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Supplementary Table S2: Cystectomy Pathologic Staging

Supplementary Figure Legends

Purpose: To assess the clinical and pharmacodynamic activity of dovitinib in a treatment-resistant, molecularly enriched non–muscle-invasive urothelial carcinoma of the bladder (NMIUC) population.Experimental Design: A multi-site pilot phase II trial was conducted. Key eligibility criteria included the following: Bacillus Calmette-Guerin (BCG)-unresponsive NMIUC (>2 prior intravesical regimens) with increased phosphorylated FGFR3 (pFGFR3) expression by centrally analyzed immunohistochemistry (IHC+) or FGFR3 mutations (Mut+) assessed in a CLIA-licensed laboratory. Patients received oral dovitinib 500 mg daily (5 days on/2 days off). The primary endpoint was 6-month TURBT-confirmed complete response (CR) rate.Results: Between 11/2013 and 10/2014, 13 patients enrolled (10 IHC+ Mut−, 3 IHC+ Mut+). Accrual ended prematurely due to cessation of dovitinib clinical development. Demographics included the following: median age 70 years; 85% male; carcinoma in situ (CIS; 3 patients), Ta/T1 (8 patients), and Ta/T1 + CIS (2 patients); median prior regimens 3. Toxicity was frequent with all patients experiencing at least one grade 3–4 event. Six-month CR rate was 8% (0% in IHC+ Mut−; 33% in IHC+ Mut+). The primary endpoint was not met. Pharmacodynamically active (94–5,812 nmol/L) dovitinib concentrations in urothelial tissue were observed in all evaluable patients. Reductions in pFGFR3 IHC staining were observed post-dovitinib treatment.Conclusions: Dovitinib consistently achieved biologically active concentrations within the urothelium and demonstrated pharmacodynamic pFGFR3 inhibition. These results support systemic administration as a viable approach to clinical trials in patients with NMIUC. Long-term dovitinib administration was not feasible due to frequent toxicity. Absent clinical activity suggests that patient selection by pFGFR3 IHC alone does not enrich for response to FGFR3 kinase inhibitors in urothelial carcinoma. Clin Cancer Res; 23(12); 3003–11. ©2016 AACR.

Supplementary Figure 2 from Expression and Functions of Transmembrane Mucin MUC13 in Ovarian Cancer

Supplementary Figure Legends 1-4 from Expression and Functions of Transmembrane Mucin MUC13 in Ovarian Cancer

MUC13, a transmembrane mucin, is normally expressed in gastrointestinal and airway epithelium. Its aberrant expression has been correlated with gastric colon and cancer. However, the expression and functions of MUC13 in ovarian cancer are unknown. In the present study, the expression profile and functions of MUC13 were analyzed to elucidate its potential role in ovarian cancer diagnosis and pathogenesis. A recently generated monoclonal antibody (clone PPZ0020) was used to determine the expression profile of MUC13 by immunohistochemistry using ovarian cancer tissue microarrays and 56 additional epithelial ovarian cancer (EOC) samples. The expression of MUC13 was significantly (P < 0.005) higher in cancer samples compared with the normal ovary/benign tissues. Among all ovarian cancer types, MUC13 expression was specifically present in EOC. For the functional analyses, a full-length MUC13 gene cloned in pcDNA3.1 was expressed in a MUC13 null ovarian cancer cell line, SKOV-3. Here, we show that the exogenous MUC13 expression induced morphologic changes, including scattering of cells. These changes were abrogated through c-Jun NH2 kinase (JNK) chemical inhibitor (SP600125) or JNK2 siRNA. Additionally, a marked reduction in cell-cell adhesion and significant (P < 0.05) increases in cell motility, proliferation, and tumorigenesis in a xenograft mouse model system were observed upon exogenous MUC13 expression. These cellular characteristics were correlated with up-regulation of HER2, p21-activated kinase 1, and p38 protein expression. Our findings show the aberrant expression of MUC13 in ovarian cancer and that its expression alters the cellular characteristics of SKOV-3 cells. This implies a significant role of MUC13 in ovarian cancer. [Cancer Res 2009;69(3):765–74]

Supplementary Figure 1 from Expression and Functions of Transmembrane Mucin MUC13 in Ovarian Cancer

National and international guidelines recommend the use of 1 dose of intravesical chemotherapy immediately following surgery for nonmuscle invasive bladder cancer, which is performed infrequently on a population level. We sought to understand the importance of potential environmental and clinical dimensions involved in the decision to offer this therapy.Urologists from the Michigan Urological Surgery Improvement Collaborative (MUSIC) rated 8 distinct clinical vignettes involving patients with nonmuscle invasive bladder cancer. A ratings-based conjoint analysis method was used to evaluate the clinical vignette responses. Each vignette included 4 clinical dimensions and 2 environmental dimensions, with each dimension consisting of 2 possible attributes. The relative importance of each attribute was derived from the regression model and ranked in order.A total of 58 urologists answered the clinical vignettes which represents75% of MUSIC sites. The median age of urologists was 53, most were male, and median years in practice was 20 years post residency. An environmental attribute, having a recovery room protocol for instilling and disposing of the chemotherapy, ranked as the most influential attribute for giving postoperative chemotherapy (utility=8.6). The clinical attribute yielding the strongest preference for giving chemotherapy was tumor grade (utility=4.9). These preferences varied by different subgroups of urologists, particularly regarding the type of practice a urologist was in.This study demonstrates that urologists have clear preferences for when they offer postoperative immediate chemotherapy. Factors beyond just clinical variables play a role in this decision making process such as the structure of the recovery room.

The target of this chapter is the evaluation of gradients in inverse problems where spatial field parameters and geometry parameters are treated separately. Such an approach can be beneficial especially when the geometry needs to be detected accurately using L2-norm-based regularization. Emphasis is laid upon the computation of the gradients directly from the governing equations. Working in a statistical framework, the Karhunen-Loève (K-L) expansion is used for discretization of the spatial random field and inversion is done using the gradient-based Hamiltonian Monte Carlo (HMC) algorithm. The HMC gradients involve sensitivities w.r.t the random spatial field and geometry parameters. Building on a method developed by the authors, a procedure is developed which considers the gradients of the associated integral eigenvalue problem (IEVP) as well as the interaction between the gradients w.r.t random spatial field parameters and the gradients w.r.t the geometry parameters. The same mesh and linear shape functions are used in the finite element method employed to solve the forward problem, the artificial elastic deformation problem and the IEVP. Analysis of the rate of convergence using seven different meshes of increasing density indicates a linear rate of convergence of the gradients of the log posterior.

Objective To characterize the health-related quality of life reported by patients who received an ileal conduit (IC), Indiana pouch, or neobladder urinary diversion after radical cystectomy. Materials and Methods The Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index survey was administered to patients with bladder cancer undergoing radical cystectomy and urinary diversion from 2015-2018. Surveys were completed prior to radical cystectomy and then longitudinally throughout the postoperative course. Results A total of 146 patients completed questionnaires over a median of 12.3 months, 83 (56.8%) received an IC, 31 (21.2%) an Indiana pouch, and 32 (21.9%) an orthotopic neobladder. There were no significant differences in health related quality of life among urinary diversion groups considering the Trial Outcome Index scores, general overall FACT-G assessment, or total Functional Assessment of Cancer Therapy-Vanderbilt Cystectomy Index instruments. Patients who received IC were older and had higher Charlson Comorbidity Index scores (p Conclusions To our knowledge this is the first and largest quality of life analysis comparing all three methods of urinary diversion in a longitudinal fashion utilizing a standardized, validated, treatment-specific health survey. Proper preoperative counseling is critical to ensure understanding of the benefits of available urinary diversion.

Objective: To compare peri-operative factors and renal function following open partial nephrectomy (OPN) and robotic partial nephrectomy (RPN) for intermediate and high complexity tumors when contr...

The International Collaboration on Cancer Reporting (ICCR) is an alliance of major pathology organisations in Australasia, Canada, Europe, United Kingdom, and United States of America that develops internationally standardised, evidence-based datasets for the pathology reporting of cancer specimens. This dataset was developed by a multidisciplinary panel of international experts based on previously published ICCR guidelines for the production of cancer datasets. It is composed of Required (core) and Recommended (noncore) elements identified on the basis of literature review and expert consensus. The document also includes an explanatory commentary explaining the rationale behind the categorization of individual data items and provides guidance on how these should be collected and reported. The dataset includes nine required and six recommended elements for the reporting of cancers of the urinary tract in biopsy and transurethral resection (TUR) specimens. The required elements include specimen site, operative procedure, histological tumor type, subtype/variant of urothelial carcinoma, tumor grade, extent of invasion, status of muscularis propria, noninvasive carcinoma, and lymphovascular invasion (LVI). The recommended elements include clinical information, block identification key, extent of T1 disease, associated epithelial lesions, coexistent pathology, and ancillary studies. The dataset provides a structured template for globally harmonized collection of pathology data required for management of patients diagnosed with cancer of the urinary tract in biopsy and TUR specimens. It is expected that this will facilitate international collaboration, reduce duplication of effort in updating current national/institutional datasets, and be particularly useful for countries that have not developed their own datasets.

Incontinence and impotence occur following radical prostatectomy due to injury to nerves and sphincter muscle. Preserving nerves and muscle adjacent to prostate cancer risks positive surgical margins. Advanced imaging with MRI has improved cancer localization but limitations exist.To measure the accuracy for assessing extra-prostatic extension at nerve bundles for 2 PSMA-PET tracers and to compare the PET accuracy to standard-of-care predictors including MRI and biopsy results.We studied men with PSMA-targeted PET imaging, performed prior to prostatectomy in men largely with intermediate to high-risk prostate cancer, and retrospectively evaluated for assessment of extra-prostatic extension with whole-mount analysis as reference standard. Two different PSMA-PET tracers were included:Pre-operative PSMA-PET imaging was available for 71 patients with eitherPresurgical PSMA-PET appeared useful as a tool for surgical planning, changing treatment plans in men with ≥4+3 or multi-core 3+4 prostate cancer resulting in preservation of nerve-bundles.

HNO 70(1), 44-50 (2022). doi:10.1007/s00106-021-01029-w, Published by Springer, New York

Summary Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for PC, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9 × 10−7 and GAB2, p = 2.0 × 10−6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% confidence interval [CI] = 0.94–1.36); whereas decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04–1.50). These results suggest that germline genetics may help inform and individualize the decision of AS—or the intensity of monitoring on AS—versus treatment for the initial management of patients with low-risk PC., Genetic factors may distinguish who should receive active surveillance (AS) versus treatment following prostate cancer diagnosis. We undertook the first study to investigate this and report novel variants, genes, and risk scores associated with AS outcomes. These findings could help inform and individualize the decision of AS.

Winter wheat growing areas in the Northern hemisphere are regularly exposed to heavy frost. Due to the negative impact on yield, the identification of genetic factors controlling frost tolerance (FroT) and development of tools for breeding is of prime importance. Here, we detected QTL associated with FroT by genome wide association studies (GWAS) using a diverse panel of 276 winter wheat genotypes that was phenotyped at five locations in Germany and Russia in three years. The panel was genotyped using the 90K iSelect array and SNPs in FroT candidate genes. In total, 17,566 SNPs were used for GWAS resulting in the identification of 53 markers significantly associated (LOD ≥4) to FroT, corresponding to 23 QTL regions located on 11 chromosomes (1A, 1B, 2A, 2B, 2D, 3A, 3D, 4A, 5A, 5B and 7D). The strongest QTL effect confirmed the importance of chromosome 5A for FroT. In addition, to our best knowledge, seven FroT QTLs were discovered for the first time in this study comprising QTLs on chromosomes 3A, 4A, 1B, and two on chromosomes 2D, 3D, and 7D. Identification of novel FroT candidate genes will help to better understand the FroT mechanism in wheat and to develop more effective combating strategies.

High-intensity focused ultrasound (HIFU) is a noninvasive treatment option used for localized prostate cancer or salvage surgery after failed radiation therapy. Histological changes in post-treatment needle biopsies are reviewed to better understand HIFU failures. Between 2016 and 2021, 50 patients with localized prostate cancer were enrolled and treated in this study. Of these, 10 patients underwent salvage therapy after radiation failure and 7 did not have post-treatment needle biopsies available for review and were excluded. Inclusion criteria included pathologically confirmed prostate cancer and clinical stage T1/T2 disease. We describe the histological changes in post-treatment needle biopsies as part of routine follow-up. Biopsies were examined for presence, distribution and extent of residual adenocarcinoma, Gleason score, and ablative tissue changes. A total of 33 patients underwent HIFU hemi-ablation treatment of localized prostate cancer as primary treatment with post-treatment biopsies available for review. The average mean age of the patients was 64 years (range, 52-81 years). The average PSA (prostate-specific antigen) level of the patients was 6.3 ng/mL (range, 2.4-14.7 ng/mL). The Gleason scores assigned in pretreatment prostate needle biopsies are as follows: 3 + 3 (1 case, 3%), 3 + 4 (21 cases, 64%), 4 + 3 (9 cases, 27%), and 4 + 4 (2 cases, 6%). In post-treatment needle biopsies, 33 cases (100%) showed variable degrees of fibrosis ranging from mild to moderate. Twenty-four of 33 cases (73%) showed necrosis usually associated with acute and/or chronic inflammation. Histological examination of benign glands revealed glandular heterogeneity including atrophy and basal cell hyperplasia. Eight cases (24%) had residual prostatic adenocarcinoma after treatment, of which 4 cases were assigned Gleason score: ≥3 + 4. In cases with residual adenocarcinoma, 8 cases (100%) showed nuclear enlargement, 5 cases (63%), cytoplasmic vacuolization, and 1 case (13%) showed nuclear pyknosis; otherwise, no discernible effects of treatment were seen. Morphological alterations included a spectrum of changes ranging from extensive coagulative stromal necrosis secondary to thermal injury to atrophic changes in benign prostatic tissue after HIFU treatment. Our findings also support the hypothesis that HIFU failure results from inadequate targeting rather than failure within a treated zone.

Introduction and objective: Traditionally, patients with renal masses in solitary kidneys were managed with an open partial nephrectomy. With improving techniques, robotic-assisted partial nephrectomy in the setting of a solitary kidney is increasingly utilized. The objective of this study was to compare open partial nephrectomy and robotic-assisted partial nephrectomy outcomes in solitary kidney patients. Methods: A retrospective study of 536 total patients who underwent partial nephrectomy between 2004–2016 was performed. Of these patients, 23 had a renal mass in a solitary kidney. Patient demographics, perioperative values, and surgical outcomes were analyzed using descriptive statistics to compare open partial nephrectomy to robotic-assisted partial nephrectomy. Results: Of the 23 patients in the cohort, 52% ( n=12) underwent open partial nephrectomy and 48% ( n=11) underwent robotic-assisted partial nephrectomy. Patient characteristics were not significantly different. The mean (standard deviation) nephrometry score was 6.9 (1.8) for open partial nephrectomy and 6.1 (1.9) for robotic-assisted partial nephrectomy ( p=0.290). The mean (standard deviation) pre-operative creatinine was 1.2 (0.3) in open partial nephrectomy and 1.5 (0.4) in robotic-assisted partial nephrectomy, which did not reach statistical significance ( p=0.110). No difference in postoperative kidney function, Clavien grade 3 or higher complication rate, blood loss, or hospitalization length was noted. Conclusion: Although traditionally patients with a tumor in a solitary kidney are counseled to undergo open partial nephrectomy, robotic-assisted partial nephrectomy is a safe alternative with no decrease in postoperative renal function when compared with a similar cohort of patients undergoing open partial nephrectomy in a solitary kidney. Level of evidence: Level II

ZUSAMMENFASSUNGDas akute Nierenversagen (ANV) mit Nierenersatztherapie-Pflichtigkeit ist ein häufiges Krankheitsbild auf den Intensivstationen, verbunden mit hoher Mortalität. Als Nierenersatztherapie-Verfahren werden v. a. extrakorporale Methoden eingesetzt. Untersuchungen in den letzten Jahren zeigen, dass die Peritonealdialysetherapie eine effektive, sichere und durchführbare komplementäre Alternative zu den extrakorporalen Verfahren nicht nur bei Patienten mit chronischem, sondern auch bei (intensivpflichtigen) Patienten mit ANV darstellt. Die Peritonealdialyse (PD) bietet methodische Vorteile wie die Vermeidung eines Kathetergefäßzuganges mit entsprechendem Bakteriämie- und Sepsisrisiko, einen gleichmäßigen Flüssigkeitsentzug mit geringerer hämodynamischer Instabilität, einem fehlenden Antikoagulationsbedarf und einer Fortführbarkeit der Nierenersatztherapie bei fortbestehender Dialysepflichtigkeit. Insbesondere wäre die PD zu erwägen bei Erkrankungen wie fortgeschrittener chronischer Herzinsuffizienz mit kardiorenalem Syndrom, Leberzirrhose mit refraktärem Aszites, akut auf chronischem Nierenversagen mit anzunehmender chronischer Nierenersatztherapiepflichtigkeit, bei schlechten Gefäßzugangsmöglichkeiten und bei erhöhtem Blutungsrisiko. Bei bestimmten klinischen Situationen wie Septikämien mit Katecholamin-Pflichtigkeit und möglichem peritonealem Ultrafiltrationsverlust sowie aktiven chronisch-entzündlichen Darmerkrankungen sollte jedoch den extrakorporalen Verfahren der Vorzug gegeben werden. Ein limitierender Faktor für den Einsatz der PD kann insbesondere die akute und zeitige Anlage des PD-Katheters beim kritisch kranken Patienten darstellen. Jedoch erscheint dies durch die Etablierung einer entsprechenden Vorgehensweise und Methode mit Kooperation der beteiligten Disziplinen vor Ort auch in der Akutsituation möglich.

The International Collaboration on Cancer Reporting (ICCR) is a not-for-profit organisation sponsored by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Association of Pathologists in association with the Canadian Partnership Against Cancer, the European Society of Pathology, the American Society of Clinical Pathology and the Faculty of Pathology, Royal College of Physicians of Ireland. Its goal is to produce standardised, internationally agreed-upon, evidence-based datasets for cancer pathology reporting throughout the world. This paper describes the development of a cancer dataset by the multidisciplinary ICCR expert panel for the reporting of carcinoma of the urethra in urethrectomy specimens. The dataset is composed of 'required' (mandatory) and 'recommended' (non-mandatory) elements, which are based on a review of the most recent evidence and supported by explanatory commentary. Fourteen required elements and eight recommended elements were agreed by the international dataset authoring committee to represent the essential/required (core) and recommended (non-core) information for the reporting of carcinoma of the urethra in urethrectomy specimens. Use of an internationally agreed, structured pathology dataset for reporting carcinoma of the urethra (in urethrectomy specimens) will provide the necessary information for optimal patient management, will facilitate consistent data collection and will provide valuable data for research and international benchmarking. The dataset will be valuable for those countries and institutions that are not in a position to develop their own datasets.

INTRODUCTION: The intravesical instillation of mitomycin C immediately following surgery for non-muscle invasive bladder cancer has been shown to be efficacious in reducing cancer recurrence. As a result, the American Urological Association adopted guidelines for non-muscle invasive bladder cancer care to support its use in low to intermediate risk patients. Despite this, urologists’ use of this drug following transurethral resection of a bladder tumor (TURBT) has been reported as low as 5% or less. Our study objective was to better understand the barriers urologists experience in using mitomycin C. METHODS: Semi-structured interviews were conducted with 13 practicing urologists at 4 geographically distinct practice locations throughout Indiana between 2017 and 2018. Cognitive task analysis was used to explore factors that influenced their clinician decision-making about Mitomycin C use following TURBT in specific patient cases. Interview transcripts were coded and analyzed using immersion/crystallization to identify emergent themes. RESULTS: The median age of the urologists interviewed was 44 (IQR 40–48). Eighty-five percent were male. Approximately 30% had completed urologic fellowship training; 62% were in private practice. Three major themes related to the use of mitomycin C emerged: cumbersome workflow processes, urologists’ fears of side effects, and issues of identifying patients most likely to benefit. CONCLUSION: Workflow, fear, and value are key factors and also represent complexities of translating efficacy into effectiveness for a drug with known benefits to patients. Areas of potential intervention development to improve the use of mitomycin C to reduce recurrence of bladder cancer are suggested. Alternatives such as gemcitabine may also help overcome these barriers.

Purpose: Magnetic resonance imaging-guided transurethral ultrasound ablation uses directional thermal ultrasound under magnetic resonance imaging thermometry feedback control for prostatic ablation. We report 12-month outcomes from a prospective multicenter trial (TACT). Materials and methods: A total of 115 men with favorable to intermediate risk prostate cancer across 13 centers were treated with whole gland ablation sparing the urethra and apical sphincter. The co-primary 12-month endpoints were safety and efficacy. Results: In all, 72 (63%) had grade group 2 and 77 (67%) had NCCN® intermediate risk disease. Median treatment delivery time was 51 minutes with 98% (IQR 95-99) thermal coverage of target volume and spatial ablation precision of ±1.4 mm on magnetic resonance imaging thermometry. Grade 3 adverse events occurred in 9 (8%) men. The primary endpoint (U.S. Food and Drug Administration mandated) of prostate specific antigen reduction ≥75% was achieved in 110 of 115 (96%) with median prostate specific antigen reduction of 95% and nadir of 0.34 ng/ml. Median prostate volume decreased from 37 to 3 cc. Among 68 men with pretreatment grade group 2 disease, 52 (79%) were free of grade group 2 disease on 12-month biopsy. Of 111 men with 12-month biopsy data, 72 (65%) had no evidence of cancer. Erections (International Index of Erectile Function question 2 score 2 or greater) were maintained/regained in 69 of 92 (75%). Multivariate predictors of persistent grade group 2 at 12 months included intraprostatic calcifications at screening, suboptimal magnetic resonance imaging thermal coverage of target volume and a PI-RADS™ 3 or greater lesion at 12-month magnetic resonance imaging (p

The detection of piping and the extent to which it progresses is important in the serviceability of natural dams and levees, where the soil is usually poorly consolidated and filters or drainage zones are absent. Practically, information of the spatial variation of hydraulic conductivity is also unavailable in the domain of interest. An approximate version of a Hamiltonian Monte Carlo (HMC) based method for combined probabilistic inversion is detailed. The inverse problem consists of Karhunen-Loeve (KL) expansion parameters and solid-void interface parameters which are determined simultaneously. The interface parameter updates are carried out using a reversible proposal in a mesh moving framework. To maintain computational efficiency, the parameter update is enforced in an approximate sense, where the covariance matrix for the KL expansion is kept constant throughout the analysis. Synthetic data from a numerical experiment on a domain containing a predefined piping region, is used to validate the approximate method. A total of 30000 samples are generated using the HMC sampler. Results show that the Markov chains converge to the stationary distribution. A good match is also observed between the inferred mean interface, and the true interface and the true spatial distribution of hydraulic conductivity is obtained.

Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland and often results in sialadenitis with the need for surgical intervention. The mechanism behind the formation of sialoliths has been elusive. Here we show that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in their dense aggregation, and the subsequent mineralization creates alternating layers of dense mineral, predominantly calcium salt deposits and DNA. Further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis in which an immune system mediated response essentially participates in the physico-chemical process of concrement formation and growth.