Tumor Adjuvant Therapy Research Articles

The Research Progress of Metformin Regulation of Metabolic Reprogramming in Malignant Tumors.

Metabolism reprogramming is a crucial hallmark of malignant tumors. Tumor cells demonstrateenhanced metabolic efficiency, converting nutrient inputs into glucose, amino acids, and lipids essential for theirmalignant proliferation and progression. Metformin, a commonly prescribed medication for type 2 diabetes mellitus,has garnered attention for its potential anticancer effects beyond its established hypoglycemic benefits. This review adopts a comprehensive approach to delineate the mechanisms underlying metabolite abnormalities within the primary metabolic processes of malignant tumors. This review examines the abnormal activation of G protein-coupled receptors (GPCRs) in these metabolic pathways, encompassing aerobic glycolysis with increased lactate production in glucose metabolism, heightened lipid synthesis and cholesterol accumulation in lipid metabolism, and glutamine activation alongside abnormal protein post-translational modifications in amino acid and protein metabolism. Furthermore, the intricate metabolic pathways and molecular mechanisms through which metformin exerts its anticancer effects are synthesized and analyzed, particularly its impacts on AMP-activated protein kinase activation and the mTOR pathway. The analysis reveals a multifaceted understanding of how metformin can modulate tumor metabolism, targeting key nodes in metabolic reprogramming essential for tumor growth and progression. The review compiles evidence that supports metformin's potential as an adjuvant therapy for malignant tumors, highlighting its capacity to interfere with critical metabolic pathways. In conclusion, this review offers a comprehensive overview of the plausible mechanisms mediating metformin's influence on tumor metabolism, fostering a deeper comprehension of its anticancer mechanisms. By expanding the clinical horizons of metformin and providing insight into metabolism-targeted tumor therapies, this review lays the groundwork for future research endeavors aimed at refining and advancing metabolic intervention strategies for cancer treatment.

Real-world effectiveness of adjuvant octreotide therapy in patients with pancreatic neuroendocrine tumors at high recurrence risk: A multicenter retrospective cohort study.

Adjuvant therapy for pancreatic neuroendocrine tumors (PanNETs) after radical resection lacks evidence-based data and remains controversial. This study aimed to validate whether long-acting octreotide is a potential candidate for adjuvant therapy in patients with G2 PanNETs at high recurrence risk by clustering real-world data. A retrospective review of patients with nonmetastatic grade 2 PanNETs who underwent radical resection at six research centers between 2008 and 2020 was conducted. Propensity score matching and inverse probability of treatment weight analysis were used to control confounding factors. Overall, 357 patients (octreotide group, n = 82; control group, n = 275) were analyzed. Kaplan-Meier survival analyses showed that the octreotide group had longer disease-free survival (DFS) compared with the control group (36 months: 93.3% vs. 79.0%, p = .0124; 60 months: 71% vs. 67.6%, p = .0596, respectively), as well as overall survival (OS) (60 months: 98% vs. 83.8%, p = .0117, respectively). Multivariate analyses indicated that octreotide long-acting repeatable (LAR) adjuvant therapy was associated with higher OS (p = .0270) at 60 months. Propensity score matching analysis showed that octreotide adjuvant therapy was associated with higher DFS (p = .0455) and OS (p = .0190) at 60 months. Similar results were obtained via inverse probability of treatment weight analysis. Subgroup analysis indicated that octreotide LAR was associated with a high DFS in patients with lymph node metastasis or Ki-67 <10% PanNETs. Adjuvant therapy with long-acting octreotide following radical resection of nonmetastatic G2 PanNETs may be associated with improved DFS and OS in a real-world setting.

The ameliorative effect on chemotherapy-induced injury and tumor immunosuppressive microenvironment of the polysaccharide from the rhizome of Menispermum dauricum DC

Combined medication has attracted increasing attention as an important treatment option for tumors due to the serious adverse effects of chemotherapy. In this study, as a new therapy strategy, a combination treatment of MDP (a polysaccharide from the rhizome of Menispermum dauricum DC.) with cyclophosphamide (CTX) was investigated. The results showed that combination treatment with MDP and CTX exerted a significantly synergistic anti-tumor effect in Lewis tumor-bearing mice, improved CTX-induced emaciation and hair loss, as well as increased the number of leukocytes, erythrocytes, hemoglobin, and platelets in the peripheral blood. In addition, compared with CTX alone, the thymus index and spleen index of the MDP + CTX group were increased, the number of CD3 + T cells, CD8 + T cells, white blood cells and B cells in spleen also increased significantly. MDP could also ameliorate the increase in liver and kidney index caused by CTX. In the Lewis lung cancer model, MDP showed a certain degree of anti-tumor effects, which may be related to its promotion of tumor-associated macrophages (TAMs) to M1 phenotype polarisation, enhancement of the number of T cells in tumor tissues and promotion of Th cells in tumor tissues to Th1 phenotype polarisation, thus alleviating the immunosuppressive microenvironment in tumor tissues. This study laid the foundation for the development of MDP as a polysaccharide drug for the treatment or adjuvant therapy of tumors and has important significance for the further clinical application of polysaccharides.

Contemporary Management of Pediatric Brainstem Tumors.

Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

Functional Materials for Subcellular Targeting Strategies in Cancer Therapy: Progress and Prospects.

Neoadjuvant and adjuvant therapies have made significant progress in cancer treatment. However, tumor adjuvant therapy still faces challenges due to the intrinsic heterogeneity of cancer, genomic instability, and the formation of an immunosuppressive tumor microenvironment. Functional materials possess unique biological properties such as long circulation times, tumor-specific targeting, and immunomodulation. The combination of functional materials with natural substances and nanotechnology has led to the development of smart biomaterials with multiple functions, high biocompatibilities, and negligible immunogenicities, which can be used for precise cancer treatment. Recently, subcellular structure-targeting functional materials have received particular attention in various biomedical applications including the diagnosis, sensing, and imaging of tumors and drug delivery. Subcellular organelle-targeting materials can precisely accumulate therapeutic agents in organelles, considerably reduce the threshold dosages of therapeutic agents, and minimize drug-related side effects. This review provides a systematic and comprehensive overview of the research progress in subcellular organelle-targeted cancer therapy based on functional nanomaterials. Moreover, it explains the challenges and prospects of subcellular organelle-targeting functional materials in precision oncology. The review will serve as an excellent cutting-edge guide for researchers in the field of subcellular organelle-targeted cancer therapy.

Abstract A172: TP-317, a first-in-class resolvin E1 small molecule, drives adjuvant efficacy in solid tumors by engaging innate and adaptive anti-tumor immunity in the tumor microenvironment (TME) and has neoadjuvant potential

Abstract Background: TP-317 is a novel salt of resolvin E1 (RvE1), an endogenous lipid agonist of ChemR23 that stimulates tumor debris phagocytosis/clearance by myeloid cells (Sulciner et al., 2018, J.Exp.Med). We recently reported TP-317 anti-tumor efficacy in murine solid tumors as monotherapy and in combination with immune checkpoint inhibitors (ICI) and chemotherapy (Kipper, 2023, Can. Res, 83 (7_Supp: 1135). Here we elaborate on the mechanism of action (MOA) of TP-317 in the adjuvant setting and report TP-317 efficacy in a neoadjuvant regimen Methods: 125-240 mm3 established subcutaneous murine melanoma (B16F10) and pancreatic (Panc02-H7; KPC) tumors were treated with placebo, TP-317 or ICI and tumors excised at 12-14 days for bulk RNAseq or flow cytometry. Placebo, TP-317 (300 ug/kg s.c. 2 hr prior to and Q6D after resection), cisplatin (5 mg/kg i.p. 24 hrs prior to resection) or anti-PD1 (8 mg/kg i.p. 24 hr prior to resection only) or TP-317 + anti-PD1 were evaluated in the LLC lung tumor model with tumors resected when reaching ~ 1500 mm3. Endpoints were lung/lymph node metastases or survival. Results: RNAseq analysis showed that adjuvant TP-317 broadly engages innate (macrophage, dendritic, NK cells) and adaptive (CD8, CD4, B cells) immune pathways in the TME of PANC2-H7, KPC and B16F10 models. Depletion studies suggest TP-317 efficacy is CD8- and NK cell-dependent, consistent with the RNAseq data and flow cytometry, which confirmed expression of ChemR23 (RvE1 receptor) on M1/M2 macrophages, conventional cDC1/cDC2, NK and lymphoid subsets. In the TME of PANC2-H7, KPC and B16-F10 models, TP-317 induced a gene signature with upregulated IFNg responses, effector CD8/NK receptors, antigen-presenting pathways, cDC1/NK cell cross-talk, and chemokines/cytokines involved in anti-tumor immunity. In the B16F10 model TP-317 + dual ICI combined therapy synergistically upregulated an IFNg response signature relative to dual ICI therapy. In the LLC resection model, TP-317 monotherapy reduced lung (p&amp;lt;0.05) and lymph node metastases (p&amp;lt;0.01) 19 days post-resection, but cisplatin was not effective. Neoadjuvant cisplatin or anti-PD1 monotherapy did not improve survival relative to placebo, but TP-317 combined with neoadjuvant anti-PD1 induced long term survival (&amp;gt;100 days) in 3 of 7 treated mice (p &amp;lt;0.05 vs placebo or anti-PD1). Conclusions: In adjuvant therapy of murine tumors, TP-317 broadly modulates innate/adaptive immune cell compartments in the TME, consistent with resetting the immunogenic tone and favoring anti-tumor immunity. Mechanistic synergy was observed for TP-317 combined with dual ICI therapy. TP-317 monotherapy shows metastasis control when initated prior to surgical resection and long term survival when combined with neoadjuvant anti-PD1 in the LLC model of NSCLC. Citation Format: John F Parkinson, Eva Rothenberger, Abigail Kelly, Diane Bielenberg, Ahmed Attaya, Sui Huang, Lance Pflieger, Wayne Klohs, Gary Mathias, Dipak Panigrahy. TP-317, a first-in-class resolvin E1 small molecule, drives adjuvant efficacy in solid tumors by engaging innate and adaptive anti-tumor immunity in the tumor microenvironment (TME) and has neoadjuvant potential [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A172.

Dendrobium officinale polysaccharide Converts M2 into M1 Subtype Macrophage Polarization via the STAT6/PPAR-r and JAGGED1/NOTCH1 Signaling Pathways to Inhibit Gastric Cancer.

Dendrobium officinale polysaccharide (DOP) has shown various biological activities. However, the ability of DOP to participate in immune regulation during anti-gastric cancer treatment has remained unclear. In this study, the in vitro results showed that DOP has the potential to polarize THP-1 macrophages from the M2 to the M1 phenotype, downregulate the STAT6/PPAR-r signaling pathway and the protein expression of their down-targeted ARG1 and TGM2, and further decrease the main protein and mRNA expression in the JAGGED1/NOTCH1 signaling pathway. DOP suppressed the migration of gastric cancer cells by decreasing the protein expression of N-cadherin and Vimentin and increasing E-cadherin. In addition, CM-DOP promoted the apoptosis of gastric cancer cells by upregulating Caspase-3 and increasing the ratio of Bax/Bcl-2. In vivo, DOP effectively inhibited the growth of tumors and the expression of Ki-67. In summary, these findings demonstrated that DOP converted the polarization of M2 subtype macrophages into M1 subtypes via the STAT6/PPAR-r and JAGGED1/NOTCH1 signaling pathways in order to reduce apoptosis and prevent migration, thus indicating the potential of DOP as an adjuvant tumor therapy in preclinical and clinical trials.

Identification and analysis of anti-tumor effective substances in Yangzheng Mixture.

Yangzheng Mixture is a traditional Chinese medicine used in clinical practice as an adjuvant therapy for tumors. However, little is known about its active components in tumor treatment. The purpose of this study was to explore the potential anti-tumor components of Yangzheng Mixture to better promote its clinical application. Using LC-MS/MS, 43 components were detected in concentrated Yangzheng Mixture. Six components, comprising astragaloside, calycosin, formononetin, isoquercitrin, ononin, and calycosin-7-O-β-D-glucoside, were identified in rat plasma. The cancer cell absorption assay showed that the intracellular concentration of four components, calycosin, calycosin-7-O-β-D-glucoside, formononetin, and ononin, increased with extended incubation time and demonstrated potential anti-tumor effects. The MTT assay results confirmed that Yangzheng Mixture inhibited different tumor cells proliferation. Additionally, the colony formation assay, flow cytometry analysis and wound healing displayed that Yangzheng Mixture and a combination of four components could inhibit colony formation, arrest the cell cycle and impair cell migration of tumor cells, including HCT-116, MHCC-97L, MCF-7 and NCI-H1299. In summary, our study highlighted the plausible application of Yangzheng Mixture as a potential adjuvant treatment for tumors. Furthermore, it identified effective anti-tumor components and provided evidences for the further clinical application of Yangzheng Mixture.

Cannabidiol as a Promising Adjuvant Therapy for Estrogen Receptor-Positive Breast Tumors: Unveiling Its Benefits with Aromatase Inhibitors.

Estrogen receptor-positive (ER+) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine and targeted therapies, have been applied. Recently, we demonstrated that cannabidiol (CBD) induces anti-tumor actions in ER+ breast cancer cells by targeting aromatase and ERs. Considering this, we studied, in vitro, whether CBD when combined with AIs could improve their effectiveness. MCF-7aro cells were used and the effects on cell viability and on the modulation of specific targets were investigated. CBD when combined with anastrozole (Ana) and letrozole (Let) caused no beneficial effect in comparison to the isolated AIs. In contrast, when combined with the AI exemestane (Exe), CBD potentiated its pro-cell death effects, abolished its estrogen-like effect, impaired ERα activation, and prevented its oncogenic role on the androgen receptor (AR). Moreover, this combination inhibited ERK1/2 activation, promoting apoptosis. The study of the hormonal microenvironment suggests that this combination should not be applied in early stages of ER+ breast tumors. Contrary to Ana and Let, this study highlights the potential benefits of combining CBD with Exe to improve breast cancer treatment and opens up the possibility of new therapeutic approaches comprising the use of cannabinoids.

PMON105 Giant Growth Hormone (GH)-Secreting Pituitary Tumor with Massive Sphenoid Sinus Invasion and Spontaneous Cerebrospinal Fluid (CSF) Leak: A Case Report

Abstract Introduction Giant pituitary tumor, defined as &amp;gt;4cm, comprise 6-10% of all pituitary tumors. Giant GH-secreting pituitary tumors are rare and difficult to treat. They typically invade surrounding structures ​such as the cavernous sinus, making ​complete resection challenging or impossible. This report highlights a case of giant GH-secreting pituitary tumor with an unusual clinical presentation.CLINICAL CASE: A 56 Y/O male with hypertension, cardiomyopathy, obesity, and OSA presented to the ER with stroke-like symptoms. Brain CT and MRI revealed small acute to subacute infarcts within the left occipital, left frontal, right frontal, right parietal areas, and right cerebellum. An incidental finding was a 4.3 cm T2 hyperintense enhancing mass centered within the skull base with involvement of the sella, extension into bilateral cavernous sinuses, clivus, encasement of bilateral carotid arteries, and invasion through the sphenoid sinus into the nasopharyngeal space resulting in a preoperative CSF. He was overtly acromegalic with coarse facial features, prominent frontal bossing, early prognathism, and macroglossia. Hands and feet were enlarged, but non-edematous. Visual field testing was normal. Laboratory values: IGF-1, 317 ng/mL (NL &amp;lt;170): GH, 4 ng/ml (NL&amp;lt;10); prolactin, 17.6 ng/mL (NL 2.5-17.4); total testosterone, 11 ng/dL (NL 130-810); free testosterone, 2 pg/dL (NL 36-146). ACTH stimulation produced a normal cortisol response. Test for AIP gene mutation was negative. Emergent packing of the CSF leak site was done. He underwent trans-sphenoidal (TSS) debulking of the tumor along with reconstruction of the ​skull base and repair of CSF leak. Postoperatively, IGF-1 level decreased to 216 ng/mL. Immunohistochemical stains of the tumor were strongly positive for GH and somatostatin receptor type2 (SSTR2). Three weeks postoperatively, IGF-1 increased to 482 ng/mL. IGF-1 level decreased to 326 ng/mL after 3 doses of lanreotide 90 mg/month. He will be now monitored on 120 mg/month. Currently, he requires only testosterone replacement. Conclusion This patient had the unique presentation of florid acromegaly and CSF leak mainly related to his delay in seeking medical care. Absence of visual defects has been noted in only 15% of reported patients with giant GH-secreting adenomas. Massive replacement of the sphenoid sinus by a giant pituitary tumor causing a CSF leak with invasion into the ​cavernous sinuses and clivus has been rarely reported. Trans-sphenoidal resection is the preferred first-line treatment for patients with acromegaly. The remission rate decreases and can reach almost 0% for giant GH-secreting tumors. Somatostatin receptor analogs (SRA) are the preferred first-line pharmacological treatment as an adjuvant therapy for residual tumor. Our patient likely will need continued SRA and potentially other modalities to control acromegaly due to unresectable tumor anatomy. This case also highlights the complications of delayed detection and benefits of extensive TSS surgical resection with the goal to enhance his response to SRA. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Postoperative communicating hydrocephalus following glioblastoma resection: Incidence, timing and risk factors.

IntroductionGlioblastoma (GBM) is the most common malignant primary brain tumor. Treatment includes maximally safe surgical resection followed by radiation and/or chemotherapy. However, resection can lead to ventricular opening, potentially increasing the risk for development of communicating hydrocephalus (CH). Complications such as rebleeding and infection may also lead to CH and, eventually, the need for cerebrospinal fluid (CSF) diversion surgery. In this study, we evaluated the incidence of different types of hydrocephalus and potential risk factors for the development of CH following glioblastoma resection.Methods726 GBM patients who underwent tumor resection at our department between 2006 and 2019 were analyzed retrospectively. Potential risk factors that were determined for each patient were age, sex, tumor location, the number of resection surgeries, ventricular opening during resection, postoperative CSF leak, ventriculitis, and rebleeding. Uni- as well as multivariate analyses were performed to identify associations with CH and independent risk factors.Results55 patients (7.6%) needed CSF diversion surgery (implantation of a ventriculoperitoneal or ventriculoatrial shunt) following resection surgery. 47 patients (6.5%) had CH, on median, 24 days after the last resection (interquartile range: 17-52 days). 3 patients had obstructive hydrocephalus (OH) and 5 patients had other CSF circulation disorders. Ventricular opening (odds ratio (OR): 7.9; p=0.000807), ventriculitis (OR 3.3; p=0.000754), and CSF leak (OR 2.3; p=0.028938) were identified as significant independent risk factors for the development of post-resection CH. Having more than one resection surgery was associated with CH as well (OR 2.1; p=0.0128), and frontal tumors were more likely to develop CH (OR 2.4; p=0.00275), while temporal tumors were less likely (OR 0.41; p=0.0158); However, none of those were independent risk factors. Age, sex, or rebleeding were not associated with postoperative CH.ConclusionPostoperative CH requiring CSF shunting is not infrequent following GBM resection and is influenced by surgery-related factors. It typically occurs several weeks after resection. If multiple risk factors are present, one should discuss the possibility of postoperative CH with the patient and maybe even consider pre-emptive shunt implantation to avoid interruption of adjuvant tumor therapy. The incidence of CH requiring shunting in GBM patients could rise in the future.

Frontier progress and challenges based on excited-state porphyrins and their derivatives

<p indent="0mm">Porphyrins and their derivatives feature advantages of strong resonance plane structure and facile modification of molecular, thereby showing great development prospects in the area of biochemistry and optical materials. In this review, based on excited porphyrin and phthalocyanine substrates, modification methods and mechanism research are discussed, and latest progress and challenges of photoacoustic imaging technology for photodynamic therapy, acoustic therapy and adjuvant tumor therapy are reviewed.

LINC-09. Coexisting glioneuronal tumor and adrenal ganglioneuroma

BACKGROUND: While both glial/glioneuronal neoplasia and ganglioneuroma have been reported as components of multiple primary neoplasms, no patient has been diagnosed with multiple primary neoplasms of cerebral glial/glioneuronal tumors with oligodendroglioma-like features and adrenal ganglioneuroma up to now. CASE: A previously healthy five-year-old girl was admitted with a two-week history of headaches and vomiting. Brain Magnetic resonance imaging (MRI) showed a massive heterogenous multi-cystic enhancing lesion in the right temporoparietal area with substantial vasogenic edema. The patient underwent craniotomy and tumor gross total resection. The intra-operative histomorphological assessment of the tumor was well-matched with a glial tumor. The patient developed systolic hypertension during postoperative care in the Intensive Care Unit. Subsequent abdominal CT scan unveiled a calcified mass of the left adrenal gland origin. Blood and urine catecholamine tests, vanillylmandelic acid (VMA), were within the normal range. The surgical excision specimen exhibited a clear cell neoplasm with diffuse infiltrative growth. A distinguishing combination of oligodendroglioma-like perinuclear haloes, clear cell appearance and vascular proliferation rendered the diffuse Glioneuronal tumor with Oligodendroglioma-like features. With the combination of oligodendroglial-like appearance, negative 1p/19q codeletion, Wild IDH, no BRAF mutation, weak GFAP, and positive synaptophysin altogether, the tumor was compatible with the novel diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC). The patient underwent laparotomy and tumor resection subsequently. Morphologic histopathological examinations of the adrenal mass were in line with ganglioneuroma. After discharge, no pathological uptake was identified with iodine-131 meta-iodobenzylguanidine scan (MIBG scan). No tumor residue was apparent on postoperative brain MRI. The patient received no adjuvant therapy for brain and adrenal tumors and underwent close surveillance for both tumors. No clinical or radiologic recurrence was recognized after six months of follow-up. CONCLUSIONS: Concurrent glioneuronal tumor and ganglioneuroma can be managed safely when diagnosed timely, leading to favorable outcomes.

Ranunculus ternatus Thunb extract attenuates renal fibrosis of diabetic nephropathy via inhibiting SMYD2

Context Ranunculus ternatus Thunb (Ranunculaceae), (RTT) is used clinically for the treatment of tuberculosis or as tumour adjuvant therapy, but its potential effect on diabetic nephropathy (DN) has not been studied. Objective To investigate the effect of RTT extract in renal fibrosis of DN. Materials and methods C57BL/6 mice were randomly divided into four groups (n = 12). Diabetes mellitus (DM) mice were induced by streptozotocin (STZ, 55 mg/kg/day) for five consecutive days and treated by RTT extract (2 g/kg). Afterward, blood glucose, HE and Masson staining were assayed. The expression levels of Vimentin, ɑ-SMA, TNF-ɑ, NF-κB p-p65, NF-κB p65, SMYD2, H3K36me3, H3K4me3 were determined by western blots. Firbronectin was respectively assayed by western blot and immunofluorescent staining. Results RTT extract significantly ameliorated renal injury and renal fibrosis in the renal tissue of STZ-induced diabetic mice as demonstrated by the decreased expression level of Fibronectin (65%), Vimentin and α-SMA (75% & 53%). In addition, the levels of TNF-α (57%), NF-κB p-p65 and NF-κB p65 (35% & 25%) were elevated in the DN mice. Importantly, these were alleviated after RTT extract treatment. Moreover, we observed that the protein levels of SMYD2 (30%), H3K36me3 and H3K4me3 (53% & 75%) were reduced in DN mice after treatment with RTT extract. Discussion and conclusions RTT extract mediates antifibrotic effects and anti-inflammatory responses in STZ-induced DN mainly through suppressing SMYD2 activation and H3K36me3 and H3K4me3 protein expression. RTT extract might have therapeutic potential against high glucose-induced nephropathy.

A Rare Case of Quadruple Negative GIST with an Unusual Presentation in a Young Female

Gastrointestinal stromal tumors (GISTs) are an uncommon malignancy, with origin in the interstitial cells of Cajal located in the myenteric plexus. The incidence is 5000 new cases every year in the US. It is important to determine genetic alterations in GIST. Approximately 90% of GISTs have a gain of function mutation in either the c-KIT protooncogene (which encodes for the receptor tyrosine kinase KIT) accounting for 75%, or the platelet derived growth factor receptor alpha (PDGFRA) protooncogene which accounts for 15%. Only 5-10% constitute Wild Type (WT) GISTs with mutations observed in BRAF, NF1, &amp; SDH. While Imatinib, a Tyrosine Kinase Inhibitor (TKI), is used as adjuvant therapy for most KIT-positive tumors, it cannot be used in TKI-resistant tumors that harbor alternative genetic mutations. We present a rare case of quadruple negative (negative for all aforementioned genes) GIST with a mutation identified as ETV6-NTRK3 fusion. This mutation was first described in a case of rectal quadruple negative WT GIST.

Open questions and controversies in the systemic treatment of breast cancer.

Personalized therapy has revolutionized our approach to breast cancer (BC). Patient selection strategies and new biomarkers are the basis for increasingly complex diagnostic and therapeutic algorithms. In this short review, we discuss recent developments in breast oncology, focusing on controversial topics with relevance for clinical practice. The use of gene expression signatures to guide adjuvant therapy in hormone receptor-positive tumors and personalized strategies for systemic treatment of early stage HER2-positive disease represent significant advances. Additionally, the current role of platinum salts, immune checkpoint inhibitors, and CDK4/6 inhibitors in the (neo)adjuvant treatment remains controversial, with several ongoing randomized clinical trials exploring their use. In the metastatic disease setting, we identify important unmet needs such as the development of predictive biomarkers and the definition of the ideal sequencing algorithm with the incorporation of innovative agents in all subtypes of BC. Advances in understanding the molecular biology and heterogeneity of BC have led to the development of new biomarkers and therapeutic agents that significantly impact current and future clinical practice.

Mucoepidermoid carcinoma of the parotid gland: Twenty-year experience in treatment and outcomes.

Parotid gland mucoepidermoid carcinoma (MEC) has published five-year cancer-specific survival (CSS) rates of 77%-97%, with variance related to grade. Patients receiving primary surgery for parotid gland MEC from 1995 to 2014 at a tertiary medical center underwent clinical review, histopathologic review, and cytogenetic analysis. Survival outcomes were evaluated. Among 58 patients, T/N/M classification was as follows: T1 in 35 patients, T2 in 14, T4a in 9, N0 in 53, N1 in 2, N2b in 3. Histologic grade was low in 27, intermediate in 17, and high in 12 patients with 98% MAML2 positivity. All patients underwent parotidectomy, and seven patients received adjuvant radiation therapy. CSS was 100% at 5 years and 94.1% at 10 and 15 years. Two patients experienced locoregional recurrence. Treatment with adequate surgical resection and adjuvant radiation therapy for high-grade or advanced-stage tumors yields excellent survival, independent of clinical stage or pathologic grade.

Novel topical and transdermal delivery of colchicine with chitosan based biocomposite nanofiberous system; formulation, optimization, characterization, ex vivo skin deposition/permeation, and anti-melanoma evaluation

Melanoma bears the highest mortality rate in skin cancers. The unique properties of chitosan-based nanofibers provide a great potential to formulate an effective topical drug delivery system. With the emphasis on Colchicine systemic toxicity as an obstacle against the administration in systemic chemotherapy and considering its superiority over approved chemotherapeutic agents for melanoma management, it was chosen to be formulated in a nanofiber based topical drug delivery system. The optimization assay was conducted by AFM and SEM based on the morphology, topographic data, and mean diameter size of the nanofibers. Other characterization studies include FTIR, XRD, STA, contact angle measurement, tensile test, ex vivo skin permeation, deposition analysis, release kinetic and anti-melanoma efficiency against A-375 cell line. As a result, significant colchicine deposition in the skin with remarkable cytotoxicity against melanoma cell line makes it a desirable formulation to be administered as a topical or local reservoir system for neoadjuvant chemotherapy before other interventions and adjuvant therapy of tumors after surgery and, also, for other skin diseases with dose adjustment. Besides, the observed first order release kinetic behavior through the skin could suggest it as a transdermal colchicine delivery system which improves its efficiency in systemic indications.

Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.

Adjuvant systemic therapy for small bowel gastrointestinal stromal tumor (GIST): Is there a survival benefit after R0 resection?

BackgroundThe utility of adjuvant systemic therapy in small bowel gastrointestinal stromal tumor remains unclear. MethodsWe queried the National Cancer Data Base for individuals having enterectomy to negative margins for small bowel gastrointestinal stromal tumor between 2010 and 2015. Subjects were categorized by tumor size (2.1–5 cm, 5.1–10 cm, >10 cm) and histologic grade (≤5 mitoses/50 high-power field and >5 mitoses/50 high-power field). Cox proportional hazard analysis was performed to evaluate the association between adjuvant therapy and overall survival. ResultsOne thousand five hundred fifty-nine patients met the inclusion criteria. On univariate comparison to resection alone, adjuvant therapy was associated with improved overall survival for individuals with high-grade tumors of intermediate and large size (85% vs 48%, P = .010; 75% vs 47%, P = .003) but not for those with high-grade tumors of small size or low-grade tumors of any size. On multivariable analysis adjusted for age, comorbid disease state, and tumor size, adjuvant therapy was independently associated with reduced risk of mortality for high-grade (hazard ratio 0.37, 95% confidence interval: 0.21–0.64) but not low-grade tumors. ConclusionAdjuvant therapy after R0 resection for small bowel gastrointestinal stromal tumor should be administered after careful consideration of the size and grade of a patient’s tumor.