Outcomes of chemotherapy/chemoradiation vs. R2 surgical debulking vs. palliative care in nonresectable locally recurrent rectal cancer.

Locally recurrent rectal cancer is resected with clear margins in only 50% of cases, and these patients achieve a three-year survival rate of 50%. Outcomes and therapeutic strategies for nonresectable locally recurrent rectal cancer have been much less explored. The aim of the study was to assess the three-year progression-free survival and the three-year overall survival in locally recurrent rectal cancer patients treated by chemotherapy/chemoradiation only vs. chemotherapy/chemoradiation and R2 surgical debulking vs. palliative care. A total of 86 patients affected by nonresectable locally recurrent rectal cancer were included: three-year progression-free survival was 15.8% with chemotherapy/chemoradiation vs. 20.3% with R2 surgical debulking (Log-rank p=0.567), but both rates were higher than best palliative care (0.0%, Log-rank p=0.0004). Three-year overall survival rates were respectively 62.0%, 70.8% and 0.0% (Log-rank p<0.0001). Chemotherapy/chemoradiation (HR 0.33, p=0.028) and R2 surgical debulking with or without chemotherapy/chemoradiation (HR 0.23, p=0.005) were independent predictors of improved progression-free survival on multivariate analysis. In conclusion, both chemotherapy/chemoradiation alone and R2 surgery with or without chemotherapy/chemoradiation provide a survival benefit over palliative care in nonresectable locally recurrent rectal cancer. However, considering that pelvic debulking is burdened by a high rate of complications, and considering its negligible impact on progression-free survival and overall survival when associated to medical therapy, surgery should be avoided in this setting.

Effect of neoadjuvant chemoradiation on anorectal function assessed with anorectal manometry: A systematic review and meta-analysis.

AIM: Improvement in oncological survival for rectal cancer increases attention to anorectal dysfunction. Diagnostic questionnaires can evaluate quality of life but are subjective and dependent on patients' compliance. Anorectal manometry can objectively assess the continence mechanism and identify functional sphincter weakness and rectal compliance. Neoadjuvant chemoradiotherapy is presumed to affect anorectal function. We aim to assess anorectal function in rectal cancer patients who undergo total mesorectal excision, with or without neoadjuvant chemoradiation, using anorectal manometry measurements. METHOD: MEDLINE, Embase, and Cochrane databases were searched for studies comparing perioperative anorectal manometry between neoadjuvant chemoradiation and upfront surgery for rectal cancers. Primary outcomes were resting pressure, squeeze pressure, sensory threshold volume and maximal tolerable volume. RESULTS: Eight studies were included in the systematic review, of which seven were included for metanalysis. 155 patients (45.3%) had neoadjuvant chemoradiation before definitive surgery, and 187 (54.6%) underwent upfront surgery. Most patients were male (238 vs. 118). The standardized mean difference of mean resting pressure, mean and maximum squeeze pressure, maximum resting pressure, sensory threshold volume, and maximal tolerable volume favored the upfront surgery group but without statistical significance. CONCLUSION: Currently available evidence on anorectal manometry protocols failed to show any statistically significant differences in functional outcomes between neoadjuvant chemoradiation and upfront surgery. Further large-scale prospective studies with standardized neoadjuvant chemoradiation and anorectal manometry protocols are needed to validate these findings.

Cell Membrane Fragment-Wrapped Parenteral Nanoemulsions: A New Drug Delivery Tool to Target Gliomas.

Poor prognosis in high-grade gliomas is mainly due to fatal relapse after surgical resection in the absence of efficient chemotherapy, which is severely hampered by the blood-brain barrier. However, the leaky blood-brain-tumour barrier forms upon tumour growth and vascularization, allowing targeted nanocarrier-mediated drug delivery. The homotypic targeting ability of cell-membrane fragments obtained from cancer cells means that these fragments can be exploited to this aim. In this experimental work, injectable nanoemulsions, which have a long history of safe clinic usage, have been wrapped in glioma-cell membrane fragments via co-extrusion to give targeted, homogeneously sized, sterile formulations. These systems were then loaded with three different chemotherapeutics, in the form of hydrophobic ion pairs that can be released into the target site thanks to interactions with physiological components. The numerous assays performed in two-dimensional (2D) and three-dimensional (3D) cell models demonstrate that the proposed approach is a versatile drug-delivery platform with chemo-tactic properties towards glioma cells, with adhesive interactions between the target cell and the cell membrane fragments most likely being responsible for the effect. This approach's promising translational perspectives towards personalized nanomedicine mean that further in vivo studies are foreseen for the future.

Navigating the Nose-to-Brain Route: A Systematic Review on Lipid-Based Nanocarriers for Central Nervous System Disorders.

BACKGROUND: The blood-brain barrier (BBB) regulates brain substance entry, posing challenges for treating brain diseases. Traditional methods face limitations, leading to the exploration of non-invasive intranasal drug delivery. This approach exploits the direct nose-to-brain connection, overcoming BBB restrictions. Intranasal delivery enhances drug bioavailability, reduces dosage, and minimizes systemic side effects. Notably, lipid nanoparticles, such as solid lipid nanoparticles and nanostructured lipid carriers, offer advantages like improved stability and controlled release. Their nanoscale size facilitates efficient drug loading, enhancing solubility and bioavailability. Tailored lipid compositions enable optimal drug release, which is crucial for chronic brain diseases. This review assesses lipid nanoparticles in treating neuro-oncological and neurodegenerative conditions, providing insights for effective nose-to-brain drug delivery. METHODS: A systematic search was conducted across major medical databases (PubMed, Ovid MEDLINE, and Scopus) up to 6 January 2024. The search strategy utilized relevant Medical Subject Heading (MeSH) terms and keywords related to "lipid nanoparticles", "intranasal administration", "neuro-oncological diseases", and "neurodegenerative disorders". This review consists of studies in vitro, in vivo, or ex vivo on the intranasal administration of lipid-based nanocarriers for the treatment of brain diseases. RESULTS: Out of the initial 891 papers identified, 26 articles met the eligibility criteria after a rigorous analysis. The exclusion of 360 articles was due to reasons such as irrelevance, non-reporting selected outcomes, the article being a systematic literature review or meta-analysis, and lack of method/results details. This systematic literature review, focusing on nose-to-brain drug delivery via lipid-based nanocarriers for neuro-oncological, neurodegenerative, and other brain diseases, encompassed 60 studies. A temporal distribution analysis indicated a peak in research interest between 2018 and 2020 (28.3%), with a steady increase over time. Regarding drug categories, Alzheimer's disease was prominent (26.7%), followed by antiblastic drugs (25.0%). Among the 65 drugs investigated, Rivastigmine, Doxorubicin, and Carmustine were the most studied (5.0%), showcasing a diverse approach to neurological disorders. Notably, solid lipid nanoparticles (SLNs) were predominant (65.0%), followed by nanostructured lipid carriers (NLCs) (28.3%), highlighting their efficacy in intranasal drug delivery. Various lipids were employed, with glyceryl monostearate being prominent (20.0%), indicating preferences in formulation. Performance assessment assays were balanced, with in vivo studies taking precedence (43.3%), emphasizing the translation of findings to complex biological systems for potential clinical applications. CONCLUSIONS: This systematic review reveals the transformative potential of intranasal lipid nanoparticles in treating brain diseases, overcoming the BBB. Positive outcomes highlight the effectiveness of SLNs and NLCs, which are promising new approaches for ailments from AD to stroke and gliomas. While celebrating progress, addressing challenges like nanoparticle toxicity is also crucial.

Alendronate-Grafted Nanoemulsions for Bone-Targeted Vincristine Delivery: Preliminary Studies on Cell and Animal Models.

Bone is a site of distant metastases, which are a common cause of morbidity and mortality with a high socio-economic impact, for many malignant tumours. In order to engineer pharmacological therapies that are suitable for this debilitating disease, this experimental work presents injectable lipid nanoemulsions, which are endowed with a long history of safe clinical usage in parenteral nutrition, their loading with vincristine and their grafting with alendronate, with a dual purpose: merging the anticancer activity of bisphosphonates and vincristine, and enhancing bone-targeted delivery. In cell studies, alendronate synergised with the anti-migration activity of vincristine, which is important as migration plays a key role in the metastatisation process. In preliminary animal studies, carried out thanks to IVIS technology, alendronate conjugation enhanced the bone targeting of fluorescently labelled nanoemulsions. These encouraging results will drive further studies on suitable animal models of the disease.

Impact of Perioperative Systemic Chemotherapy on Survival for Patients Who have Diffuse Malignant Peritoneal Mesothelioma Treated with CRS-HIPEC.

BACKGROUND: The available data on the role of perioperative systemic chemotherapy (SC) for diffuse malignant peritoneal mesothelioma (DMPM) patients undergoing (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is heterogeneous and unstandardized. This study aimed to evaluate the impact of SC on the survival outcomes of DMPM patients undergoing CRS-HIPEC and to identify prognostic factors that affect the decision to administer SC. METHODS: Patients who underwent CRS-HIPEC in the National Cancer Institute Milan (1995-2020) were retrospectively analyzed using propensity score-matching of known covariates. The patients were grouped into three groups: group A (neoadjuvant chemotherapy [NACT] and no-SC), group B (no-SC and adjuvant chemotherapy [ACT]), and group C (NACT and ACT). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meir method, and prognostic factors were calculated using the Cox-regression method. RESULTS: After a median follow-up period of 45 months (95% confidence interval [CI], 6.348-83.652 months) for group A, 115 months (95% CI, 44.379-185.621 months) for group B, and 88 months (95% CI, 3.296-172.704 months) for group C, the study analyzed 154 DMPM patients consisting of matched group A (NACT: 60 + no-SC: 52 = 112), group B (ACT: 38 + no-SC: 38 = 76), and group C (NACT: 31 + ACT: 31 = 62). The patients undergoing ACT had better 5-year OS and PFS than the patients undergoing NACT. In the multivariate analysis, ACT was significantly associated with improved OS by 48% (hazard ratio [HR], 0.52; 95% CI, 0.280-0.965, p = 0.038). For PFS, the association of ACT did not reach statistical significance (HR, 0.531; 95% CI, 0.266-1.058; p = 0.072). CONCLUSION: The optimum treatment sequence for DMPM is CRS-HIPEC followed by adjuvant chemotherapy for high-risk patients. Upfront surgery appears preferable to NACT for patients amenable to complete CRS.

Surface Functionalised Parenteral Nanoemulsions for Active and Homotypic Targeting to Melanoma.

Despite recent progressions in cancer genomic and immunotherapies, advanced melanoma still represents a life threat, pushing to optimise new targeted nanotechnology approaches for specific drug delivery to the tumour. To this aim, owing to their biocompatibility and favourable technological features, injectable lipid nanoemulsions were functionalised with proteins owing to two alternative approaches: transferrin was chemically grafted for active targeting, while cancer cell membrane fragments wrapping was used for homotypic targeting. In both cases, protein functionalisation was successfully achieved. Targeting efficiency was preliminarily evaluated using flow cytometry internalisation studies in two-dimensional cellular models, after fluorescence labelling of formulations with 6-coumarin. The uptake of cell-membrane-fragment-wrapped nanoemulsions was higher compared to uncoated nanoemulsions. Instead, the effect of transferrin grafting was less evident in serum-enriched medium, since such ligand probably undergoes competition with the endogenous protein. Moreover, a more pronounced internalisation was achieved when a pegylated heterodimer was employed for conjugation (p < 0.05).

Exploiting Nanomedicine for Cancer Polychemotherapy: Recent Advances and Clinical Applications.

The most important limitations of chemotherapeutic agents are severe side effects and the development of multi-drug resistance. Recently, the clinical successes achieved with immunotherapy have revolutionized the treatment of several advanced-stage malignancies, but most patients do not respond and many of them develop immune-related adverse events. Loading synergistic combinations of different anti-tumor drugs in nanocarriers may enhance their efficacy and reduce life-threatening toxicities. Thereafter, nanomedicines may synergize with pharmacological, immunological, and physical combined treatments, and should be increasingly integrated in multimodal combination therapy regimens. The goal of this manuscript is to provide better understanding and key considerations for developing new combined nanomedicines and nanotheranostics. We will clarify the potential of combined nanomedicine strategies that are designed to target different steps of the cancer growth as well as its microenvironment and immunity interactions. Moreover, we will describe relevant experiments in animal models and discuss issues raised by translation in the human setting.

Impact of Microscopically Positive (≤1 mm) Distal Margins on Disease Recurrence in Rectal Cancer Treated by Neoadjuvant Chemoradiotherapy.

BACKGROUND: The adequate distal resection margin is still controversial in rectal cancer treated by neoadjuvant chemoradiotherapy (nCRT). The aim of this study was to assess the impact of a distal margin of ≤1 mm on locoregional recurrence-free survival (LRRFS). METHODS: Among 255 patients treated with nCRT and surgery at the National Cancer Institute of Milan, 83 (32.5%) had a distal margin of ≤1 mm and 172 (67.5%) had a distal margin of >1 mm. Survival analyses were performed to assess the impact of distal margin on 5-year LRRFS, as well as Cox survival analysis. The role of distal margin on survival was analyzed according to different tumor regression grades (TRGs). RESULTS: The overall 5-year LRRFS rate was 77.6% with a distal margin of ≤1 mm vs. 88.3% with a distal margin of >1 mm (Log-rank p = 0.09). Only stage ypT4 was an independent predictor of worse LRRFS (HR 15.14, p = 0.026). The 5-year LRRFS was significantly lower in TRG3-5 patients with a distal margin of ≤1 mm compared to those with a distal margin of >1 mm (68.5% vs. 84.2%, p = 0.027), while no difference was observed in case of TRG1-2 (p = 0.77). CONCLUSIONS: Low-responder rectal cancers after nCRT still require a distal margin of >1 mm to reduce the high likelihood of local relapse.

Multidrug-Loaded Lipid Nanoemulsions for the Combinatorial Treatment of Cerebral Cavernous Malformation Disease.

Cerebral cavernous malformation (CCM) or cavernoma is a major vascular disease of genetic origin, whose main phenotypes occur in the central nervous system, and is currently devoid of pharmacological therapeutic strategies. Cavernomas can remain asymptomatic during a lifetime or manifest with a wide range of symptoms, including recurrent headaches, seizures, strokes, and intracerebral hemorrhages. Loss-of-function mutations in KRIT1/CCM1 are responsible for more than 50% of all familial cases, and have been clearly shown to affect cellular junctions, redox homeostasis, inflammatory responses, and angiogenesis. In this study, we investigated the therapeutic effects of multidrug-loaded lipid nanoemulsions in rescuing the pathological phenotype of CCM disease. The pro-autophagic rapamycin, antioxidant avenanthramide, and antiangiogenic bevacizumab were loaded into nanoemulsions, with the aim of reducing the major molecular dysfunctions associated with cavernomas. Through Western blot analysis of biomarkers in an in vitro CCM model, we demonstrated that drug-loaded lipid nanoemulsions rescue antioxidant responses, reactivate autophagy, and reduce the effect of pro-angiogenic factors better than the free drugs. Our results show the importance of developing a combinatorial preventive and therapeutic approach to reduce the risk of lesion formation and inhibit or completely revert the multiple hallmarks that characterize the pathogenesis and progression of cavernomas.

Delayed onset of fatal encephalitis in a COVID-19 positive patient.

BACKGROUND: The SARS-nCoV-2019 epidemic has spread since December 2019, quickly gaining worldwide attention. Symptoms consist of fever, cough and breathing difficulties. An increasing number of studies are focusing on neurological manifestations. In addition to the typical ageusia and anosmia, up to 30% of cases can present headache, nausea and vomiting. More serious neurological manifestations, such as encephalitis, thrombosis and cerebral haemorrhage have been reported. CASE DESCRIPTION: We described the case of a 47-year-old man who tested positive for COVID-19 virus in early March 2020. After two negative nasopharyngeal swabs, 41 days after the diagnosis of COVID-19 infection, he developed intense headache with fever, and he was hospitalized. He had subsequent generalized epileptic seizures and intubation was necessary. Contrast Head MRI was negative for brain abscesses or tumours but detected severe vasogenic oedema of the white matter with 10 mm shift of the midline and compression of the right lateral ventricle. Massive cortisone support therapy was ineffective. We diagnosed brain death on day 43 from the infection diagnosis. DISCUSSION: COVID-19 virus can reach the brain, penetrating into the neuronal cells through the interaction between the spike protein S1 and the host ACE-2 receptor, expressed in the capillary endothelium. We believe that in this infection, the pro-inflammatory state induced by the cytokine storm can cause a cerebral cell-mediated response, with subsequent vasodilatation and brain oedema. CONCLUSION: To our knowledge, this is the first description of a delayed onset cell-mediated encephalitis caused by COVID-19 virus after more than 40 days from the diagnosis.

Parenteral Nanoemulsions Loaded with Combined Immuno- and Chemo-Therapy for Melanoma Treatment.

High-grade melanoma remains a major life-threatening illness despite the improvement in therapeutic control that has been achieved by means of targeted therapies and immunotherapies in recent years. This work presents a preclinical-level test of a multi-pronged approach that includes the loading of immunotherapeutic (ICOS-Fc), targeted (sorafenib), and chemotherapeutic (temozolomide) agents within Intralipid®, which is a biocompatible nanoemulsion with a long history of safe clinical use for total parenteral nutrition. This drug combination has been shown to inhibit tumor growth and angiogenesis with the involvement of the immune system, and a key role is played by ICOS-Fc. The inhibition of tumor growth in subcutaneous melanoma mouse models has been achieved using sub-therapeutic drug doses, which is most likely the result of the nanoemulsion's targeting properties. If translated to the human setting, this approach should therefore allow therapeutic efficacy to be achieved without increasing the risk of toxic effects.

Pathologic complete response after neoadjuvant chemotherapy/(re)chemoradiation for pelvic relapse of rectal cancer undergoing complex pelvic surgery: more frequent than expected?

PURPOSE: To estimate the rate of pathologic complete response (pCR) after neoadjuvant chemotherapy/(re)chemoradiation and its impact on survival in locally recurrent rectal cancer (LRRC) and to identify predictors of pCR or differences between neoadjuvant treatments. METHODS: Among 394 LRRC patients treated at the National Cancer Institute of Milan (Italy), 74 (27.8%) were treated with neoadjuvant chemotherapy with or without (re)chemoradiation before surgery. The pCR rate was estimated, and its impact on 5-year survival was evaluated with the Kaplan-Meier survival method. Univariate analysis was performed to find pre-treatment predictors of pCR. RESULTS: After surgery, in 12 (16.2%) patients, a pCR was observed. All patients who reached pCR had R0 margins after surgery; among the 62 non-pCR patients, R0 margins were obtained in 29 (46.8%) cases only (p = 0.0004). pCR patients showed a significantly higher 5-year overall survival compared to non-pCR cases (33.3% vs. 21.0%, p = 0.045) and a trend toward better 5-year re-local recurrence-free survival. On univariate analysis, no predictor of pCR was found in the present study based on pre-treatment features. CONCLUSION: Since pCR is significantly associated to R0 resection and 5-year overall survival, pCR could be a target for LRRC cure. However, pCR is currently unpredictable based on pre-treatment features.

Gut microbiota composition in colorectal cancer patients is genetically regulated.

The risk of colorectal cancer (CRC) depends on environmental and genetic factors. Among environmental factors, an imbalance in the gut microbiota can increase CRC risk. Also, microbiota is influenced by host genetics. However, it is not known if germline variants influence CRC development by modulating microbiota composition. We investigated germline variants associated with the abundance of bacterial populations in the normal (non-involved) colorectal mucosa of 93 CRC patients and evaluated their possible role in disease. Using a multivariable linear regression, we assessed the association between germline variants identified by genome wide genotyping and bacteria abundances determined by 16S rRNA gene sequencing. We identified 37 germline variants associated with the abundance of the genera Bacteroides, Ruminococcus, Akkermansia, Faecalibacterium and Gemmiger and with alpha diversity. These variants are correlated with the expression of 58 genes involved in inflammatory responses, cell adhesion, apoptosis and barrier integrity. Genes and bacteria appear to be involved in the same processes. In fact, expression of the pro-inflammatory genes GAL, GSDMD and LY6H was correlated with the abundance of Bacteroides, which has pro-inflammatory properties; abundance of the anti-inflammatory genus Faecalibacterium correlated with expression of KAZN, with barrier-enhancing functions. Both the microbiota composition and local inflammation are regulated, at least partially, by the same germline variants. These variants may regulate the microenvironment in which bacteria grow and predispose to the development of cancer. Identification of these variants is the first step to identifying higher-risk individuals and proposing tailored preventive treatments that increase beneficial bacterial populations.

Low baseline neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios predict increased overall survival in locally recurrent rectal cancer despite R1 margins.

BACKGROUND: Prognostic features in locally recurrent rectal cancer (LRRC), beyond R0 surgery, are unknown. AIMS: Aim of the present study was to evaluate the prognostic role of peripheral immune estimators, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), on survival outcomes in LRRC patients. METHODS: 184 LRRC patients treated at the National Cancer Institute of Milan (Italy) were included. Optimal cut-off values for NLR and PLR were determined. Kaplan-Meier curves and multivariate Cox analyses were used to assess the 5-yr overall survival (OS) according to NLR and PLR, also considering margins status. RESULTS: NLR >3.9 (hazard ratio [HR] 3.96, P = 0.049), PLR >275 (HR 5.39, P = 0.002) and size on imaging (HR 1.36, P = 0.044) were associated to worse OS. R+ patients with NLR >3.9 showed a significantly lower 5-yr OS compared to NLR ≤3.9 (13.5% vs. 36.7%, P < 0.0001). Also PLR >275 was related with a lower 5-yr OS compared to PLR ≤275 in R+ patients (6.4% vs. 36.8%, P = 0.0003). Conversely, NLR and PLR were irrelevant in case of R0 surgery. CONCLUSION: NLR and PLR predict 5-yr OS in LRRC, also identifying a subset of R+ patients with a similar expected survival compared to R0 cases.

Exploring the association with disease recurrence of miRNAs predictive of colorectal cancer.

INTRODUCTION: Disease recurrence after surgery is a crucial predictor of poor prognosis in colorectal cancer, where disseminated disease at the time of intervention can also be observed in localized early-stage cases. We evaluated the ability to predict disease recurrence of miRNAs from two signatures that we have found linked to the presence of colorectal cancer (CL signature) or adenoma (HgA signature) in higher-risk subjects. METHODS: miRNAs from the signatures were studied longitudinally by quantitative real-time polymerase chain reaction in plasma from 24 patients with resectable colorectal cancer collected at the time of surgery and during scheduled follow-up across 36 months. Patients either showed relapse within 36 months (alive with disease (AWD)), or remained disease-free (no evidence of disease (NED)) for the same period. RESULTS: Although the signatures did not predict recurrence, expression of the miRNAs from the CL signature decreased 1 year after surgery, and one miRNA of the signature, miR-378a-3p, almost reached significance in the NED subgroup (Wilcoxon signed-rank test: p-value = 0.078). Also, miR-335-5p from the HgA signature was higher in AWD patients before surgery (Kruskal-Wallis test: p-value = 0.019). CONCLUSIONS: These data, although from a small cohort of patients, support the possible use of miRNAs as non-invasive biomarkers in liquid biopsy-based tests to identify patients at risk of relapse and to monitor them during follow-up.

Nanotechnology Addressing Cutaneous Melanoma: The Italian Landscape.

Cutaneous melanoma is one of the most aggressive solid tumors, with a low survival for the metastatic stage. Currently, clinical melanoma treatments include surgery, chemotherapy, targeted therapy, immunotherapy and radiotherapy. Of note, innovative therapeutic regimens concern the administration of multitarget drugs in tandem, in order to improve therapeutic efficacy. However, also, if this drug combination is clinically relevant, the patient's response is not yet optimal. In this scenario, nanotechnology-based delivery systems can play a crucial role in the clinical treatment of advanced melanoma. In fact, their nano-features enable targeted drug delivery at a cellular level by overcoming biological barriers. Various nanomedicines have been proposed for the treatment of cutaneous melanoma, and a relevant number of them are undergoing clinical trials. In Italy, researchers are focusing on the pharmaceutical development of nanoformulations for malignant melanoma therapy. The present review reports an overview of the main melanoma-addressed nanomedicines currently under study in Italy, alongside the state of the art of melanoma therapy. Moreover, the latest Italian advances concerning the pre-clinical evaluation of nanomedicines for melanoma are described.