Augmented EPR effect post IRFA to enhance the therapeutic efficacy of arsenic loaded ZIF-8 nanoparticles on residual HCC progression

Background Insufficient radiofrequency ablation (IRFA) can promote the local recurrence and distal metastasis of residual hepatocellular carcinoma (HCC), which makes clinical treatment extremely challenging. In this study, the malignant transition of residual tumors after IRFA was explored. Then, arsenic-loaded zeolitic imidazolate framework-8 nanoparticles (As@ZIF-8 NPs) were constructed, and their therapeutic effect on residual tumors was studied. Results Our data showed that IRFA can dramatically promote the proliferation, induce the metastasis, activate the epithelial–mesenchymal transition (EMT) and accelerate the angiogenesis of residual tumors. Interestingly, we found, for the first time, that extensive angiogenesis after IRFA can augment the enhanced permeability and retention (EPR) effect and enhance the enrichment of ZIF-8 nanocarriers in residual tumors. Encouraged by this unique finding, we successfully prepared As@ZIF-8 NPs with good biocompatibility and confirmed that they were more effective than free arsenic trioxide (ATO) in sublethal heat-induced cell proliferation suppression, apoptosis induction, cell migration and invasion inhibition, and EMT reversal in vitro. Furthermore, compared with free ATO, As@ZIF-8 NPs exhibited remarkably increased therapeutic effects by repressing residual tumor growth and metastasis in vivo. Conclusions This work provides a new paradigm for the treatment of residual HCC after IRFA. Graphical Abstract

THUNDER 2: THeragnostic Utilities for Neoplastic DisEases of the Rectum by MRI guided radiotherapy

Background Neoadjuvant chemoradiation therapy (nCRT) is the standard treatment modality in locally advanced rectal cancer (LARC). Since response to radiotherapy (RT) is dose dependent in rectal cancer, dose escalation may lead to higher complete response rates. The possibility to predict patients who will achieve complete response (CR) is fundamental. Recently, an early tumour regression index (ERI) was introduced to predict pathological CR (pCR) after nCRT in LARC patients. The primary endpoints will be the increase of CR rate and the evaluation of feasibility of delta radiomics-based predictive MRI guided Radiotherapy (MRgRT) model. Methods Patients affected by LARC cT2-3, N0-2 or cT4 for anal sphincter involvement N0-2a, M0 without high risk features will be enrolled in the trial. Neoadjuvant CRT will be administered using MRgRT. The initial RT treatment will consist in delivering 55 Gy in 25 fractions on Gross Tumor Volume (GTV) plus the corresponding mesorectum and 45 Gy in 25 fractions on the drainage nodes. Chemotherapy with 5-fluoracil (5-FU) or oral capecitabine will be administered continuously. A 0.35 Tesla MRI will be acquired at simulation and every day during MRgRT. At fraction 10, ERI will be calculated: if ERI will be inferior than 13.1, the patient will continue the original treatment; if ERI will be higher than 13.1 the treatment plan will be reoptimized, intensifying the dose to the residual tumor at the 11th fraction to reach 60.1 Gy. At the end of nCRT instrumental examinations are to be performed in order to restage patients. In case of stable disease or progression, the patient will undergo surgery. In case of major or complete clinical response, conservative approaches may be chosen. Patients will be followed up to evaluate toxicity and quality of life. The number of cases to be enrolled will be 63: all the patients will be treated at Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome. Discussion This clinical trial investigates the impact of RT dose escalation in poor responder LARC patients identified using ERI, with the aim of increasing the probability of CR and consequently an organ preservation benefit in this group of patients. Trial registration ClinicalTrials.gov Identifier: NCT04815694 (25/03/2021).

Novel Multifunctional NIR-II Aggregation-Induced Emission Nanoparticles Assisted Intraoperative Identification and Elimination of Residual Tumor

Incomplete tumor resection is the direct cause of the tumor recurrence and metastasis after surgery. Intraoperative accurate detection and elimination of microscopic residual cancer improve surgery outcomes. In this study, a powerful D1-π-A-D2-R type phototheranostic based on aggregation-induced emission (AIE)-active the second near-infrared window (NIR-II) fluorophore is designed and constructed. The prepared theranostic agent, A1 nanoparticles (NPs), simultaneously shows high absolute quantum yield (1.23%), excellent photothermal conversion efficiency (55.3%), high molar absorption coefficient and moderate singlet oxygen generation performance. In vivo experiments indicate that NIR-II fluorescence imaging of A1 NPs precisely detect microscopic residual tumor (2 mm in diameter) in the tumor bed and metastatic lymph nodes. More notably, a novel integrated strategy that achieves complete tumor eradication (no local recurrence and metastasis after surgery) is proposed. In summary, A1 NPs possess superior imaging and treatment performance, and can detect and eliminate residual tumor lesions intraoperatively. This work provides a promising technique for future clinical applications achieving improved surgical outcomes.

Intraoperative Magnetic Resonance Imaging Assisted Endoscopic Endonasal Resection of Clival Chordomas

BackgroundCranial base chordomas are typically indolent and usually appear as encapsulated tumors. They slowly grow by infiltrating the bone, along with the lines of least resistance. Due to its relationship with important neurovascular structures, skull base chordoma surgery is challenging.ObjectiveThe usefulness of intraoperative magnetic resonance imaging (IO-MRI) in achieving the goal of surgery, is evaluated in this study.MethodsBetween March 2018 and March 2020, 42 patients were operated on for resection of skull base chordomas in our institution. All of them were operated on under IO-MRI. Patients were analyzed retrospectively for identifying common residue locations, complications and early post-operative outcomes.ResultsIn 22 patients (52,4%) gross total resection was achieved according to the final IO-MRI. In 20 patients (47,6%) complete tumor removal was not possible because of extension to the petrous bone (8 patients), pontocerebellar angle (6 patients), prepontine cistern (4 patients), temporobasal (1 patient), cervical axis (1 patient). In 13 patients, the surgery was continued after the first IO-MRI control was performed, which showed a resectable residual tumor. 7 of these patients achieved total resection according to the second IO-MRI, in the other 6 patients all efforts were made to ensure maximal resection of the tumor as much as possible without morbidity. Repeated IO-MRI helped achieve gross total resection in 7 patients (53.8%).ConclusionsOur study proves that the use of IO-MRI is a safe method that provides the opportunity to show the degree of resection in skull base chordomas and to evaluate the volume and location of the residual tumor intraoperatively. Hence IO-MRI can improve the life expectancy of patients because it provides an opportunity for both gross total resection and maximal safe resection in cases where total resection is not possible.

WHO Grade Loses Its Prognostic Value in Molecularly Defined Diffuse Lower-Grade Gliomas

BackgroundWhile molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting.Material and MethodsA total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed.ResultsThere was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01–1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00–1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00–1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01–1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08).ConclusionOur findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.

Absence of residual tumor tissue after Gamma Knife radiosurgery followed by resection of a vestibular schwannoma: illustrative case

BACKGROUND Late pathology after vestibular schwannoma radiosurgery is uncommon. The authors presented a case of a resected hemorrhagic mass 13 years after radiosurgery, when no residual tumor was found. OBSERVATIONS A 56-year-old man with multiple comorbidities, including myelodysplastic syndrome cirrhosis, received Gamma Knife surgery for a left vestibular schwannoma. After 11 years of stable imaging assessments, the lesion showed gradual growth until a syncopal event occurred 2 years later, accompanied by progressive facial weakness and evidence of intralesional hemorrhage, which led to resection. However, histopathological analysis of the resected specimen showed hemorrhage and reactive tissue but no definitive residual tumor. LESSONS This case demonstrated histopathological evidence for the role of radiosurgery in complete elimination of tumor tissue. Radiosurgery for vestibular schwannoma carries a rare risk for intralesional hemorrhage in select patients.

Diffusion Weighted and Dynamic Contrast Enhanced Magnetic Resonance Imaging in Carcinoma of Cervix: Role of Apparent Diffusion Coefficient Value and Time Intensity Curve Pattern in Chemoradiotherapeutic Response Evaluation

Introduction: Magnetic resonance imaging (MRI) is a widely used imaging modality in the imaging evaluation of carcinoma of cervix. The aim of our study was to evaluate the response in carcinoma cervix patients following chemoradiotherapy by Diffusion weighted (DW-MRI) and Dynamic contrast enhanced-MRI (DCE-MRI). Methods: 21 inoperable biopsy proven patients (mean age 48.43 years) of carcinoma cervix were included in the study. All patients underwent MRI (conventional, DW and DCE) of the pelvis thrice. Baseline MRI, Post chemotherapy MRI after neoadjuvant chemotherapy and Post chemoradiotherapy MRI after completion of concurrent chemoradiotherapy. Post treatment apparent diffusion coefficient(ADC) values and Time intensity curve(TIC) pattern were compared with baseline values. Results: Baseline meanADC value of all patients was 0.82 x10-3 mm2/s. After completion of treatment, 18 patients showed complete resolution of tumor and showed 0.50 x10-3 mm2/s increase in meanADC value from baseline MRI which was significantly higher than remaining 3 patients with residual tumor (0.50 x10-3 mm2/s v/s 0.17 x10-3 mm2/s). ADC threshold value of 1.15 x10-3 mm2/s was defined, differentiating the residual tumor from the healthy cervical tissue after chemoradiation. On post treatment MRI, 17 out of 18 patients with complete resolution of tumor showed increasing trend of enhancement on TIC and only one patient showed plateau pattern. 2 of the 3 patients with residual tumor showed washout pattern and one patient showed plateau pattern. Conclusion: ADC values and TIC pattern differ in patients with complete response to chemoradiotherapy from patients with residual tumor, so helps in differentiating residual tumor from cancer free cervix. Keywords: Carcinoma of cervix; Chemoradiotherapy; Diffusion weighted MRI; Dynamic contrast enhanced MRI; Time intensity curve.

Bioglass and its application in modern treatment of osteooncological diseases

Bone tumor diseases are one of the main problems in modern clinical practice. After surgery, some of the tumor cells capable of proliferation may remain, leading to tumor recurrence. In addition, surgical ablation of bone tumors creates bone tissue defects. Therefore, the problem of manufacturing specific biomaterials with a dual function of treating bone tumors and regeneration of bone defects has become a priority. The use of methods of targeted delivery and local controlled release of drugs contributes to the creation of the desired therapeutic concentration of drugs in the disease focus and increases their bioavailability. In recent years, promising samples capable of effective controlled release have been developed in which cisplatin, doxorubicin and gemcitabine have been used as model chemotherapeutic drugs. These approaches have been promising and have shown the potential to destroy residual tumor cells, however, they may become resistant to such drugs, which leads to treatment failure. The main purpose of the review is to summarize the latest world experience in the synthesis, research and use of composites based on bioactive ceramic materials and modern antitumor drugs as promising implants, embodying a new generation of complex remedies for targeted delivery with osteoconductive and antitumor properties, prolonged action, for local application. Examples are given of bioglass application with cytotoxic / cytostatic components, as well as results of development of the newest directions of antitumor therapy of bones, in which acquisition of resistance of tumor cells is not observed. The antitumor functions of such multifunctional samples are performed, for example, by chemotherapy, photothermal therapy, magnetic hyperthermia, and photodynamic therapy. These data are of scientific, practical and methodical interest.

Volumetric Resection and Complications in Nonfunctioning Pituitary Adenoma by Fully Endoscopic Transsphenoidal Approach along 15 Years of Single-Center Experience

Objective The aim of this study was to evaluate the rate of complications and the extent of resection (EOR) of nonfunctioning pituitary adenomas by endoscopic endonasal approach (EEA) in a 15-year learning curve. Methods A total of 100 patients operated by the same surgical team were divided chronologically into two, three, and four groups, comparing differences in EOR measured by a semiautomatic software (Smartbrush, Brainlab), rate of immediate postoperative complications, and the visual and hormonal status at 6 months. Results There were no significant differences over the years in rates of postoperative complications and in visual status at 6 months. A significant linear correlation between the EOR and the number of surgeries (rho = 0.259, p = 0.007) was found. The analysis was performed in three groups because of the remarkable differences among them; the EOR were: 87.2% (early group), 93.03% (intermediate group), and 95.1% (late group) (p = 0.019). Gross total resection was achieved in 30.3, 51.5, and 64%, respectively (p = 0.017); also, the rate of reoperation and the worsening of at least one new hormonal axis were worse in the early group. Consequently, the early group had a higher risk of incomplete resection compared with the late group (odds ratio: 4.2; 95% confidence interval: 1.5–11.7). The three groups were not different in demographic and volume tumor variables preoperatively. Conclusions The first 33 interventions were associated with a lower EOR, a high volume of residual tumor, a high reoperation rate, and a higher rate of hormonal dysfunction. We did not find differences in terms of postoperative complications and the visual status at 6-month follow-up.