIATRIC BRAIN TUMOR PATIENTS

Abstract BACKGROUND Unusual olfactory perception has been reported during brain radiation treatments but is infrequent and does not typically interfere with the ability to deliver treatment or cause notable distress. METHODS We performed a retrospective review of 127 pediatric patients treated with proton radiation therapy (PRT) for primary brain tumors in a single institution between 2016-2021. Patients received PRT to the brain as part of craniospinal irradiation (CSI) followed by a boost to the brain. Proton CSI was delivered with 3D-CRT protons (n=53) or pencil beam scanning technique (PBS) (n=74). Within the PBS group, treatment delivery to the CSI utilized a single PA field (n=24) or two posterior oblique fields (n=50). We collected data on abnormal olfactory sensations, nausea/vomiting, and the use of medical intervention for those symptoms. RESULTS Our cohort included 80 males and 47 females. The median age of patients was 10 years old (range, 3 – 21). Seventy-one patients received concurrent chemotherapy. Prior to PRT, 31 patients were nauseous. During the radiation course, 104 patients developed worsening nausea while 63 patients reported episodes of emesis. Four patients vomited while receiving radiation. Seventeen patients reported olfactory perceptions during CSI. We found a higher rate of olfactory perception in patients treated with PBS (n=16, 22%) than 3D-CRT (n=1, 2%) (p=0.001) and, within the PBS group, patients treated with a single PA field (n=11, 46%) than two oblique fields (n=5, 10%) (p=0.002). Seventy-eight patients required intervention including addition of anti-emetic or anti-anxiety medication. Two patients required sedation due to the malodorous smell during CSI. We did not find any significant difference in nausea/vomiting based on treatment technique. CONCLUSIONS PBS and PBS technique influence olfactory perceptions but not the occurrence of the rate of nausea/vomiting. Further studies should be performed to validate these findings and determine techniques to minimize unpleasant olfactory perceptions.

STEM-01. PHAGE DISPLAY BIOPANNING IDENTIFIES AMOT REGULATING CELL MOTILITY OF BRAIN METASTATIC STEM-LIKE CELLS

Abstract OBJECTIVE Metastatic brain tumors (MBTs) are the most common type of malignant brain tumors. Due to the deviation of MBTs from the parental tumors, the effective therapies for primary tumors often are not useful in brain metastases. Even more new intracranial lesions were developed though the primary lesion was under control. The model of brain metastatic stem-like cells (BMSCs) could partially explain the progression of intracranial lesions. Here we aimed to explore the biological behavior in cell motility of BMSCs and understand the potential mechanisms. METHODS In vitro and in vivo phage display biopanning strategies were used to isolate dodecapeptides that specifically target BMICs by selecting against primary lung cancer cells and normal brain cells. In silico analysis was used to derive specific protein targets in BMICs. Potential targets were narrowed down through analysis in patient databases and verified for their presence in BMIC through RT-PCR. Cell migration and adhesion in BMICs were analyzed using Transwell, scratch, and adhesion assays. Protein expression and cell morphology were detected by immunofluorescence. Immune blot was performed to detect the epithelial-mesenchymal related molecules and explore protein-protein interactions. RESULTS In silico analysis of BMSCs specific peptides revealed Angiomotin (Amot) as a potential target in BMSCs. Amot was found to be overexpressed in BMSCs compared to primary lung cancer cells. Kaplan-Meier analysis demonstrated Amot was negatively correlated with overall survival among lung adenocarcinoma patients. Functionally, knockdown of AMOT in BMSCs decreased the capability of cell migration and adhesion by reduced active Cdc42/Rac1 signals caused by downregulation of E-Cadherin. Amot was found to maintain the E-Cadherin in BMSCs through reducing ubiquitination of E-Cadherin. CONCLUSIONS Amot plays a role in promoting migration and adhesion in BMSCs through preservation of E-cadherin.

Status Quo and Trends of Intra-Arterial Therapy for Brain Tumors: A Bibliometric and Clinical Trials Analysis.

Intra-arterial drug delivery circumvents the first-pass effect and is believed to increase both efficacy and tolerability of primary and metastatic brain tumor therapy. The aim of this update is to report on pertinent articles and clinical trials to better understand the research landscape to date and future directions. Elsevier’s Scopus and ClinicalTrials.gov databases were reviewed in August 2021 for all possible articles and clinical trials of intra-arterial drug injection as a treatment strategy for brain tumors. Entries were screened against predefined selection criteria and various parameters were summarized. Twenty clinical trials and 271 articles satisfied all inclusion criteria. In terms of articles, 201 (74%) were primarily clinical and 70 (26%) were basic science, published in a total of 120 different journals. Median values were: publication year, 1986 (range, 1962–2021); citation count, 15 (range, 0–607); number of authors, 5 (range, 1–18). Pertaining to clinical trials, 9 (45%) were phase 1 trials, with median expected start and completion years in 2011 (range, 1998–2019) and 2022 (range, 2008–2025), respectively. Only one (5%) trial has reported results to date. Glioma was the most common tumor indication reported in both articles (68%) and trials (75%). There were 215 (79%) articles investigating chemotherapy, while 13 (65%) trials evaluated targeted therapy. Transient blood–brain barrier disruption was the commonest strategy for articles (27%) and trials (60%) to optimize intra-arterial therapy. Articles and trials predominately originated in the United States (50% and 90%, respectively). In this bibliometric and clinical trials analysis, we discuss the current state and trends of intra-arterial therapy for brain tumors. Most articles were clinical, and traditional anti-cancer agents and drug delivery strategies were commonly studied. This was reflected in clinical trials, of which only a single study had reported outcomes. We anticipate future efforts to involve novel therapeutic and procedural strategies based on recent advances in the field.

Enhancing Natural Killer Cell Targeting of Pediatric Sarcoma

Osteosarcoma, Ewing sarcoma (EWS), and rhabdomyosarcoma (RMS) are the most common pediatric sarcomas. Conventional therapy for these sarcomas comprises neoadjuvant and adjuvant chemotherapy, surgical resection of the primary tumor and/or radiation therapy. Patients with metastatic, relapsed, or refractory tumors have a dismal prognosis due to resistance to these conventional therapies. Therefore, innovative therapeutic interventions, such as immunotherapy, are urgently needed. Recently, cancer research has focused attention on natural killer (NK) cells due their innate ability to recognize and kill tumor cells. Osteosarcoma, EWS and RMS, are known to be sensitive to NK cell cytotoxicity in vitro. In the clinical setting however, NK cell cytotoxicity against sarcoma cells has been mainly studied in the context of allogeneic stem cell transplantation, where a rapid immune reconstitution of NK cells plays a key role in the control of the disease, known as graft-versus-tumor effect. In this review, we discuss the evidence for the current and future strategies to enhance the NK cell-versus-pediatric sarcoma effect, with a clinical focus. The different approaches encompass enhancing antibody-dependent NK cell cytotoxicity, counteracting the NK cell mechanisms of self-tolerance, and developing adoptive NK cell therapy including chimeric antigen receptor-expressing NK cells.

Clinical Outcomes of Patients With Hepatocellular Carcinoma Treated With MR-guided Stereotactic Body Radiation Therapy With Online Adaptive Planning

<h3>Purpose/Objective(s)</h3> Stereotactic body radiation therapy (SBRT) for primary liver tumors may be limited by proximity to organs-at-risk (OAR). MR-guided SBRT (MRgSBRT) with online adaptive planning has shown promise in delivering ablative doses to the liver safely. We reported the clinical outcomes of patients with unresectable hepatocellular carcinoma (HCC) treated with MRgSBRT with online adaptive planning. <h3>Materials/Methods</h3> Patients with unresectable HCC treated with MRgSBRT between 2015 and 2019 with minimum 3 months of follow-up were retrospectively reviewed at a single institution. Local progression was defined by mRECIST. Survival analysis was performed with the Kaplan-Meier method. Toxicity was assessed using Common Terminology Criteria for Adverse Events Version 5. <h3>Results</h3> Thirty-five patients with a total of 41 HCC lesions, all treated to 50 Gy in 5 fractions, were analyzed. The median tumor size was 2.9 cm (IQR: 2.0-4.5). Barcelona-Clinic Liver Cancer (BCLC) Staging was 0, A, B, C, and D in 2 (6%), 8 (23%), 18 (51%), 6 (17%), and 1 (3%), respectively. Twenty-seven (77%) patients had previous liver-directed therapy (chemoembolization, radioembolization, cryoablation) to the target lesion with evidence of residual disease or progression on follow-up imaging. The median follow-up from completion of MRgSBRT was 21 months (IQR, 10-34). Online adaptive planning was performed for 19% of all fractions. It was done due to exceeding dose constraints to OARs in 26/33 (79%) fractions, and to improve tumor coverage in 7/33 (21%) fractions. Clinical response assessed at a median of 2.4 months (IQR: 2.0-3.0) after MRgSBRT revealed a complete response in 26% (9/35), partial response in 23% (8/35), stable disease in 40% (14/35), and progressive disease in 9% (3/35). One (3%) patient did not have repeat imaging at the time of initial clinical follow-up. The 1- and 2-year freedom from local progression (FFLP) rates were both 91% (95% CI: 83-100%). The 1- and 2-year freedom from progression elsewhere in the liver (FFELP) rates were 58% (95% CI: 44-78%) and 50% (95% CI: 35-72%), respectively. The 1- and 2-year overall survival were 83% (95% CI: 71-96%) and 58% (95% CI: 43-77%), respectively. The most commonly noted acute grade ≤2 clinical toxicities were fatigue, abdominal pain, and nausea. Four patients had grade 3 toxicity: 1 (3%) ascites, 1 (3%) portal hypertension, 2 (6%) hepatic failure. One patient (3%) had grade 4 gangrenous cholecystitis. Eleven (31%) patients later underwent an orthotopic liver transplant. <h3>Conclusion</h3> MRgSBRT with online adaptive planning allows delivery of ablative doses to HCC with excellent local control and acceptable toxicity. Additional studies evaluating the role of MRgSBRT in the treatment of liver tumors are warranted.

Management of Primary Hepatopancreatobiliary and Ampulla Large Cell Neuroendocrine Carcinoma.

Background: Large cell neuroendocrine carcinoma (LCNEC) of the liver, gallbladder, pancreas, and ampulla is rare and usually arises in case reports, and thus to date, no studies have well described the treatment options and outcomes of those patients. Methods: The data of 108 patients diagnosed as hepatopancreatobiliary and ampulla LCNEC between 2004 and 2015 were retrieved from the surveillance, epidemiology, and final results. Results: In the entire cohort, the median overall survival (OS) was 10 months. For nonmetastatic patients, the median OS was 32 months for surgery of the primary tumor alone (n = 17), 19 months for surgery of the primary tumor and adjuvant therapy (n = 19), and 1 month for nonsurgical treatment (n = 8). For metastatic patients, the median OS was 14 months for patients who received surgery of the primary tumor with and without adjuvant therapy (n = 16), 9 months for patients undergoing adjuvant treatment alone (n = 30), and 1 month for patients who had no treatment (n = 16). Multivariate analysis revealed that surgery of the primary tumor was an independent factor for improved survival. Conclusions: This disease offers a very poor prognosis despite aggressive treatment. Radical resection is the first choice for resectable tumors, whereas surgical resection of the primary tumor plus adjuvant therapy might represent a valid option for metastatic disease. However, further studies are needed to confirm this.

The Microbiome Tumor Axis: How the Microbiome Could Contribute to Clonal Heterogeneity and Disease Outcome in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers. It is characterized by a poor prognosis with a 5-year survival rate of only around 10% and an ongoing increase in death rate. Due to the lack of early and specific symptoms, most patients are diagnosed at an advanced or even metastasized stage, essentially limiting curative treatment options. However, even curative resection of the primary tumor and adjuvant therapy often fails to provide a long-term survival benefit. One reason for this dismal situation can be seen in the evolution of therapy resistances. Furthermore, PDAC is characterized by high intratumor heterogeneity, pointing towards an abundance of cancer stem cells (CSCs), which are regarded as essential for tumor initiation and drug resistance. Additionally, it was shown that the gut microbiome is altered in PDAC patients, promotes Epithelial-Mesenchymal-Transition (EMT), determines responses towards chemotherapy, and affects survival in PDAC patients. Given the established links between CSCs and EMT as well as drug resistance, and the emerging role of the microbiome in PDAC, we postulate that the composition of the microbiome of PDAC patients is a critical determinant for the abundance and plasticity of CSC populations and thus tumor heterogeneity in PDAC. Unravelling this complex interplay might pave the way for novel treatment strategies.

A pH-response chemotherapy synergistic photothermal therapy for tumor suppression and bone regeneration by mussel-inspired Mg implant.

Primary malignant bone tumors can be life-threatening. Surgical resection of tumor plus chemotherapy is the standard clinical treatment. However, postoperative recovery is hindered due to tumor recurrence caused by residual tumor cells and bone defect caused by resection of tumor tissue. Herein, a multifunctional mussel-inspired film was fabricated on Mg alloy, that is, an inner hydrothermal-treated layer, a middle layer of polydopamine, and an outer layer of doxorubicin. The modified Mg alloy showed excellent photothermal effect and thermal/pH-controlled release of doxorubicin. The synergistic effect of chemotherapy and photothermal therapy enabled the modified Mg alloy to kill bone tumor in vitro and inhibit tumor growth in nude mice. Moreover, because of the controlled release of Mg ions and biocompatibility of polydopamine, the modified Mg alloy supported extracellular matrix mineralization, alkaline phosphatase activity, and bone-related gene expression in C3H10T1/2. Bone implantation model in rats verified that the modified Mg showed excellent osteointegration. These findings prove that the use of mussel-inspired multifunction film on Mg alloy offers a promising strategy for the therapy of primary malignant bone tumor.

Experience in the treatment of primary malignant tumors (retinoblastoma and osteosarcoma): analysis of the clinical case

Background. Retinoblastoma is a malignant intraocular tumor developing from the retinal neuroectoderm and diagnosed primarily in young children. This type of cancer is associated with a high risk of multiple primary tumors emerging after treatment completion. Multiple primary tumors are two or more independent tumors developing in one patient. Treatment of this disease is challenging.Objective – to evaluate the impact of risk factors on the efficacy of therapy for multiple primary tumors and to analyze treatment outcomes.Materials and methods. A 2-year-old boy was diagnosed with bilateral retinoblastoma (OD – stage T3bN0M0 and OS – stage T3cN0M0). He received special treatment from September 2005 to November 2006. In 2012, the patient underwent cataract surgery: the lens was removed, then an intraocular lens was installed, and laser dissection of the posterior capsule of the lens was performed. Six years later, in August 2018, the patient was diagnosed with osteosarcoma. The boy received combination organ-sparing therapy according to the EURAMOS-1 treatment protocol for osteosarcoma. During therapy, he developed a secondary tumor, namely osteoblastic osteosarcoma. Both the boy and his father were found to have a mutation in the RB1 gene.Results. Currently, patient’s condition is satisfactory; he has no complains. The boy is in remission for 2 years.Conclusion. The development of secondary tumors depends on the genetic factors, type of treatment for primary tumor, and environmental factors. Therefore, it is extremely important to assess risk factors for multiple primary tumors at the moment of primary retinoblastoma detection. The results of such assessment will help to choose an optimal treatment strategy.

BSCI-06. Phage display biopanning identifies Amot regulating cell motility in brain metastasis-initiating cells

ObjectiveMetastatic brain tumors (MBTs) are the most common type of malignant brain tumors. Due to the deviation of MBTs from the parental tumors, the effective therapies for primary tumors often are not working in brain metastases. Even more new intracranial lesions were developed though the primary lesion was controlled. The occurrence of brain metastasis-initiating cells (BMICs) suggested the possibility of its spread intracranially. Here we aimed to explore the biological behavior in cell motility of BMICs and understand the potential mechanisms.MethodsIn vitro and in vivo phage display biopanning strategies were used to isolate dodecapeptides that specifically target BMICs by selecting against primary lung cancer cells and normal brain cells. In silico analysis was used to derive specific protein targets in BMICs. Potential targets were narrowed down through analysis in patient databases and verified for their presence in BMIC through RT-PCR. Cell migration and adhesion in BMICs were analyzed using Transwell, scratch, and adhesion assays. Protein expression and cell morphology were detected by immunofluorescence. Immune blot was performed to detect the epithelial-mesenchymal related molecules and explore protein-protein interactions.ResultsIn silico analysis of BMICs specific peptides revealed Angiomotin (Amot) as a potential target in BMICs. Amot was found to be overexpressed in BMICs compared to primary lung cancer cells. Kaplan-Meier analysis demonstrated Amot was negatively correlated with overall survival among lung adenocarcinoma patients. Knockdown of AMOT in BMICs decreased the capability of cell migration and adhesion, through the downregulation of E-Cadherin. Amot was found to maintain the E-Cadherin in BMICs through reducing ubiquitination of E-Cadherin. Furthermore, the knockdown of E-Cadherin decreased cell migration and adhesion due to the decrease in cdc42 activity.ConclusionsAmot plays a role in promoting migration and adhesion in BMICs through preservation of E-Cadherin.

Tumor Blood Flow Is a Predictor of Radiotherapy Response in Patients With Nasopharyngeal Carcinoma.

PurposeThe aim of this study was to evaluate tumor blood flow (TBF) as a predictor of radiotherapy response for nasopharyngeal carcinoma (NPC).Materials and MethodA total of 134 patients were divided into two groups, the complete response (CR) group and the partial response (PR) group based on RECIST 1.1 recommendations. The statistical difference was evaluated for pre- and mid- or post-treatment TBF and changes of TBF for tumors and metastatic lymph nodes between CR and PR, respectively. The receiver operation characteristic (ROC) curve was utilized to evaluate the accuracy of TBF in predicting the response of radiation therapy. The association between TBF and SUVmax was also investigated.ResultsThe reduction of TBF in CR was significantly lower than that in PR for primary tumors (P <0.001) and metastatic lymph nodes (P <0.001). The multivariate logistic regression analysis indicated that the reduction of TBF is an independent predictor of the response of radiation therapy for primary tumors (P <0.001) and metastatic lymph nodes (P <0.001). The accuracy of TBF reduction in predicting the response of radiation therapy was 0.817 in primary tumors and 0.924 in metastatic lymph nodes, respectively. No significant correlation was observed between the TBF values and SUVmax of primary tumors (r = -0.008, P = 0.954) and metastasis lymph nodes (r = -0.061, P = 0.652).ConclusionThis study suggests that the reduction of TBF is a promising parameter for evaluating the response of radiation therapy.