- A Single Dose of 225Ac-RPS-074 Induces a Complete Tumor Response in a LNCaP Xenograft Model. [Journal Article]
- JNJ Nucl Med 2018 Nov 09
- Promising biochemical responses to 225Ac-PSMA-617, even in patients that are refractory to beta-particle radiation, illustrate the potential of targeted alpha therapy (TAT) for the treatment of metas...
Promising biochemical responses to 225Ac-PSMA-617, even in patients that are refractory to beta-particle radiation, illustrate the potential of targeted alpha therapy (TAT) for the treatment of metastatic castrate-resistant prostate cancer. However, side effects such as xerostomia are severe and irreversible. In order to fully harness the potential of TAT, it is necessary to increase the therapeutic index of the targeted radioligands. One emerging strategy is to Increase clearance half-life through enhanced binding to serum albumin. We have evaluated the albumin-binding PSMA-targeting ligand RPS-074 in a LNCaP xenograft model to determine its potential value to the treatment of prostate cancer. Methods: 225Ac-RPS-074 was evaluated in male BALB/c mice bearing LNCaP xenograft tumors. A biodistribution study was performed over 21 d to determine the dosimetry in tumors and normal tissue. The dose response was measured in groups of 7 mice using 37 kBq, 74 kBq, and 148 kBq 225Ac-RPS-074 and compared to positive and negative control groups. Mice were sacrificed when tumor volume exceeded 1500 mm3Results: 225Ac-RPS-074 was labeled in >98% radiochemical yield and showed high (>10 %ID/g) and sustained accumulation in LNCaP tumors from 24 h to beyond 14 d. Signal in blood and highly vascularized tissues was evident over the first 24 h p.i., and cleared by 7 d. The tumor-to-kidney ratio was 4.3 ± 0.7 at 24 h and 62.2 ± 9.5 at 14 d. A single injection of 148 kBq induced a complete response in 6/7 tumors with no apparent toxic effects. Treatment with 74 kBq induced a partial response in 7/7 tumors, but from 42 d, 6/7 experienced significant regrowth. The 37 kBq group experienced a survival benefit relative to the negative control, but not compared to the positive control group. Conclusion: A single dose of 148 kBq 225Ac-RPS-074 induced a complete response in 86% of tumors, with tumor-to-normal tissue ratios that predict an improved therapeutic index. The use of the macropa chelator enabled quantitative radiolabeling and may facilitate the clinical translation of this promising targeted alpha therapeutic.
- Patterns of failure, treatment outcomes and late toxicities of head and neck cancer in the current era of IMRT. [Journal Article]
- OOOral Oncol 2018; 86:225-233
- Intensity modulated radiotherapy (IMRT) in head and neck cancer allows sculpting of radiation dose to conform closely to target volumes and spare organs at risk. However, this may be offset by an inc...
Intensity modulated radiotherapy (IMRT) in head and neck cancer allows sculpting of radiation dose to conform closely to target volumes and spare organs at risk. However, this may be offset by an increased risk of a geographical miss and reduction in survival outcomes. We reviewed the data from 5 prospective randomized controlled trials, one prospective phase II trial and 10 retrospective comparative series in terms of patterns of failure, treatment outcomes and late toxicities to determine any compromise in survival outcomes in favour of reduced late toxicity. Whilst there was some variablility in target volume delineation, radiation dose and technique, the published data consistently show reduced long term xerostomia (ranging from 0.5 to 87%) with IMRT compared to older radiation techniques. Some studies showed reduced incidence of >10% weight loss and grade ≥2 dysphagia with IMRT, and 2 studies reported higher rates of dysphagia with IMRT. Most studies demonstrated better, though non-significant, locoregional, disease-free and overall survival. The 4 studies that did demonstrate significantly better overall survival with IMRT were the largest cohorts with around 250 patients or greater. Standardization of target volume delineation, treatment verification protocols and outcome reporting will reduce heterogeneity and allow data to be pooled in order to be adequately powered for survival analyses.
- Determinants of level Ib involvement in oral squamous cell carcinoma and implications for submandibular gland-sparing neck dissection. [Journal Article]
- IJInt J Oral Maxillofac Surg 2018; 47(12):1507-1510
- Traditional neck dissection for oral squamous cell carcinoma (OSCC) involves removal of the submandibular salivary gland. Several studies have cited the low incidence of direct gland invasion by tumo...
Traditional neck dissection for oral squamous cell carcinoma (OSCC) involves removal of the submandibular salivary gland. Several studies have cited the low incidence of direct gland invasion by tumours and have recommended gland-sparing neck dissection. In this study, a detailed audit of level Ib involvement in OSCC was performed in order to assess the feasibility of submandibular gland-sparing in neck dissection; the rate of direct involvement by the primary tumours, the involvement of periglandular level Ib nodes, and their determinants were investigated. A total of 586 neck dissection specimens obtained between 2005 and 2014 from patients operated on at the study institution for floor of mouth, tongue, and buccal primaries, were evaluated for direct invasion of the gland and periglandular lymphadenopathy. Of 226 node-positive patients, 21 (9.3%) had direct gland invasion by tumour. Risk factors were tumour diameter >4cm (P=0.002) and depth of invasion >10mm (P=0.003). Determinants of periglandular lymphadenopathy were depth of invasion >10mm (P<0.001), perineural invasion (P=0.02), lymphovascular invasion (P=0.014), and moderate/poor differentiation (P<0.0001). Gland-sparing neck dissection is safe in early tumours (pT1pN0-1), with a good chance of minimizing xerostomia without radiotherapy. Larger tumours without clear evidence of submandibular gland invasion or suspicious level Ib lymphadenopathy may be considered for gland preservation, however the oncological safety is unclear.
- Quality of Life for Patients with Favorable Risk HPV-Associated Oropharyngeal Cancer After De-Intensified Chemoradiotherapy. [Journal Article]
- IJInt J Radiat Oncol Biol Phys 2018 Nov 02
- CONCLUSIONS: The use of de-intensified chemoradiotherapy in HPV-associated oropharynx cancer led to favorable patient-reported outcomes, with early recovery of quality of life and continued improvement of xerostomia and dysphagia beyond 1-year post-treatment.
- Wettability of 3 different artificial saliva substitutes on heat-polymerized acrylic resin. [Journal Article]
- JPJ Prosthet Dent 2018 Oct 31
- CONCLUSIONS: Human saliva had the lowest advancing, receding, and equilibrium contact angle values and the highest angle of hysteresis on heat-polymerized acrylic resin. Aqwet had better wetting ability than the other artificial salivary substitutes tested and was comparable to the human saliva on heat-polymerized acrylic resin. All saliva substitutes have better wetting properties than distilled water.
- Dosimetry estimate and initial clinical experience with 90Y-PSMA-617. [Journal Article]
- JNJ Nucl Med 2018 Nov 02
- Due to different physical properties, the beta-emitters 177Lu and 90Y offer specific radiation-biological advantages in dedicated clinical situations, respectively. Our objective was to introduce 90Y...
Due to different physical properties, the beta-emitters 177Lu and 90Y offer specific radiation-biological advantages in dedicated clinical situations, respectively. Our objective was to introduce 90Y-PSMA-617 to clinical application, providing additional avenues for personalized medicine. Here we present our dosimetry-estimate for 90Y-PSMA-617, report initial clinical experiences and discuss the advantages and drawbacks of varying the beta-emitter in prostate-specific membrane antigen (PSMA) targeting radioligand therapy (RLT). Methods: To approximate radiation dosimetry, 4 patients with metastatic castration-resistant prostate cancer (mCRPC) underwent serially performed imaging up to 1 week after 177Lu-PSMA-617 therapy; time-activity-curves were extrapolated to the half-life of 90Y and OLINDA was used to calculate the dosimetry estimate. In clinical practice 11 patients with PSMA-positive lymphonodal bulk disease were stratified to received 90Y-PSMA-617 RLT (mean 3.2 GBq; range 2.8-3.7 GBq). Safety lab tests, PSA-response and clinical findings were thoroughly followed after treatment. Results: The projected dosimetry for 90Y-PSMA-617 estimated a mean kidney dose of 3.47±1.40 Gy/GBq, red marrow dose of 0.11±0.04 Gy/GBq and salivary glands dose of 5.57±1.34 Gy/GBq; randomly chosen metastases were approximated with 22.8±16.10 Gy/GBq. The observed acute hematological toxicity (n = 5 leucopenia, n = 2 thrombocytopenia; all grade-1/2) and clinical side-effects (n = 2 transient xerostomia, n = 1 nausea; all grade-1/2) as well as PSA-response (any PSA response 7/11 patients, >50% PSA decline 5/11 patients) was comparable to 177Lu-PSMA-617 literature data. Conclusion: A factor 3-4 lower treatment activity for 90Y-PSMA-617 translates into a comparable dosimetry estimate and also similar clinical findings in comparison to 177Lu-PSMA-617. However, safety was only demonstrated for patients with oligo-metastatic disease. Further studies are needed to evaluate its potential in patients with more disseminated bone involvement or visceral metastasis.
- Parasympathectomy increases resting secretion of the submandibular gland in minipigs in the long term. [Journal Article]
- JCJ Cell Physiol 2018 Nov 01
- Parasympathectomy leads to retrogressive alteration and dysfunction of the submandibular gland (SMG) within 1 month, but its long-term effect is unclear. Excessive secretion is observed in half of th...
Parasympathectomy leads to retrogressive alteration and dysfunction of the submandibular gland (SMG) within 1 month, but its long-term effect is unclear. Excessive secretion is observed in half of the patients 4-6 months after SMG transplantation, which completely denervates the gland. Here, we investigated the long-term effect of parasympathectomy on the secretion of SMGs in minipigs. The results showed that the resting salivary secretion of SMGs decreased by 82.9% of that in control at 2 months after denervation, but increased by 156% at 6 months. Although experiencing an atrophic period, the denervated glands regained their normal morphology by 6 months. The expression of the function-related proteins, including muscarinic acetylcholine receptor (mAChR) 3, aquaporin 5 (AQP5), tight junction protein claudin-3, and claudin-4 was decreased at 2 months after denervation. Meanwhile, the protein expression of stem cell markers, including sex-determining region Y-box 2 and octamer-binding transcription factor 4, and the number of Ki67+ cells were significantly increased. However, at 6 months after denervation, the expression of mAChR3, AQP5, claudin-1, claudin-3, and claudin-4 was significantly raised, and the membrane distribution of these proteins was increased accordingly. The autonomic axonal area of the glands was reduced at 2 months after denervation but returned to the control level at 6 months, suggesting that reinnervation took place in the long term. In summary, parasympathectomy increases resting secretion of the SMGs in the long term with a possible mechanism involving improved transepithelial fluid transport. This finding may provide a new strategy for xerostomia treatment.
- Short-term intra-arterial infusion chemotherapy for head and neck cancer patients maintaining quality of life. [Journal Article]
- JCJ Cancer Res Clin Oncol 2018 Oct 31
- CONCLUSIONS: Short-term intra-arterial infusion chemotherapy achieves promising response rates and lacks severe adverse effects.
- Involvement of Aquaporins in the Pathogenesis, Diagnosis and Treatment of Sjögren's Syndrome. [Review]
- IJInt J Mol Sci 2018 Oct 30; 19(11)
- Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands resulting in diminished production of saliva and tears. The pathophys...
Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands resulting in diminished production of saliva and tears. The pathophysiology of SS has not yet been fully deciphered. Classically it has been postulated that sicca symptoms in SS patients are a double step process whereby lymphocytic infiltration of lacrimal and salivary glands (SG) is followed by epithelial cell destruction resulting in keratoconjunctivitis sicca and xerostomia. Recent advances in the field of the pathophysiology of SS have brought in new players, such as aquaporins (AQPs) and anti AQPs autoantibodies that could explain underlying mechanistic processes and unveil new pathophysiological pathways offering a deeper understanding of the disease. In this review, we delineate the link between the AQP and SS, focusing on salivary glands, and discuss the role of AQPs in the treatment of SS-induced xerostomia.
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- Sialendoscopy for Definitive Management of a Submandibular Abscess following Radiotherapy for Oropharyngeal Squamous Cell Carcinoma. [Case Reports]
- OJORL J Otorhinolaryngol Relat Spec 2018 Oct 31; :1-4
- CONCLUSIONS: Sialendoscopy should thus, in select patients, be considered as an initial intervention for patients with intraparenchymal salivary gland abscesses in which prior therapy creates an increased risk of complication from an open transcervical approach.