Bimodal Treatment Research Articles

Retinoblastoma with and without Extraocular Tumor Extension: A Global Comparative Study of 3435 Patients

PurposeTo study the treatment, and outcomes of children with retinoblastoma (RB) with extraocular tumor extension (RB-EOE) and compare them with RB without extraocular tumor extension (RB-w/o-EOE). DesignMulticenter intercontinental collaborative prospective study from 2017 to 2020. RB-EOE cases included those with overt orbital tumor extension in treatment-naïve patients. Cases with microscopic orbital extension detected post-enucleation were excluded from the study. ParticipantsA total of 319 children with RB-EOE and 3116 children with RB-w/o-EOE Intervention(s)Chemotherapy, enucleation, exenteration, radiotherapy. Main outcomes(s)Systemic metastasis and death. ResultsOf the 3435 RB patients included in this study, 309 (9%) were from low-income countries, 1448 (42%) from lower-middle income, 1012 (29%) from upper-middle income, and 666 (19%) patients from high-income countries. There was an inverse relationship between the percentage of RB-EOE and national income level, with 96 (31%) patients from low-income countries, 197 (6%) lower middle-income, 20 (2%) upper-middle income, and 6 (1%) patients from high-income countries (p=0.0001). The outcomes were statistically significant for RB-EOE compared to RB-w/o-EOE: systemic metastasis (32% vs 4% respectively; p=0.0001) and metastasis-related death (63% vs 6% respectively; p=0.0001). Multimodal treatment was the most common form of treatment (n=177; 54%) for RB-EOE, with most cases undergoing a combination of intravenous chemotherapy and enucleation (n=97; 30%). Adjuvant external beam radiotherapy after surgery (enucleation/orbital exenteration) was given in only 68 (21%) cases. Kaplan-Meier analysis for systemic metastasis and metastasis-related death in RB-EOE was 28% and 57% at 1 year, 29% and 60% at 2 years, and 29% and 61% at 3 years, respectively. Cox regression analysis revealed that the risk for death from RB-EOE was greater in patients aged >4 years than <2 years (hazard ratio (HR)=2.912; p<0.001) and for unimodal (surgery or intravenous chemotherapy) and bimodal (surgery and intravenous chemotherapy) treatment than trimodal treatment (surgery, intravenous chemotherapy and external beam radiotherapy) (HR=2.023; p=0.004 and HR 1.819; p=0.027 respectively). ConclusionRetinoblastoma with extraocular tumor extension is associated with a higher risk for metastasis and death. Patients with RB-EOE are likely to benefit from trimodal treatment (intravenous chemotherapy, surgery, and external beam radiotherapy) rather than treatment protocols excluding external beam radiotherapy.

Combining sound with tongue stimulation for the treatment of tinnitus: a multi-site single-arm controlled pivotal trial

Bimodal neuromodulation is emerging as a nonsurgical treatment for tinnitus. Bimodal treatment combining sound therapy with electrical tongue stimulation using the Lenire device is evaluated in a controlled pivotal trial (TENT-A3, NCT05227365) consisting of 6-weeks of sound-only stimulation (Stage 1) followed by 6-weeks of bimodal treatment (Stage 2) with 112 participants serving as their own control. The primary endpoint compares the responder rate observed in Stage 2 versus Stage 1, where a responder exceeds 7 points in the Tinnitus Handicap Inventory. In participants with moderate or more severe tinnitus, there is a clinically superior performance of bimodal treatment (58.6%; 95% CI: 43.5%, 73.6%; p = 0.022) compared to sound therapy alone (43.2%; 95% CI: 29.7%, 57.8%), which is not observed in the full cohort across all severity groups. Consistent results are observed for the secondary endpoint based on the Tinnitus Functional Index (bimodal treatment: 45.5%; 95% CI: 31.7%, 59.9%; sound-only stimulation: 29.6%; 95% CI: 18.2%, 44.2%; p = 0.010), where a responder exceeds 13 points. There are no device related serious adverse events. These positive outcomes led to FDA De Novo approval of the Lenire device for tinnitus treatment.

Primary intracranial germ cell tumors in adolescents and adults: Results of an international, multicenter, retrospective cohort study.

2061 Background: Primary Intracranial Germ Cell Tumors (iGCT) are rare. Previous prospective and retrospective studies mainly included pediatric patients (pts) with a median age of 10-14 years. The aim of this retrospective analysis was to evaluate characteristics, treatment and outcome of adolescents and adults with iGCT. Methods: Data were collected from 10 institutions in Germany and Switzerland. Pts aged &gt;/= 16 years at first diagnosis or at relapse with a primary iGCT were included. Objective responses were evaluated by local investigators. Statistics (Cox proportional hazard model, progression-free survival (PFS) and overall survival (OS) analyzed by Kaplan-Meier method) were performed with SPSS v29. Results: We identified 75 pts (92.0% male) with a median age of 23 years (range 16-60, 94.7% &gt;/= 18 years). At first diagnosis, histology was pure germinoma in 70.7%, pure teratoma in 10.7%, other non-germinomatous GCT (NGGCT) in 13.3%, unknown in 5.3% of pts. Localized, bifocal, and metastatic disease was found in 72.0, 6.7, and 21.3% of pts. As part of their first line (1L) treatment, 69.3%, 80.0%, and 62.7% received surgery, radiotherapy, and chemotherapy, respectively. High dose chemotherapy/ autologous stem cell transplantation (HDCT/ASCT) was part of 1L treatment in n=3 pts with NGGCT. Trimodal and bimodal treatment was performed in 48.0% and 32.0% of pts. Response to 1L therapy was complete remission (CR) in 61.3%, partial remission tumor marker negative (PRm-) in 16.0%, PRm+ in 4.0%, PR with tumor marker status unknown in 4.0%, progressive disease (PD) in 2.7%, and unknown in 12.0%. Relapse occurred in 13/75 pts (17.3%) with unknown histology (n=4), teratoma (n=2), other NGGCT (n=4), and germinoma (n=3). In 2 pts. in whom germinoma was diagnosed at time of first diagnosis, at time of recurrence PNET and Yolk sac tumor were histologically proven. Median time to relapse was 19.0 months (mo.; range 3-223). HDCT/ASCT as salvage treatment was performed in 5 pts with NGGCT and in one pt with germinoma as 2L (n=5) or 3L (n=1). NGGCT histology was associated with increased risk for recurrence or death (p=0.012 and 0.039).3-year PFS was 90.7% (germinoma: 98.1%, NGGCT: 73.9%) and 5-year OS was 92.0% (germinoma: 98.1%; NGGCT: 78.3%). Median follow-up time was 60 mo (range 0-339). Conclusions: Disease characteristics, treatment and outcomes of adolescent/ adult iGCT pts are comparable to those reported in pediatric pts. High cure rates are achieved in pts with pure germinoma and current treatment concepts. In pts with NGGCT further investigation is needed to improve survival outcomes.

Meta-analysis of multi-modality therapies in sinonasal undifferentiated carcinoma-A timely update.

Sinonasal undifferentiated carcinoma (SNUC) is a rare but aggressive tumour with very poor prognosis. There are currently no well-established clinical trials to guide therapy and the impact of various treatment modalities on survival is not well defined. We aim to provide an updated systematic review on current treatment modalities on survival outcomes. Individual patient data were extracted, and survival data pooled in a one-stage meta-analysis. Descriptive statistics were analysed using the Kaplan-Meier method. Patient-level comparisons stratified by treatment modalities, adjusted for demographics, were conducted using shared-frailty Cox regression. Participants include all patients diagnosed with SNUC based on histological evidence. We looked at the overall cumulative survival outcome for different treatment modalities and overall survival by treatment modality in low versus high stage SNUC patients. Seventeen studies were identified, comprising 208 patients from 1993 to 2020. There was no significant difference in cumulative overall survival in low versus high stage patients, and no significant difference in outcomes by treatment modality. The overall cumulative survival of SNUC is 30% at 95 months. Among patients treated with various combinations of treatment modalities, patients with chemoradiotherapy had the highest cumulative survival of 42% at 40 months. Definitive chemoradiotherapy was associated with improved disease survival rate. Regardless of tumour stage, patients should be treated early and aggressively, with no superiority of one treatment regimen over another. Trimodality treatment does not confer survival advantage over bimodality treatment.

Increased efficacy of biologics following inhibition of autophagy in A549 lung cancer cells in bimodal treatment of doxorubicin and SAR405-loaded chitosan nanoparticles

Conventional anti-cancer drugs, including doxorubicin, are associated with high toxicity and non-specific distribution in the body which results in a cascade of side effects. Cancer cells can utilize autophagy to promote tolerance to the stress induced by anti-cancer agents; this may be the major cause of drug resistance in advanced tumors. Owing to the molecular dynamism of cancer cells, targeting the pro-apoptotic survival pathways such as autophagy may increase the effectiveness of existing therapeutic agents at lower concentrations, thereby reducing the side effects of such agents. SAR405 is an inhibitor of autophagy activity due to its molecular interactions within the ATP binding site; however, it suffers from extracellular premature degradation and poor cellular uptake. Conversely, chitosan nanoparticles are considered biologically degradable, non-toxic, and biocompatible drug delivery agents that can be used to minimize the side effects of conventional therapeutic agents whilst increasing their intracellular uptake. In this study, a binary therapeutic strategy for the enhancement of the efficacy of doxorubicin while simultaneously inhibiting autophagy via a nano-mediated delivery system is reported. Autophagic inhibition was achieved via the improvement of SAR405 cellular uptake using SAR405-loaded chitosan nanoparticles. The synthesized nanoparticles were subsequently characterized for parameters of hydrodynamic diameter and polydispersity, while encapsulation and drug loading efficiencies were determined. Morphological characterization of the nanoparticles was elucidated using electron microscopy, and the cytotoxicity of the SAR405-loaded chitosan nanoparticles in combination treatments with doxorubicin was assessed through MTT and Annexin-v apoptosis assays. Autophagy progression through autophagosome formation was also evaluated using CYTO-ID staining. Following encapsulation, the size of the SAR405-loaded chitosan nanoparticles significantly increased from 54 nm to 161 nm at 10 µM SAR405 concentration, while the polydispersity index increased from 0.11 to 0.31 denoting presence of both encapsulated and unencapsulated moieties. When A549 lung cancer cells were treated with the IC50 values of doxorubicin in combination with SAR405-encapsulated CNP, an approximately 47% more reduction in cell viability was observed via the Annexin V-FITC/PI assay compared to using doxorubicin alone. Inhibition of autophagy was also detected in cells treated with SAR405 delivered using the nanoparticle system and was thought to be the primary reason towards a decrease in the resistance of the cancer cells to doxorubicin and thus increased its efficacy at lower concentrations. Therefore, this study has demonstrated a potential way of targeting cancer cell survival pathways that can be considered an effective way of increasing the efficacy of chemotherapeutic drugs.

Mortality, morbidity and sequelae of COVID-associated mucormycosis; 18 months follow up study

Background: The second wave of the COVID-19 pandemic in India was associated with an increased incidence of rhino-orbital-cerebral mucormycosis. The objective of this paper was to prospectively explore the epidemiology, management, and results of 18 months follow-up of patients presenting with COVID associated mucormycosis at a tertiary referral centre in India. Methods: Patients presenting with symptoms suggestive of COVID-associated mucormycosis over two months were included in the study. Patients were staged based on the extent of the disease. Surgery was the primary modality of treatment except in those with intracranial spread, altered sensorium, and poor prognosis. A combination of liposomal amphotericin B and posaconazole was used as adjunct medical treatment. Patients were followed up and outcomes at one year of treatment were recorded. Results: Out of a total of 26 patients who were diagnosed with COVID associated mucormycosis, 21 patients underwent bimodality treatment (medical and surgical). The extent of surgery was based on the stage of the disease. Six eyes received retrobulbar injections of Amphotericin B to salvage vision. The overall mortality was 38.46% and 23.8% in those where the intent of treatment was curative. At the end of one year, 16 of 21 operated patients survived with mild to severe sequelae. Conclusions: Mucormycosis is a deadly fungal infection with high mortality. Early diagnosis and prompt, aggressive treatment is paramount in preventing mortality. A multidisciplinary approach is useful for effective management. Continuous follow up is paramount to identifying and treating complications.

Hyperthermic intraperitoneal chemotherapy and colorectal cancer: From physiology to surgery.

The pursuit of this paper is to collect principal reviews and systematic reviews about hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) used in colorectal cancer (CRC). We focus on principal biological aspects of CRC, hyperthermia effects, and surgical procedures. We searched PubMed/MEDLINE for the principal reviews and systematic reviews published from 2010 to 2021 regarding the bimodal treatment (CRS + HIPEC) against local and advanced CRC. In the literature, from several studies, it seems that the efficacy of bimodal treatment with an accurate CRS can extend overall survival. Despite these studies, there are not still any straight guidelines more detailed and scheduled about the use of combined treatment in patients with CRC. Even if the concept is still not very clear and shared, after a careful evaluation of the published data, and after some technical and pathophysiological descriptions, we concluded that it is possible to improve the overall survival and quality of life and to reduce the tumor relapse in patients affected by locally advanced (pT4) CRC with peritoneal metastases.

Dual-Functionalized Nanoliposomes Achieve a Synergistic Chemo-Phototherapeutic Effect.

The enhancement of photodynamic therapy (PDT) effectiveness by combining it with other treatment modalities and improved drug delivery has become an interesting field in cancer research. We have prepared and characterized nanoliposomes containing the chemotherapeutic drug irinotecan (CPT11lip), the photodynamic agent protoporphyrin IX (PpIXlip), or their combination (CPT11-PpIXlip). The effects of individual and bimodal (chemo-phototherapeutic) treatments on HeLa cells have been studied by a combination of biological and photophysical studies. Bimodal treatments show synergistic cytotoxic effects on HeLa cells at relatively low doses of PpIX/PDT and CPT11. Mechanistic cell inactivation studies revealed mitotic catastrophe, apoptosis, and senescence contributions. The enhanced anticancer activity is due to a sustained generation of reactive oxygen species, which increases the number of double-strand DNA breaks. Bimodal chemo-phototherapeutic liposomes may have a very promising future in oncological therapy, potentially allowing a reduction in the CPT11 concentration required to achieve a therapeutic effect and overcoming resistance to individual cancer treatments.

Effectiveness of bimodal auditory and electrical stimulation in patients with tinnitus: A feasibility study.

BackgroundTinnitus is a common symptom, affecting about 10–15% of the adult population. When input from the somatosensory system can influence and/or elicit tinnitus, this type of subjective tinnitus is called somatosensory tinnitus. Recently, a new type of bimodal neurostimulation treatment has shown promising results for a specific subgroup within the somatosensory tinnitus population. It is, however, not clear if this bimodal stimulation is also effective in patients with other types of subjective tinnitus.AimThe aim of this study was to evaluate the feasibility and efficacy of non-invasive bimodal auditory-somatosensory stimulation in reducing tinnitus severity among a general population of people with subjective tinnitus.MethodsChronic subjective tinnitus patients were recruited from the ENT department of the Antwerp University Hospital. Somatosensory stimulation was delivered by Transcutaneous Electrical Nerve Stimulation (TENS), and it was combined with auditory stimulation via headphones. The therapy comprised six sessions of thirty minutes twice a week for a period of 3 consecutive weeks. Follow up measurements were scheduled 9–12 weeks after the last treatment session. The change of the Tinnitus Functional Index (TFI) score, a questionnaire evaluating tinnitus burden and effects on the quality of life, was the primary outcome measure.ResultsTwenty-nine patients were enrolled in the study. A linear mixed-effects model was used to analyze the efficacy of bimodal treatment. The results of this analysis showed a statistically significant decrease (by 6, 9 points) in average TFI score at the follow up visit when compared to baseline. The ability to modulate tinnitus did not have an influence on the treatment results.ConclusionOur study showed that bimodal stimulation is a feasible and safe method of tinnitus treatment. The method might be an effective treatment for some participants with tinnitus, especially those who have accompanying neck/temporomandibular problems, although, the evidence from this trial is quite weak. Additional research is needed toward establishing the optimal treatment protocol, as well as selecting the most appropriate inclusion criteria.

Different bimodal neuromodulation settings reduce tinnitus symptoms in a large randomized trial

More than 10% of the population suffers from tinnitus, which is a phantom auditory condition that is coded within the brain. A new neuromodulation approach to treat tinnitus has emerged that combines sound with electrical stimulation of somatosensory pathways, supported by multiple animal studies demonstrating that bimodal stimulation can elicit extensive neural plasticity within the auditory brain. More recently, in a large-scale clinical trial, bimodal neuromodulation combining sound and tongue stimulation drove significant reductions in tinnitus symptom severity during the first 6 weeks of treatment, followed by diminishing improvements during the second 6 weeks of treatment. The primary objective of the large-scale randomized and double-blinded study presented in this paper was to determine if background wideband noise as used in the previous clinical trial was necessary for bimodal treatment efficacy. An additional objective was to determine if adjusting the parameter settings after 6 weeks of treatment could overcome treatment habituation effects observed in the previous study. The primary endpoint at 6-weeks involved within-arm and between-arm comparisons for two treatment arms with different bimodal neuromodulation settings based on two widely used and validated outcome instruments, Tinnitus Handicap Inventory and Tinnitus Functional Index. Both treatment arms exhibited a statistically significant reduction in tinnitus symptoms during the first 6-weeks, which was further reduced significantly during the second 6-weeks by changing the parameter settings (Cohen’s d effect size for full treatment period per arm and outcome measure ranged from − 0.7 to − 1.4). There were no significant differences between arms, in which tongue stimulation combined with only pure tones and without background wideband noise was sufficient to reduce tinnitus symptoms. These therapeutic effects were sustained up to 12 months after the treatment ended. The study included two additional exploratory arms, including one arm that presented only sound stimuli during the first 6 weeks of treatment and bimodal stimulation in the second 6 weeks of treatment. This arm revealed the criticality of combining tongue stimulation with sound for treatment efficacy. Overall, there were no treatment-related serious adverse events and a high compliance rate (83.8%) with 70.3% of participants indicating benefit. The discovery that adjusting stimulation parameters overcomes previously observed treatment habituation can be used to drive greater therapeutic effects and opens up new opportunities for optimizing stimuli and enhancing clinical outcomes for tinnitus patients with bimodal neuromodulation.

Bimodal Treatment of Hepatocellular Carcinoma by Targeted Minimally Interventional Photodynamic/Chemotherapy Using Glyco-Covalent-Organic Frameworks-Guided Porphyrin/Sorafenib

Very limited treatment options are available to fight hepatocellular carcinoma (HCC), a serious global health concern with high morbidity and mortality. The integration of multiple therapies into one nanoplatform to exert synergistic therapeutic effects offers advantages over monotherapies. Here, we describe the construction of the nanoplatform Sor@GR-COF-366 for synergistic chemotherapy and photodynamic therapy (PDT) for HCC using a porphyrin-based covalent organic framework (COF-366) coated with N-acetyl-galactosamine (GalNAc) and rhodamine B (RhB), and loaded with the first-line agent, Sorafenib (Sor). The nanoplatform is targeted towards ASGPR-overexpressed HCC cells and liver tissues by GalNAc and observed by real-time imaging of RhB in vitro and in vivo. The nanoplatform Sor@GR-COF-366 exerts an enhanced synergistic tumor suppression effect in a subcutaneous HCC mouse model with a tumor inhibition rate (TGI) of 97% while significantly prolonging survival at very low toxicity. The potent synergistic therapeutic outcome is confirmed in an orthotopic mouse model of HCC with the TGI of 98% with a minimally invasive interventional PDT (IPDT). Sor@GR-COF-366 is a promising candidate to be combined with chemo-IPDT for the treatment of HCC. Statement of significanceThis work describes the construction of covalent-organic frameworks (COFs) modified with glyco-moieties to serve as hepato-targeted multitherapy delivery systems. They combine minimally invasive interventional photodynamic therapy (IPDT) triggered synergism with chemotherapy treatment for hepatocellular carcinoma (HCC). With the aid of minimally invasive intervention, PDT can elicit potent anti-cancer activity for deep solid tumors. This platform shows strong therapeutic outcomes in both subcutaneous and orthotopic mouse models, which can significantly prolong survival. This work showed an effective combination of a biomedical nano-formulation with the clinical operational means in cancer treatment, which is greatly promising in clinical translation.

Guidelines for Best Practice in the Audiological Management of Adults Using Bimodal Hearing Configurations.

Clinics are treating a growing number of patients with greater amounts of residual hearing. These patients often benefit from a bimodal hearing configuration in which acoustic input from a hearing aid on 1 ear is combined with electrical stimulation from a cochlear implant on the other ear. The current guidelines aim to review the literature and provide best practice recommendations for the evaluation and treatment of individuals with bilateral sensorineural hearing loss who may benefit from bimodal hearing configurations. Specifically, the guidelines review: benefits of bimodal listening, preoperative and postoperative cochlear implant evaluation and programming, bimodal hearing aid fitting, contralateral routing of signal considerations, bimodal treatment for tinnitus, and aural rehabilitation recommendations.

Selection Criteria for Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) Treatment in Patients with Peritoneal Metastases.

Simple SummaryStandard treatment protocol for PIPAC consists of three procedures and completion of treatment has been shown to be prognostic of improved survival. The aim of this study was to identify predictors for completion of treatment. This retrospective multicentric cohort study included all patients with peritoneal metastases undergoing PIPAC at three PIPAC expert centers. Overall, 183 patients had 517 PIPACs. Bimodal treatment was found as an independent predictive factor for completing the three procedures (OR = 4.202, 95%CI [1.813, 10.630], p < 0.001), as well as prior bowel obstruction (OR = 0.389, 95%CI [0.153, 0.920], p = 0.037). In conclusion, the absence of ascites and prior bowel obstruction can help to select patients suitable for PIPAC. Best results seem to be achieved when PIPAC is combined with systemic chemotherapy.Background: The standard treatment protocol for PIPAC consists of three procedures. Completion of treatment has been shown to be prognostic of improved survival. The aim of this study was to identify predictors for completion of treatment. Methods: Retrospective multicentric cohort study of patients with peritoneal metastases undergoing PIPAC in three PIPAC expert centers. Per protocol (PP) treatment was defined as patients receiving ≥3 PIPACs and was compared to patients receiving <3. Results: Overall, 183 patients had 517 PIPACs. The main reasons for stopping PIPAC were disease progression in 50% patients, bowel obstruction in 15%, patient’s refusal to pursue in 10%, conversion to cytoreductive surgery in 7%, and medical reasons in 8%. Overall, 95 patients (52%) had PP treatment. The PP median OS was 17 vs. 7 months, p = 0.001. PP patients had r ascites (410 ± 100 mL vs. 960 ± 188 mL, p = 0.001), no prior history of bowel obstruction (12% vs. 24%, p = 0.028), and more bimodal treatment (39% vs. 13%, p < 0.001). After multiple regression, bimodal treatment was found as an independent predictive factor for completing PP (OR = 4.202, 95%CI [1.813, 10.630], p < 0.001), along with prior bowel obstruction (OR = 0.389, 95%CI [0.153, 0.920], p = 0.037). Conclusion: The absence of ascites and prior bowel obstruction can help to select patients suitable for PIPAC. Best results seem to be achieved when PIPAC is combined with systemic chemotherapy.

Bimodal Treatment of Hepatocellular Carcinoma by Targeted Minimally Interventional Photodynamic/Chemotherapy Using Glyco-Covalent-Organic Frameworks-Guided Porphyrin/Sorafenib

Bimodal Treatment of Hepatocellular Carcinoma by Targeted Minimally Interventional Photodynamic/Chemotherapy Using Glyco-Covalent-Organic Frameworks-Guided Porphyrin/Sorafenib

Adenoid cystic Carcinoma and Carbon ion Only irradiation (ACCO): Study protocol for a prospective, open, randomized, two-armed, phase II study

BackgroundAdenoid cystic carcinoma is a rare form of head and neck cancer with a slow, but aggressive growth pattern which remains a challenge for local tumor control. Based on phase II data, radiation treatment using partially high LET radiation results in a prolonged PFS and OS. There is a paucity of randomized clinical data examining the role of the use of high LET radiation only. Therefore, the purpose of this prospective clinical trial is to analyze local control rates in patients with node negative ACC treated with carbon ion radiotherapy alone compared to a combined modality approach.MethodsThis trial is conducted as a prospective, open-label, phase II, two-armed, investigator-initiated study comparing the local control rates in node negative ACCs of the head and neck treated either with sole carbon ion radiotherapy or a combination of carbon ions and photons. Secondary outcomes investigated are progression-free survival, overall survival, acute and late toxicity, and quality of life. A total of 314 patients will be randomly assigned to C12 treatment alone or bimodal treatment: Patients in the experimental group will receive a dose of 51 Gy (RBE) in 17 fractions and a boost of 15 Gy (RBE) in 5 fractions. Patients in the control group will receive 25 fractions photon IMRT 50Gy and a boost using 8 × 3 Gy (RBE) carbon ions. Local control will be assessed in regular follow up examinations until 5 years after the completion of treatment.DiscussionThe present trial aims to evaluate local control rates to compare sole carbon ion radiotherapy to bimodal radiotherapy with carbon ions and photons in patients with node negative ACCs of the head and neck region. Local control is selected as the primary endpoint due to its major clinical relevance because of slow but aggressive growth patterns.Trial registrationThe study was prospectively registered on 2nd January 2020: ClinicalTrials.gov, NCT04214366. “Adenoid Cystic Carcinoma and Carbon Ion Only Irradiation (ACCO)”.Study statusUnder recruitment, participant recruitment is not completed. Start of recruitment was January 2020. There are no results been published or submitted to any journal.

Outcomes in Elderly Patients with Glioblastoma Multiforme Treated with Short-Course Radiation Alone Compared to Short-Course Radiation and Concurrent and Adjuvant Temozolomide Based on Performance Status and Extent of Resection.

(1) Background: Studies in elderly patients over the age of 65 with glioblastoma have shown survival benefits of short-course radiation therapy with concurrent and adjuvant temozolomide, making it the standard of care adopted at Juravinski Cancer Center. Our study retrospectively examines patients with GBM aged ≥ 70 at the JCC treated with short-course radiation alone compared to those treated with short-course radiation and concurrent and adjuvant TMZ, to determine if there is a difference in outcomes based on performance status. (2) Methods: A retrospective chart review was conducted at JCC using patients diagnosed with GBM in 2014–2017 (treated with the old protocol of short-course RT alone) versus those diagnosed in 2017–2019 (treated with the new protocol of short-course radiation and TMZ). Patient demographics, treatments, outcomes, and baseline KPS were analyzed. (3) Results: No clear benefit and more neurologic decline post treatment were seen in patients with borderline performance status and subtotal resection who underwent concurrent treatment with temozolomide and radiation. The addition of temozolomide was most helpful in patients with good performance status and a gross total resection. Variable outcomes were seen in patients with mixed traits. (4) Conclusions: This study suggests that performance status and extent of resection are significant determinants of patient response to treatment. In the case of elderly patients with borderline performance status and GTR or those with good performance status and STR, also described as “mixed traits”, it may be beneficial to pursue single modality treatment, ideally based on MGMT promoter methylation status as opposed to bimodality treatment in order to maintain the best QOL.

Optimization of bimodal automated peritoneal dialysis prescription using the three-pore model.

Previous studies suggested that automated peritoneal dialysis (APD) could be improved in terms of shorter treatment times and lower glucose absorption using bimodal treatment regimens, having 'ultrafiltration (UF) cycles' using a high glucose concentration and 'clearance cycles' using low or no glucose. The purpose of this study is to explore such regimes further using mathematical optimization techniques based on the three-pore model. A linear model with constraints is applied to find the shortest possible treatment time given a set of clinical treatment goals. For bimodal regimes, an exact analytical solution often exists which is herein used to construct optimal regimes giving the same Kt/V urea and/or weekly creatinine clearance and UF as a 6 × 2 L 1.36% glucose regime and an 'adapted' (2 × 1.5 L 1.36% + 3 × 3 L 1.36%) regime. Compared to the non-optimized (standard and adapted regimes), the optimized regimens demonstrated marked reductions (>40%) in glucose absorption while having an identical weekly creatinine clearance (35 L) and UF (0.5 L). Larger fill volumes of 1200 mL/m2 (UF cycles) and 1400 mL/m2 (clearance cycles) can be used to shorten the total treatment time. These theoretical results imply substantial improvements in glucose absorption using optimized APD regimens while achieving similar water and solute removal as non-optimized APD regimens. While the current results are based on a well-established theoretical model for peritoneal dialysis, experimental and clinical studies need to be performed to validate the current findings.

Combined Phacoemulsification and 360-Degree Endocyclophotocoagulation with and without a Kahook Dual Blade in Patients with Primary Open-Angle Glaucoma.

PurposeThe present study aimed to compare the outcomes of combined phacoemulsification and 360-degree endocyclophotocoagulation with and without goniotomy using a Kahook Dual Blade in patients with glaucoma.Patients and MethodsWe enrolled 37 patients, 21 of whom underwent combined phacoemulsification with 360-degree endocyclophotocoagulation and goniotomy using a Kahook Dual Blade (tri-modal therapy (T-MT) group). The remaining 16 patients underwent phacoemulsification with endocyclophotocoagulation (bi-modal therapy (B-MT) group). Visual acuity, intraocular pressure, and number of glaucoma medications were recorded before the study and postoperatively on the first day, at week 1, and at 1, 3, 6, 9, and 12 months. Surgical success was defined as an IOP ≤12 mmHg and ≥6 mmHg or an at least 20% reduction in IOP from baseline with (qualified success) or without medications (complete success).ResultsForty-nine eyes were included. Baseline mean IOP was 16.96±3.66 mmHg and 15.64±4.88 mmHg in the T-MT and B-MT groups (p=0.122), respectively. At the 12-month follow-up, mean IOP values were 11.44±2.15 mmHg and 12.45±1.90 mmHg (p=0.031) in the T-MT and B-MT groups, respectively. Complete success rates were 37% in the T-MT group and 31% in the B-MT group, while qualified success rates were 74% and 50%, respectively. Glaucoma medications decreased from 2.0±1.4 to 0.8±1.0 (p<0.001) in the T-MT group and from 1.5±1.3 to 1.0±1.5 in the B-MT group (p=0.032). Similar improvements in visual acuity were observed in both groups. Complications were mild and resolved without intervention.ConclusionThe tri-modal treatment is safe and may be more effective in reducing IOP and glaucoma medication requirements than bi-modal treatment.

Laparoscopic sentinel lymph node dissection followed by open radical hysterectomy for early stage cervical cancer: A pilot study.

To propose a treatment algorithm, after the LACC trial, of laparoscopic sentinel lymph node biopsy with frozen section, followed by immediate open radical hysterectomy in node-negative cases, for early stage cervical cancer. We retrospectively collected all cases of cervical cancer that were surgically treated between 2019-2020. In all cases, surgery began with laparoscopic sentinel lymph node biopsy±ovarian transposition. Node-negative cases continued with open radical hysterectomy. In node-positive cases, surgery was discontinued, sparing the patient a laparotomy incision. Nine patients with cervical cancer were referred for surgery. Laparoscopic bilateral lymph node identification was achieved in all. In two cases, sentinel lymph nodes were positive for metastatic cancer and surgery was discontinued. For the other seven, node-negative patients, open radical hysterectomy was completed. Four patients had laparoscopic ovarian transposition. There were no cases where nodes were negative on frozen section but positive on final pathology. Laparoscopic sentinel lymph node biopsy before open radical hysterectomy may spare a considerable number of laparotomies on the one hand and bi-modal treatment with surgery and radiation on the other, for node-positive patients. The oncological safety of this approach is yet to be determined.

Dendritic cell vaccination and CD40-agonist combination therapy licenses T cell-dependent antitumor immunity in a pancreatic carcinoma murine model.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is notoriously resistant to treatment including checkpoint-blockade immunotherapy. We hypothesized that a bimodal treatment approach consisting of dendritic cell (DC) vaccination to prime tumor-specific T cells, and a strategy to reprogram the desmoplastic tumor microenvironment (TME) would be needed to break tolerance to these pancreatic cancers. As a proof-of-concept, we investigated the efficacy of combined DC vaccination with CD40-agonistic antibodies in a poorly immunogenic murine model of PDAC. Based on the rationale that mesothelioma and pancreatic cancer share a number of tumor associated antigens, the DCs were loaded with either pancreatic or mesothelioma tumor lysates.MethodsImmune-competent mice with subcutaneously or orthotopically growing KrasG12D/+;Trp53R172H/+;Pdx-1-Cre (KPC) PDAC tumors were vaccinated with syngeneic bone marrow-derived DCs loaded with either pancreatic cancer (KPC) or mesothelioma (AE17) lysate and consequently treated with FGK45 (CD40 agonist). Tumor progression was monitored and immune responses in TME and lymphoid organs were analyzed using multicolor flow cytometry and NanoString analyzes.ResultsMesothelioma-lysate loaded DCs generated cross-reactive tumor-antigen-specific T-cell responses to pancreatic cancer and induced delayed tumor outgrowth when provided as prophylactic vaccine. In established disease, combination with stimulating CD40 antibody was necessary to improve survival, while anti-CD40 alone was ineffective. Extensive analysis of the TME showed that anti-CD40 monotherapy did improve CD8 +T cell infiltration, but these essential effector cells displayed hallmarks of exhaustion, including PD-1, TIM-3 and NKG2A. Combination therapy induced a strong change in tumor transcriptome and mitigated the expression of inhibitory markers on CD8 +T cells.ConclusionThese results demonstrate the potency of DC therapy in combination with CD40-stimulation for the treatment of pancreatic cancer and provide directions for near future clinical trials.