Introduction: Breast-cancer-related lymphedema (BCRL) is a frequently occurring and debilitating condition. When lymphedema is diagnosed late, treatment can be expected to be less effective. Lymphofluoroscopy can provide details about the superficial lymphatic architecture and can detect an early disturbance of lymphatic transport (i.e., dermal backflow) before the lymphedema is clinically visible. The main objective of this study is to investigate whether this early disturbance of lymphatic transport visualized by lymphofluoroscopy is a risk factor for the development of BCRL. Methodology: All patients scheduled for unilateral breast cancer surgery with axillary lymph node dissection or sentinel node biopsy were considered. Patients were assessed at baseline and 1, 3, 6, 9, 12, 18, 24 and 36 months postoperatively. During each visit, a clinical assessment was performed to determine the volume difference between both arms and hands (through circumference measurements and water displacement). Clinical BCRL was defined as a ≥5% increase in relative arm volume difference compared to the baseline value. Variables related to (1) the disturbance of lymphatic transport (through lymphofluoroscopy), (2) the demographics and general health of the patient and (3) the breast cancer and treatment of the patient were collected. Results: We included data of 118 patients in the present study. Thirty-eight patients (39.8%) developed BCRL. Early disturbance of lymphatic transport was identified as a risk factor for the development of clinical BCRL (HR 2.808). Breast-cancer- and treatment-related variables such as axillary lymph node dissection (ALND) (HR 15.127), tumor stage (HR 1.745), mastectomy (HR 0.186), number of positive lymph nodes (HR 1.121), number of removed lymph nodes (HR 1.055), radiotherapy of the axilla (HR 2.715), adjuvant taxanes (HR 3.220) and postsurgical complications (HR 2.590) were identified as significant risk factors for the development of BCRL. In the multivariate analysis, age and ALND were withheld as independent risk factors for the development of BCRL. Conclusion: Lymphofluoroscopy can identify an early disturbance of lymphatic transport after breast cancer treatment. Patients with an early disturbance of lymphatic transport are considered to be a high-risk group for the development of BCRL. This study also confirms that age and ALND are predictors for the development of BCRL. Therefore, a surveillance program of these patients with lymphofluoroscopy could be useful to identify lymphedema in subclinical stages. Full article

To determine the role of adjuvant chemotherapy in stage IA G2-3 and stage IB-IC pure ovarian immature teratoma (POIT), we performed a systematic review and meta-analysis by searching PubMed, Embase, Cochrane library, Web of Science, and ClinicalTrials.gov. Randomized controlled trials or cohort studies on stage IA G2-G3 or stage IB-IC POIT between 1 January 1970 and 15 December 2022 were enrolled. The recurrence rate and mortality rate were the primary outcomes, and subgroup analysis based on the tumor stage and grade was also conducted. In total, 15 studies with 707 patients were included. Compared with surveillance, adjuvant chemotherapy significantly decreased the mortality rate (RR 0.31, 95% CI 0.11–0.88, p = 0.03), but not recurrence (RR 0.74, 95% CI 0.39–1.42, p = 0.37), in the overall population. Subgroup analysis showed no statistical difference in the recurrence rate and mortality rate between patients who received adjuvant chemotherapy and surveillance in pediatric POIT, stage IA G2-3 POIT, stage IB-IC POIT, and stage IA-IC G3 POIT (all with p > 0.05). However, patients who underwent adjuvant chemotherapy appeared to have a lower risk of both recurrence (RR 0.17, 95% CI 0.03–0.83, p = 0.03) and death (RR 0.04, 95% CI 0.00–1.00, p = 0.05) in adult POIT. Adjuvant chemotherapy significantly decreased the mortality rate in patients with stage I POIT and lowered the risk of recurrence in the adult subgroup. Surveillance administered in stage I POIT over IA G1 should be cautious, especially in adult patients. Full article

Von Hippel–Lindau (VHL) is a rare autosomal dominant hereditary cancer predisposition syndrome. Patients with VHL have a high risk for developing retinal and central nervous system hemangioblastoma, pheochromocytoma, renal cell carcinoma, and pancreatic neuroendocrine neoplasms (PNEN). About a fifth of patients with VHL will develop PNEN, and only a tenth of them will develop metastatic or unresectable (advanced) PNEN requiring medical intervention. In this review, we performed a literature search for studies, written in English, on the medical interventions for VHL-related localized and advanced PNENs and their clinical outcomes. We detail the various medical interventions for this rare group of patients, including their mode of action and potential efficacy and toxicity. Finally, based on the current literature, we delineate a possible management algorithm for patients with VHL and advanced PNEN. We can conclude that data on the efficacy of various vascular endothelial growth factor (VEGF) receptor inhibitors, and on the efficacy of belzutifan, a novel hypoxia-inducible factor 2 inhibitor, for the management of advanced PNEN in VHL, are scarce. Hence, deduction from the management of sporadic PNEN is required, and is implemented in the proposed management algorithm provided within this review. Full article

Background: There is little evidence that supports the registered high dose of dexamethasone used around docetaxel. However, this high dose is associated with considerable side effects. This study evaluates the feasibility of reducing the prophylactic oral dosage of dexamethasone around docetaxel infusion. Patients and methods: Eligible patients had a histologically confirmed diagnosis of prostate or breast cancer and had received at least three cycles of docetaxel as monotherapy or combination therapy. Prophylactic dexamethasone around docetaxel infusion was administered in a de-escalating order per cohort of patients. Primary endpoint was the occurrence of grade III/IV fluid retention and hypersensitivity reactions (HSRs). Results: Of the 46 enrolled patients, 39 were evaluable (prostate cancer (n = 25), breast cancer (n = 14). In patients with prostate cancer, the dosage of dexamethasone was reduced to a single dose of 4 mg; in patients with breast cancer, the dosage was reduced to a 3-day schedule of 4 mg–8 mg–4 mg once daily, after which no further reduction has been tested. None of the 39 patients developed grade III/IV fluid retention or HSR. One patient (2.6%) had a grade 1 HSR, and there were six patients (15.4%) with grade I or II edema. There were no differences in quality of life (QoL) between cohorts. Conclusions: It seems that the prophylactic dose of dexamethasone around docetaxel infusion can be safely reduced with respect to the occurrence of grade III/IV HSRs or the fluid retention syndrome. Full article

Background: Flap reconstruction is commonly used in advanced tongue carcinoma in order to compensate for the loss of tongue tissue and function. Surprisingly, a large number of reconstructed early-stage tongue cancer can be found. Survival or functional benefits in these cases remain unclear. Methods: A retrospective data analysis of 384 surgically treated tongue carcinoma patients was conducted aiming to find epidemiologic and survival differences between patients with (n = 158) or without flap reconstruction (n = 226). A prospective functional analysis was performed on 55 early-stage tongue cancer patients, 33 without and 22 with radial-forearm flap reconstruction, focusing on post-therapeutic swallowing function as the primary endpoint, speech as the secondary endpoint, xerostomia, quality of life, and mouth opening. Results: Consistent with the current literature, we demonstrated the significantly more frequent use of flap grafts in advanced tongue carcinomas. For the first time, we depicted a higher female ratio in the reconstructed group (p = 0.02). There were no significant differences in survival or functional outcomes between the groups. The none-reconstructed group showed more frequent use of adjuvant C/RT despite presenting fewer N+ stages. Conclusions: The higher female ratio in the reconstruction group is plausible due to the anatomically smaller oral cavity and relatively larger carcinoma in women. A higher presence of close margins in the none-reconstruction group may explain the more frequent use of adjuvant C/RT. Since we found no survival or functional differences between the groups, we propose a critical approach toward flap reconstruction in T1/2 tongue carcinoma. At the same time, proportional aspects and adequate resection margins should be taken into account. Full article

Acute myelogenous leukemia (AML), the most prevalent acute and aggressive leukemia diagnosed in adults, often recurs as a difficult-to-treat, chemotherapy-resistant disease. Because chemotherapy resistance is a major obstacle to successful treatment, novel therapeutic intervention is needed. Upregulated ceramide clearance via accelerated hydrolysis and glycosylation has been shown to be an element in chemotherapy-resistant AML, a problem considering the crucial role ceramide plays in eliciting apoptosis. Herein we employed agents that block ceramide clearance to determine if such a “reset” would be of therapeutic benefit. SACLAC was utilized to limit ceramide hydrolysis, and D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-threo-PDMP) was used to block the glycosylation route. The SACLAC D-threo-PDMP inhibitor combination was synergistically cytotoxic in drug-resistant, P-glycoprotein-expressing (P-gp) AML but not in wt, P-gp-poor cells. Interestingly, P-gp antagonists that can limit ceramide glycosylation via depression of glucosylceramide transit also synergized with SACLAC, suggesting a paradoxical role for P-gp in the implementation of cell death. Mechanistically, cell death was accompanied by a complete drop in ceramide glycosylation, concomitant, striking increases in all molecular species of ceramide, diminished sphingosine 1-phosphate levels, resounding declines in mitochondrial respiratory kinetics, altered Akt, pGSK-3β, and Mcl-1 expression, and caspase activation. Although ceramide was generated in wt cells upon inhibitor exposure, mitochondrial respiration was not corrupted, suggestive of mitochondrial vulnerability in the drug-resistant phenotype, a potential therapeutic avenue. The inhibitor regimen showed efficacy in an in vivo model and in primary AML cells from patients. These results support the implementation of SL enzyme targeting to limit ceramide clearance as a therapeutic strategy in chemotherapy-resistant AML, inclusive of a novel indication for the use of P-gp antagonists. Full article

Background: Oncologic outcomes for pT2N0M0 upper tract urothelial carcinoma (UTUC) after nephroureterectomy are not well defined, with most previous studies focused on a heterogeneous population. Therefore, we aimed to investigate the clinical determinants of extraurinary tract recurrence and survival after radical surgery in patients with localized UTUC. Methods: We retrospectively identified 476 patients with pT2N0M0 UTUC who underwent radical nephroureterectomy or ureterectomy between October 2002 and March 2022. To evaluate the prognostic impact, patients were divided into renal pelvic, ureteral, and both-region (renal pelvis plus synchronous ureter) groups based on tumor location. The outcomes included recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Associations were evaluated using multivariable Cox regression analyses for prognostic factors and Kaplan–Meier analyses for survival curves. Results: The renal pelvic, ureteral, and both-region groups consisted of 151 (31.7%), 314 (66.0%), and 11 (2.3%) patients, respectively. Kaplan–Meier analyses comparing the three tumor types showed significant differences in 5-year RFS (83.6% vs. 73.6% vs. 52.5%, p = 0.013), CSS (88.6% vs. 80.7% vs. 51.0%, p = 0.011), and OS (83.4% vs. 70.1% vs. 45.6%, p = 0.002). Multivariable analyses showed that age >60 years, previous bladder cancer history, ureteral involvement (ureteral and both-regional groups), and positive surgical margins were significant negative prognostic factors for the studied outcomes. Conclusions: Patients with pT2 UTUC and presence of ureteral involvement had more frequent disease relapse. Subsequent adjuvant therapy regimens and close follow-up in patients with negative prognostic factors are warranted despite complete pathological removal of the tumor. Full article

Latent infection of Epstein-Barr virus (EBV) is associated with lymphoid and epithelial cell cancers, including 10% of gastric carcinomas. We previously reported that hypoxia inducible factor-1α (HIF-1α) induces EBV’s latent-to-lytic switch and identified several HIF-1α-stabilizing drugs that induce this viral reactivation. Here, we tested three classes of these drugs for preferential killing of the EBV-positive gastric cancer AGS-Akata cell line compared to its matched EBV-negative AGS control. We observed preferential killing with iron chelators [Deferoxamine (DFO); Deferasirox (DFX)] and a prolyl hydroxylase inhibitor (BAY 85-3934 (Molidustat)), but not with a neddylation inhibitor [MLN4924 (Pevonedistat)]. DFO and DFX also induced preferential killing of the EBV-positive gastric cancer AGS-BDneo and SNU-719 cell lines. Preferential killing was enhanced when low-dose DFX (10 μM) was combined with the antiviral prodrug ganciclovir. DFO and DFX induced lytic EBV reactivation in approximately 10% of SNU-719 and 20-30% of AGS-Akata and AGS-BDneo cells. However, neither DFO nor DFX significantly induced synthesis of lytic EBV proteins in xenografts grown in NSG mice from AGS-Akata cells above the level observed in control-treated mice. Therefore, these FDA-approved iron chelators are less effective than gemcitabine at promoting EBV reactivation in vivo despite their high specificity and efficiency in vitro. Full article

MYCN is a major oncogenic driver for neuroblastoma tumorigenesis, yet there are no direct MYCN inhibitors. We have previously identified PA2G4 as a direct protein-binding partner of MYCN and drive neuroblastoma tumorigenesis. A small molecule known to bind PA2G4, WS6, significantly decreased tumorigenicity in TH-MYCN neuroblastoma mice, along with the inhibition of PA2G4 and MYCN interactions. Here, we identified a number of novel WS6 analogues, with 80% structural similarity, and used surface plasmon resonance assays to determine their binding affinity. Analogues #5333 and #5338 showed direct binding towards human recombinant PA2G4. Importantly, #5333 and #5338 demonstrated a 70-fold lower toxicity for normal human myofibroblasts compared to WS6. Structure-activity relationship analysis showed that a 2,3 dimethylphenol was the most suitable substituent at the R¹ position. Replacing the trifluoromethyl group on the phenyl ring at the R² position, with a bromine or hydrogen atom, increased the difference between efficacy against neuroblastoma cells and normal myofibroblast toxicity. The WS6 analogues inhibited neuroblastoma cell phenotype in vitro, in part through effects on apoptosis, while their anti-cancer effects required both PA2G4 and MYCN expression. Collectively, chemical inhibition of PA2G4-MYCN binding by WS6 analogues represents a first-in-class drug discovery which may have implications for other MYCN-driven cancers. Full article

In recent years, chemoimmunotherapy has become effective in some advanced cancers, but its effect is still limited. Transcriptional upregulation of isocitrate dehydrogenase 3α (IDH3α) can promote tumor initiation and progression. However, it is not clear whether the aberrant expression of IDH3α is related to the efficacy of chemoimmunotherapy in cancers. Here, we found that IDH3α was elevated in uterine cervical cancer (UCC) and lung adenocarcinoma (LUAD) samples by using public databases. High expression of IDH3α could promote the epithelial–mesenchymal transition (EMT), alter the intracellular redox status, promote glycolysis, and induce an acidic microenvironments in cancer cells. Furthermore, we found that inhibition of IDH3α combined with chemoimmunotherapy (cisplatin and programmed cell death ligand 1 (PD-L1) antibodies) activated the cGAS–STING pathway, promoted CD8⁺ T cell infiltration, and decreased tumor growth in mouse models of cervical cancer. In conclusion, our data indicate that silencing IDH3α sensitizes tumors to chemoimmunotherapy by modulating the acidic microenvironment and activating the cGAS–STING pathway. Full article

Colorectal cancer (CRC) is a significant public health problem. There is increasing evidence that the host’s immune response and nutritional status play a role in the development and progression of cancer. The aim of our study was to examine the prognostic value of clinical markers/indexes of inflammation, nutritional and pathohistological status in relation to overall survival and disease free-survival in CRC. The total number of CRC patients included in the study was 111 and they underwent laboratory analyses within a week before surgery. Detailed pathohistological analysis and laboratory parameters were part of the standard hospital pre-operative procedure. Medical data were collected from archived hospital data. Data on the exact date of death were obtained by inspecting the death registers for the territory of the Republic of Serbia. All parameters were analyzed in relation to the overall survival and survival period without disease relapse. The follow-up median was 42 (24−48) months. The patients with the III, IV and V degrees of the Clavien–Dindo classification had 2.609 (HR: 2.609; 95% CI: 1.437−4.737; p = 0.002) times higher risk of death. The modified Glasgow prognostic score (mGPS) 2 and higher lymph node ratio carried a 2.188 (HR: 2.188; 95% CI: 1.413−3.387; p < 0.001) and 6.862 (HR: 6.862; 95% CI: 1.635−28.808; p = 0.009) times higher risk of death in the postoperative period, respectively; the risk was 3.089 times higher (HR: 3.089; 95% CI: 1.447−6.593; p = 0.004) in patients with verified tumor deposits. The patients with tumor deposits had 1.888 (HR: 1.888; 95% CI: 1024−3481; p = 0.042) and 3.049 (HR: 3.049; 95% CI: 1.206−7.706; p = 0.018) times higher risk of disease recurrence, respectively. The emphasized peritumoral lymphocyte response reduced the risk of recurrence by 61% (HR: 0.391; 95% CI: 0.196−0.780; p = 0.005). Standard perioperative laboratory and pathohistological parameters, which do not present any additional cost for the health system, may provide information on the CRC patient outcome and lay the groundwork for a larger prospective examination. Full article

Although Ipilimumab (anti-CTLA-4) is FDA-approved for stage III/IV melanoma adjuvant treatment, it is not used clinically in first-line therapy, given the superior relapse-free survival (RFS)/toxicity benefits of anti-PD-1 therapy. However, it is important to understand anti-CTLA-4’s mechanistic contribution to combination anti-PD-1/CTLA-4 therapy and investigate anti-CTLA-4 therapy for BRAF-wild type melanoma cases reresected after previous adjuvant anti-PD-1 therapy. Our group published that nitric oxide (NO) increased within the immune effector cells among patients with longer RFS after adjuvant ipilimumab, whereas NO increased within the immune suppressor cells among patients with shorter RFS. Herein, we measured the post-translational modifications of STAT1 (nitration-nSTAT1 and phosphorylation-pSTAT1) that are important for regulating its activity via flow cytometry and mass spectrometry approaches. PBMCs were analyzed from 35 patients undergoing adjuvant ipilimumab treatment. Shorter RFS was associated with higher pSTAT1 levels before (p = 0.007) and after (p = 0.036) ipilimumab. Ipilimumab-treated patients with high nSTAT1 levels before and after therapy in PBMCs experienced decreased RFS, but the change in nSTAT1 levels before and after ipilimumab therapy was associated with longer RFS (p = 0.01). The measurement of post-translational modifications in STAT1 may distinguish patients with prolonged RFS from ipilimumab and provide mechanistic insight into responses to ipilimumab combination regimens. Full article

Background: The outcome for patients with high-risk neuroblastoma remains poor and novel treatment strategies are urgently needed. The RIST protocol represents a novel metronomic and multimodal treatment strategy for high-risk neuroblastoma combining molecular-targeted drugs as ‘pre-treatment’ with a conventional chemotherapy backbone, currently evaluated in a phase II clinical trial. For preclinical drug testing, cancer cell growth as spheroid compared to mo-nolayer cultures is of advantage since it reproduces a wide range of tumor characteristics, including the three-dimensional architecture and cancer stem cell (CSC) properties. The objective of this study was to establish a neuroblastoma spheroid model for the rigorous assessment of the RIST treatment protocol. Methods: Evaluation of CSC marker expression was performed by mRNA and protein analysis and spheroid viability by luminescence-based assays. Aberrant expression of RNA-binding protein La in neuroblastoma was assessed by tissue microarray analysis and patients’ data mining. Results: Spheroid cultures showed increased expression of a subgroup of CSC-like markers (CXCR4, NANOG and BMI) and higher Thr389 phosphorylation of the neuroblastoma-associated RNA-binding protein La when compared to monolayer cultures. Molecular-targeted ‘pre-treatment’ of spheroids decreased neoplastic signaling and CSC marker expression. Conclusions: The RIST treatment protocol efficiently reduced the viability of neuroblastoma spheroids characterized by advanced CSC properties. Full article