BCG and Alternative Therapies to BCG Therapy for Non-Muscle-Invasive Bladder Cancer.

Bladder cancer is a heterogeneous disease. Treatment decisions are mostly decided based on disease stage (non-muscle invasive or muscle invasive). Patients with muscle-invasive disease will be offered a radical treatment combined with systemic therapy, while in those with non-muscle-invasive disease, an attempt to resect the tumor endoscopically will usually be followed by different intravesical instillations. The goal of intravesical therapy is to decrease the recurrence and/or progression of the tumor. In the current landscape of bladder cancer treatment, BCG is given intravesically to induce an inflammatory response and recruit immune cells to attack the malignant cells and induce immune memory. While the response to BCG treatment has changed the course of bladder cancer management and spared many "bladders", some patients may develop BCG-unresponsive disease, leaving radical surgery as the best choice of curative treatment. As a result, a lot of effort has been put into identifying novel therapies like systemic pembrolizumab and Nadofaragene-Firadenovac to continue sparing bladders if BCG is ineffective. Moreover, recent logistic issues with BCG production caused a worldwide BCG shortage, re-sparking interest in alternative BCG treatments including mitomycin C, sequential gemcitabine with docetaxel, and others. This review encompasses both the historic and current role of BCG in the treatment of non-muscle-invasive bladder cancer, revisiting BCG alternative therapies and reviewing the novel therapeutics that were approved for the BCG-unresponsive stage or are under active investigation.

Comparison of hyperthermic intravesical chemotherapy and Bacillus Calmette-Guerin therapy in high-risk non-muscle invasive bladder cancer: a matched-pair analysis.

PURPOSE: To compare adjuvant hyperthermic intravesical chemotherapy (HIVEC) with mitomycin C and standard Bacillus Calmette-Guerin (BCG) therapy in terms of oncological outcomes and adverse events in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: The data of patients with high-risk papillary NMIBC treated with adjuvant intravesical BCG instillations or HIVEC in our institution between June 2017 and August 2022 were analyzed retrospectively. Twenty-four patients who received HIVEC were matched 1:1 with patients receiving BCG therapy based on tumor characteristics (tumor stage and grade), age, gender, smoking status, and the number of tumors (single or multiple). HIVEC and standard BCG treatments were compared in terms of recurrence-free survival (RFS), progression-free survival (PFS), and adverse events. RESULTS: Forty-eight patients (24 in the BCG group and 24 in the HIVEC group) were included in the study. The median follow-up times of the BCG and HIVEC groups were 32 [interquartile range (IQR): 28.0-47.8] and 28 (IQR: 16.7-41.8) months, respectively (p = 0.11). There was no significant difference between the groups in terms of the 24-month RFS (BCG 83% vs HIVEC 88%, p = 0.64) and the 24-month PFS (BCG 100% vs HIVEC 94%, p = 0.61). Regarding the safety profile, at least one adverse event occurred in 13 (54%) of the patients in the BCG group and 12 (50.0%) of those in the HIVEC group (p = 0.77). CONCLUSION: This study demonstrated that HIVEC with mitomycin C has a similar oncological efficacy and safety profile to standard BCG therapy in high-risk NMIBC.

2022 Peritoneal Surface Oncology Group International Consensus on HIPEC Regimens for Peritoneal Malignancies: Colorectal Cancer.

BACKGROUND: Selected patients with peritoneal metastases of colorectal cancer (PM-CRC) can benefit from potentially curative cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC), with a median overall survival (OS) of more than 40 months. OBJECTIVE: The aims of this evidence-based consensus were to define the indications for HIPEC, to select the preferred HIPEC regimens, and to define research priorities regarding the use of HIPEC for PM-CRC. METHODS: The consensus steering committee elaborated and formulated pertinent clinical questions according to the PICO (patient, intervention, comparator, outcome) method and assessed the evidence according to the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Standardized evidence tables were presented to an international expert panel to reach a consensus (4-point, weak and strong positive/negative) on HIPEC regimens and research priorities through a two-round Delphi process. The consensus was defined as ≥ 50% agreement for the 4-point consensus grading or ≥ 70% for either of the two combinations. RESULTS: Evidence was weak or very weak for 9/10 clinical questions. In total, 70/90 eligible panelists replied to both Delphi rounds (78%), with a consensus for 10/10 questions on HIPEC regimens. There was strong negative consensus concerning the short duration, high-dose oxaliplatin (OX) protocol (55.7%), and a weak positive vote (53.8-64.3%) in favor of mitomycin-C (MMC)-based HIPEC (preferred choice: Dutch protocol: 35 mg/m2, 90 min, three fractions), both for primary cytoreduction and recurrence. Determining the role of HIPEC after CRS was considered the most important research question, regarded as essential by 85.7% of the panelists. Furthermore, over 90% of experts suggest performing HIPEC after primary and secondary CRS for recurrence > 1 year after the index surgery. CONCLUSIONS: Based on the available evidence, despite the negative results of PRODIGE 7, HIPEC could be conditionally recommended to patients with PM-CRC after CRS. While more preclinical and clinical data are eagerly awaited to harmonize the procedure further, the MMC-based Dutch protocol remains the preferred regimen after primary and secondary CRS.

Mytomicin-C, Metronomic Capecitabine, and Bevacizumab in Patients With Unresectable or Relapsed Pseudomyxoma Peritonei of Appendiceal Origin.

INTRODUCTION: Pseudomyxoma peritonei (PMP) is a rare, slow growing tumor, traditionally considered chemoresistant. The only curative approach is cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). At disease relapse, or in patients with inoperable disease at diagnosis, no standard treatment has been defined, though nonrandomized series showed promising results with fluoropyrimidine-based regimens. PATIENTS AND METHODS: We conducted a prospective study in patients with relapsed or unresectable PMP and confirmed disease progression at baseline. Patients received MMC (7 mg/m2 every 6 weeks, up to a maximum of 4 cycles) plus metronomic capecitabine (625 mg/sqm/day b.i.d.) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), overall response rate according to RECIST v1.1 criteria, serum markers response and safety. RESULTS: Fifteen patients were included. At a median follow-up of 26.1 months (IQR, 17.7-49.6), median PFS was 17.9 months (95% CI, 11.0-NE), with 1-year PFS and OS rates of 73% and 87%. Safety profile was manageable, with only 13% G3/G4 treatment-related adverse events. CONCLUSION: Metronomic capecitabine, bevacizumab, and MMC are an active regimen in advanced and progressive PMP and favorably compares with historical series.

Cisplatin exhibits superiority over MMC as a perfusion agent in a peritoneal mesothelioma patient specific organoid HIPEC platform.

Peritoneal mesothelioma (PM) is a rare malignancy with poor prognosis, representing about 10-15% of all mesothelioma cases. Herein we apply PM patient-derived tumor organoids (PTOs) in elucidating personalized HIPEC responses to bypass rarity of disease in generating preclinical data. Specimens were obtained from PM patients undergoing cytoreductive surgery with HIPEC. PTOs were fabricated with tumor cells suspended in ECM-hydrogel and treated with HIPEC regimen parameters. Viability and characterization analyses were performed post-treatment. Treatment efficacy was defined as ≥ 50% viability reduction and p < 0.05 compared to controls. From October 2020 to November 2022, 17 tumors from 7 patients were biofabricated into organoids, with 16/17 (94.1%) sites undergoing comparative 37° and 42° treatments with cisplatin and mitomycin C (MMC). Hyperthermic cisplatin and MMC enhanced cytotoxicity which reduced treatment viability by 25% and 22%, respectively, compared to normothermia. Heated cisplatin displayed the greatest cytotoxicity, with efficacy in 12/16 (75%) tumors and an average viability of 38% (5-68%). Heated MMC demonstrated efficacy in 7/16 (43.8%) tumors with an average treatment viability of 51% (17-92.3%). PTOs fabricated from distinct anatomic sites exhibited site-specific variability in treatment responses. PM PTOs exhibit patient and anatomic location treatment responses suggestive of underlying disease clonality. In PM organoids cisplatin is superior to MMC in HIPEC.

The efficacy of hyperthermic intravesical chemotherapy in high-risk non-muscle-invasive bladder cancer patients with BCG intolerance.

BACKGROUND AND AIM: Some patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are unable to receive adequate BCG instillations due to intolerance. In this study we aimed to investigate the efficacy and tolerability of hyperthermic intravesical chemotherapy (HIVEC®) treatment using Mitomycin C (MMC) in BCG-intolerant NMIBC patients. METHODS: Retrospectively collected data from a total of 22 high-risk papillary NMIBC patients who received adjuvant HIVEC therapy for BCG intolerance were analyzed. The primary outcomes of the study were recurrence-free survival (RFS), time to recurrence, progression-free survival (PFS), and time to progression following initial TURB. Detection of histologically confirmed urothelial carcinoma during follow-up was considered as recurrence, while detection of muscle-invasive disease was defined as progression. The secondary outcome was adverse events of HIVEC treatment. RESULTS: The median follow-up was 32.2 (IQR: 17.8-42.8) months. The RFS and PFS rates were 81.8% and 95.4%, respectively. The mean time to tumor recurrence and progression was 29.2 ± 14.3 and 16.7 months, respectively. Adverse events occurred in 50% of patients, and 95% of adverse events were mild to moderate. CONCLUSION: This study demonstrated that adjuvant HIVEC with MMC is an effective and safe alternative bladder sparing treatment in BCG intolerant high risk papillary NMIBC patients.

Coenzyme Q-related compounds to maintain healthy mitochondria during aging.

Mitochondrial dysfunction is one of the main factors that affects aging progression and many age-related diseases. Accumulation of dysfunctional mitochondria can be driven by unbalanced mito/autophagy or by decrease in mitochondrial biosynthesis and turnover. Coenzyme Q is an essential component of the mitochondrial electron transport chain and a key factor in the protection of membrane and mitochondrial DNA against oxidation. Coenzyme Q levels decay during aging and this can be considered an accelerating factor in mitochondrial dysfunction and aging progression. Supplementation with coenzyme Q is successful for some tissues and organs but not for others. For this reason, the role of coenzyme Q in systemic aging is a complex picture that needs different strategies depending on the organ considered the main objective to be addressed. In this chapter we focus on the different effects of coenzyme Q and related compounds and the probable strategies to induce endogenous synthesis to maintain healthy aging.

Open versus Closed technique for administration of heated intraperitoneal chemotherapy (HIPEC): Morbidity and Mortality outcomes from a high-volume centre.

BACKGROUND AND AIMS: Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) is an established treatment in selected patients with peritoneal metastases, delivered in the UK in specialist centres. HIPEC can be administered via the open coliseum technique as first described by Sugarbaker (O-HIPEC) or using a closed technique (C-HIPEC). Data comparing the safety and outcomes of these different approaches is limited. This study aims to compare morbidity and mortality rates of O-HIPEC and C-HIPEC following CRS for peritoneal metastases from colorectal cancer and appendiceal tumours. METHODS: Consecutive patients undergoing CRS with open (05/2019-04/2020) and closed (05/2020-04/2021) HIPEC were identified from a prospectively maintained database. Baseline data including primary pathology, HIPEC agent and major operative procedures were analysed using Chi-squared and Fishers exact tests to ensure comparability of groups. Primary outcomes were 30- and 60-day postoperative mortality and morbidity (Common Terminology Criteria for Adverse Events, CTCAE). Secondary outcomes were length of critical care and overall hospital stay. In addition, morbidity and mortality were compared between HIPEC agents (mitomycin and oxaliplatin/5-fluorouracil). RESULTS: 99 patients (39.3%) and 153 patients (60.7%) underwent O-HIPEC, C-HIPEC respectively. Groups were well matched for baseline demographics, pathology, and HIPEC agent. In the O-HIPEC and C-HIPEC groups respectively, the incidence of 60-day complications (CTCAE 1-4) was 40.4% vs 39.3% (chi squared 0.94) and severe complications (CTCAE 3-4) 14% vs 13% (Fisher's exact p = 1) There was no perioperative mortality but one death in each group within the follow up period. There was no difference in morbidity or mortality between those receiving mitomycin or oxaliplatin. CONCLUSION: Closed administration of HIPEC is safe with no difference in post-operative morbidity or mortality compared to open HIPEC administration. Differences in longer term oncological outcomes including overall survival and disease-free survival between open and closed HIPEC techniques are yet to be determined.

Complete Remission of BCG-Refractory High-grade Bladder CIS with Pharmacologic Ascorbate and Mistletoe.

Context: Bladder cancer is the fourth-most-common cancer in males in the U.S., who develop about 90% of the high-grade, carcinoma in situ (CIS) of non-muscle involved disease (NMIBC). Smoking and occupational carcinogens are well-known causes. For females without known risk factors, bladder cancer can be regarded as a sentinel environmental cancer. It's also one of the costliest to treat due to its high rate of recurrence. No treatment innovations have occurred in nearly two decades; intravesical instillation of Bacillus Calmette-Guerin (BCG), an agent in short supply globally, or Mitomycin-C (MIT-C) is effective in about 60% of cases. Cases refractory to BCG and MIT-C often undergo cystectomy, a procedure with numerous impacts on life styles and potential complications. The recent completion of a small Phase I trial of mistletoe in cancer patients that have exhausted known treatments at Johns Hopkins provides corroboration of its safety, with 25 % showing no disease progression. Objective: The study examined the benefits of pharmacologic ascorbate (PA) and mistletoe for a nonsmoking female patient with an environmental history of NMIBC refractory to BCG, in a non-smoking female with exposures in childhood and early adult life to several known carcinogens, including ultrafine particulate air pollution, benzene, toluene, and other organic solvents, aromatic amines and engine exhausts, and possibly arsenic in water. Design: The research team performed an integrative oncology case study on pharmacologic ascorbate (PA) and mistletoe, both agents shown to activate NK cells, enhance growth and maturation of T-cells, and induce dose-dependent pro-apoptotic cell death, suggesting shared and potentially synergistic mechanisms. Setting: The study began at the University of Ottawa Medical Center in Canada with treatment continuing over six years at St. Johns Hospital Center in Jackson, Wyoming, and George Washington University Medical Center for Integrative Medicine, with surgical, cytological, and pathological evaluations at University of California San Francisco Medical Center. Participant: The patient in the case study was a 76-year-old, well-nourished, athletic, nonsmoking female with high-grade CIS of the bladder. Her cancer was considered to be a sentinel environmental cancer. Intervention: Intravenous pharmacologic ascorbate (PA) and subcutaneous mistletoe (three times weekly) and intravenous and intravesical mistletoe (once weekly) were employed for an 8-week induction treatment, using a dose-escalation protocol as detailed below. Maintenance therapy was carried out with the same protocol for three weeks every three months for two years. Results: The patient has experienced a cancer-free outcome following 78 months of treatments that incorporated intravesical, intravenous, and subcutaneous mistletoe; intravenous PA; a program of selected nutraceuticals; exercise; and other supplementary treatments. Conclusions: This study is the first reported instance of combined treatments to achieve complete remission for high-grade NMIBC refractory to BCG and MIT-C, using intravesical, subcutaneous, and intravenous mistletoe and intravenous PA. It includes pharmacological information on possible mechanisms. In light of the global shortage of BCG, the high proportion of cases refractory to BCG and MIT-C, the unproven use of costly off-label pharmaceuticals, such as gemcitabine, and the relative cost-effectiveness of mistletoe and PA, clinicians should give serious consideration to employing these combined functional medicine treatments for BCG- and MIT-C-refractory NMIBC. Further research is needed with additional patients that can advance our understanding, including standardization of methods for systematically evaluating combined therapies-blinded and non-blinded, nomenclature regarding mistletoe preparation, doses, concentrations, regimes of administration, lengths of treatment, targeted cancer types, and other aspects.

Sodium-borohydride exfoliated bismuthene loaded with Mitomycin C for chemo-photo-radiotherapy of triple negative breast cancer.

In current study, a new remotely controlled drug delivery, radio-sensitizing, and photothermal therapy agent based on thioglycolic acid modified bismuth nanosheets is thoroughly evaluated. Bismuth nanosheets were synthesized using sodium borohydride (NaBH4) and Tween 20 through low energy (400 W) sonication within 2 h. The resultant nanosheets were 40-60 nm in size and 1-3 atomic layers in thickness. The morphological and structural characteristics of the nanosheets were studied using transmission electron microscopy, high-resolution transmission electron microscopy, X-ray diffraction, Raman spectroscopy and ultraviolet spectroscopy. The surface of the nanosheets was modified using thioglycolic acid, which resulted in enhanced Mitomycin C loading capacity to 274.35% and circumvented the burst drug release due to the improved electrostatic interactions. At pH 7.4 and 5.0, the drug release was significantly boosted from 45.1 to 69.8%, respectively. Thioglycolic acid modified bismuth nanosheets under 1064 nm laser irradiation possessed photothermal conversion efficiency of η=51.4% enabling a temperature rise of 24.9 °C at 100 µg/ml in 5 min. The combination of drug delivery, photothermal therapy, and radio-sensitization greatly damaged the MDA-MB-231 cells through apoptosis and diminished their colony forming.

Evaluation of thermal dose effect in radiofrequency-induced hyperthermia with intravesical chemotherapy for nonmuscle invasive bladder cancer.

PURPOSE: In nonmuscle invasive bladder cancer (NMIBC) patients who fail standard intravesical treatment and are unfit or unwilling to undergo a radical cystectomy, radiofrequency (RF)-induced hyperthermia combined with intravesical chemotherapy (RF-CHT) has shown promising results. We studied whether higher thermal dose improves clinical NMIBC outcome. METHODS AND MATERIALS: The cohort comprised 108 patients who started with RF-CHT between November 2013 and December 2019. Patients received intravesical mitomycin-C or epirubicin. Bladder hyperthermia was accomplished with an intravesical 915 MHz RF device guided by intravesical thermometry. We assessed the association between thermal dose parameters (including median temperature and Cumulative Equivalent Minutes of T50 at 43 °C [CEM43T50]) and complete response (CR) at six months for patients with (concomitant) carcinoma in situ (CIS), and recurrence-free survival (RFS) for patients with papillary disease. RESULTS: Median temperature and CEM43T50 per treatment were 40.9 (IQR 40.8-41.1) °C and 3.1 (IQR 0.9-2.4) minutes, respectively. Analyses showed no association between any thermal dose parameter and CR or RFS (p > 0.05). Less bladder spasms during treatment sessions was associated with increased median temperature and CEM43T50 (adjusted OR 0.01 and 0.34, both p < 0.001). CONCLUSIONS: No significant association between thermal dose and NMIBC outcome was found. Possibly thermal dose effect in patients of the current cohort exceeds a certain threshold value. On the other hand, occurrence of bladder spasms had a thermal dose limiting effect. We advise to treat patients with temperatures >40.5 °C for at least 45 min while respecting individual tolerability, including occurrence of bladder spasms.

Comparative Study of Short-Term Efficacy and Safety of Mitomycin versus Lobaplatin for Hyperthermic Intraperitoneal Chemotherapy after Radical Surgery in Colorectal Cancer with High-Risk Factors for Peritoneal Carcinomatosis: A Propensity Score Matching Analysis.

BACKGROUND: The drug selection of radical surgery (RS), with hyperthermic intraperitoneal chemotherapy (HIPEC), in pT4 colorectal cancer (CRC) remains controversial. METHODS: Adverse events after HIPEC were estimated by common terminology criteria for adverse events version 5.0. The efficacy was evaluated using overall survival (OS) and recurrence-free rate (RFR). Propensity score matching (PSM) was used to reduce the influence of confounders between Mitomycin and Lobaplatin groups. RESULTS: Of the 146 patients, from April 2020 to March 2021, 47 were managed with mitomycin and 99 with lobaplatin. There was no significant difference in the incidence of all adverse events between the two groups after PSM. OS and RFR were not significantly different between the two groups at 22 months (p = 0.410; p = 0.310). OS and RFR of the two groups also showed no significant difference for patients with T4a or T4b stage, tumor size < or ≥ 5 cm. Among patients with colon cancer, RFR at 22 months of the two groups was significantly different (100.0% vs. 63.2%, p = 0.028). CONCLUSIONS: In summary, the safety of mitomycin and lobaplatin for HIPEC was not different. Compared with lobaplatin, mitomycin for HIPEC after RS could benefit patients with colon cancer in RFR.

Medical treatment for ocular surface squamous neoplasia.

Ocular surface squamous neoplasia (OSSN) is the most common non-melanocytic tumour of the ocular surface. Surgical excision with wide margins using the "no-touch" method was originally the most popular treatment for OSSN. However, in the past two decades, the use of topical medications for OSSN treatment has gained a reputation amongst ophthalmologists for being an effective alternative to surgical excision. Furthermore, technological advancements, such as those seen in high-resolution optical coherence tomography (HR-OCT) for the anterior segment, have facilitated the diagnosis and monitoring of OSSN. When selecting a topical agent, interferon alpha-2b (IFNα-2b) and 5-fluorouracil (5-FU) are two of the gentlest medications used for OSSN and are often considered first line therapies due to their high-resolution rates and mild side effect profiles. Mitomycin C (MMC), on the other hand, has a highly toxic profile; therefore, while effective, in our hands it is considered as a second-line treatment for OSSN if the other modalities fail. In addition, newer and less studied agents, such as immune checkpoint inhibitors, retinoic acid, aloe vera, and anti-vascular endothelial growth factor have anti-neoplastic properties and have shown potential for the treatment of OSSN. We enclose an updated literature review of medical treatments for OSSN.

Immunological effects of heated intraperitoneal chemotherapy can be augmented by thymosin α1.

BACKGROUND: Peritoneal metastases of colorectal carcinoma origin (PM-CRC) are treated by cytoreductive surgery and heated intraperitoneal chemotherapy (HIPEC). However, the majority of patients recur, calling for novel treatments. We explored the immunogenic changes induced by HIPEC and the possibility to use thymosin α1 (Tα1) as an immune-stimulatory agent. METHODS: We used an experimental murine model of PM-CRC combined with mitomycin (MMC)-based HIPEC. We determined immune cell infiltration into tumor metastases after HIPEC administration by means of immunohistochemistry, and determined immunogenic cell death signals in tumor cells by real-time polymerase chain reaction. RESULTS: Mice with PM-CRC treated by HIPEC had increased overall survival (OS) compared to sham-treated mice (median OS 22.8 vs 18.9 days, respectively; P < 0.001). HIPEC induced increased infiltration of CD4+, CD8+, CD68 + and CD20 + cells into omental and visceral metastases at a magnitude of 40-100 %. We searched for potential immune signals induced by HIPEC by determining its effects on known immunogenic cell death proteins (heat-shock protein [HSP]-70, HSP-90 and calreticulin). HIPEC significantly increased HSP-90 mRNA expression (2.37 ± 1.5 vs 1-fold change, P < 0.05). The OS of Tα1 treated mice significantly improved compared to HIPEC-treated mice (16.3 ± 0.8 vs 14.1 ± 0.6 days, respectively, P = 0.02) and vs sham (11.8 ± 0.8 days, P = 0.007). CONCLUSIONS: HIPEC induced immunogenic changes that led to increased immune cell infiltration. These changes were further augmented by Tα1 treatment. Future studies aimed at optimizing Tα1 treatment should focus upon the immune response it evokes.

Thiolated Mesoporous Silica Nanoparticles as an Immunoadjuvant to Enhance Efficacy of Intravesical Chemotherapy for Bladder Cancer.

The characteristics of global prevalence and high recurrence of bladder cancer has led numerous efforts to develop new treatments. The spontaneous voiding and degradation of the chemodrug hamper the efficacy and effectiveness of intravesical chemotherapy following tumor resection. Herein, the externally thiolated hollow mesoporous silica nanoparticles (MSN-SH(E)) is fabricated to serve as a platform for improved bladder intravesical therapy. Enhanced mucoadhesive effect of the thiolated nanovector is confirmed with porcine bladder. The permeation-enhancing effect is also verified, and a fragmented distribution pattern of a tight junction protein, claudin-4, indicates the opening of tight junction. Moreover, MSN-SH(E)-associated reprogramming of M2 macrophages to M1-like phenotype is observed in vitro. The antitumor activity of the mitomycin C (MMC)-loaded nanovector (MMC@MSN-SH(E)) is more effective than that of MMC alone in both in vitro and in vivo. In addition, IHC staining is used to analyze IFN-γ, TGF-ß1, and TNF-α. These observations substantiated the significance of MMC@MSN-SH(E) in promoting anticancer activity, holding the great potential for being used in intravesical therapy for non-muscle invasive bladder cancer (NMIBC) due to its mucoadhesivity, enhanced permeation, immunomodulation, and prolonged and very efficient drug exposure.

Beneficial properties of Drimia numidica leaf methanolic extract against the cytogenotoxic effects of mitomycin C on human lymphocytes.

This study investigated the phytochemical profile of Drimia numidica leaf methanolic extract, as well as its cyto-genotoxic and cyto/genoprotective potential against mitomycin C (MMC) mediated effects on healthy human lymphocytes. Photosynthetic pigments, trace elements, and secondary metabolites were estimated and/or identified in methanolic extract of mature leaves, and the latter was further used for assessing its in vitro biological effects on MMC-free and/or MMC-treated human lymphocytes (at low, non-toxic concentrations of 0.001 and 0.01% v/v). The results showed that D. numidica leaf methanolic extract, being rich in carotenoids, phenolics, flavonoids, organic acids and bufadienolides, could be protective against MMC mediated cyto/genotoxic potential in healthy human lymphocytes. Biomolecules possessing antioxidant and antitumor potential, such as beta-carotene and lutein among others, chlorogenic acid, caffeic acid and their derivatives, minerals such as Si, as well as apigenin- and luteolin-derived glycosides, either individual or in a mixture, could be beneficial rather than harmful, at least at the extract concentrations tested. Although further in vitro and in vivo studies are still needed for elucidating the beneficial (individual and/or additive/synergistic) role of those compounds, the results of the present study are quite promising, thus encouraging new challenges for the appropriate utilization of D. numidica leaf extract.

PD-1 Blockade Combined with Heated Intraperitoneal Chemotherapy Improves Outcome in Experimental Peritoneal Metastases from Colonic Origin in a Murine Model.

BACKGROUND: Heated intraperitoneal chemotherapy (HIPEC) was shown to induce immunogenicity of peritoneal metastases from colorectal cancer (PM-CRC) by induction of immunogenic cell death. We aimed to explore whether the addition of a checkpoint inhibitor would augment the effect of HIPEC in an experimental murine model of PM-CRC. METHODS: PM-CRC was established in C57BL mice by intraperitoneal inoculation of MC38 colon cancer cells. HIPEC was administered using the closed technique with mitomycin C (MMC). Clinical and immunological parameters were compared between animals treated with HIPEC alone and those treated with HIPEC + anti-programmed death receptor-1 (aPD-1). RESULTS: MMC-based HIPEC increased the overall survival of animals compared with sham-treated animals (22.8; 95% confidence interval [CI] 21.14-24.53 vs. 18.9 days; 95% CI 17.6-20.3, p < 0.001). The extent of peritoneal disease as measured by the modified peritoneal carcinomatosis index was also reduced by HIPEC. This clinical benefit was accompanied by increased infiltration of CD8+, CD68+, and CD20+ cells into tumor metastases in HIPEC-treated animals compared with sham-treated animals. We identified heat shock protein (HSP) 90 as a potential immunogenic cell death protein whose expression is increased under HIPEC conditions (fold change: 2.37 ± 1.5 vs. 1 without HIPEC, p < 0.05). Combined HIPEC + PD-1 treatment ameliorated survival compared with HIPEC alone and sham treatment (24.66; 95% CI 20.13-29.2 vs. 19; 95% CI 15.85-22.14 and 14.33 days; 95% CI 9.6-19.04, respectively; p = 0.008). This clinical effect was accompanied by increased CD8+ tumor infiltration. CONCLUSIONS: HIPEC induced the expression of immunogenic cell death signals that can support an anti-tumor immune response. This response can be further exploited by a checkpoint inhibitor.

Comparison of cisplatin and mitomycin C/5-FU as radiosensitisers in the treatment of locally advanced vulvar cancer: results of a retrospective, observational, single-institutional cohort study.

PURPOSE: We retrospectively investigated the widely used radiosensitisers cisplatin and mitomycin C/5-fluorouracil (5-FU) in patients with locally advanced vulvar cancer for outcome and toxicity. METHODS: We screened the archive for patients treated with chemoradiation for vulvar cancer diagnosed between 01/2010 and 08/2021 at our institution. The impact of both radiosensitisers on prognosis was compared using Kaplan-Meier method and Cox-regression analysis. RESULTS: One hundred and forty-three patients with vulvar cancer were screened. Twenty-nine patients received chemoradiation (mitomycin C/5-FU n = 14; cisplatin n = 12; others n = 3) as a primary, neoadjuvant or adjuvant treatment. Median follow-up was 15.5 months. Patients in the cisplatin group were older (mean age 54.4 vs. 70.7; p = 0.004). However, the mitomycin C/5-FU group had more advanced tumour stages. The 2-year recurrence-free survival (RFS) was comparable (44.5% vs. 33.3%; p = 0.932). The 2-year overall survival (OS) showed a numerical but not statistically significant difference in favour of the mitomycin C/5-FU group (59.7% vs. 31.7%; p = 0.37). 64.3% (9 out of 14) patients, who received mitomycin C/5-FU achieved clinical complete response (cCR) compared to 41.7% (5 out of 12) who received cisplatin (p = 0.505). Radiodermatitis was the most common adverse event in both groups (81%) and more severe in the mitomycin C/5-FU cohort. Myelotoxicity was frequently observed in both groups. Eighteen patients received an additional radiation boost with 10.0 (9-16) Gy and showed a significantly prolonged RFS (p = 0.027) and OS (p = 0.003). CONCLUSION: Mitomycin C/5-FU may be considered in the treatment of young and healthy patients with locally advanced vulvar cancer.