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Supplementary Figures C1-C2 from A Molecular Classification of Papillary Renal Cell Carcinoma

Supplementary Table 1 from A Molecular Classification of Papillary Renal Cell Carcinoma

Despite the moderate incidence of papillary renal cell carcinoma (PRCC), there is a disproportionately limited understanding of its underlying genetic programs. There is no effective therapy for metastatic PRCC, and patients are often excluded from kidney cancer trials. A morphologic classification of PRCC into type 1 and 2 tumors has been recently proposed, but its biological relevance remains uncertain. We studied the gene expression profiles of 34 cases of PRCC using Affymetrix HGU133 Plus 2.0 arrays (54,675 probe sets) using both unsupervised and supervised analyses. Comparative genomic microarray analysis was used to infer cytogenetic aberrations, and pathways were ranked with a curated database. Expression of selected genes was validated by immunohistochemistry in 34 samples with 15 independent tumors. We identified two highly distinct molecular PRCC subclasses with morphologic correlation. The first class, with excellent survival, corresponded to three histologic subtypes: type 1, low-grade type 2, and mixed type 1/low-grade type 2 tumors. The second class, with poor survival, corresponded to high-grade type 2 tumors (n = 11). Dysregulation of G1-S and G2-M checkpoint genes were found in class 1 and 2 tumors, respectively, alongside characteristic chromosomal aberrations. We identified a seven-transcript predictor that classified samples on cross-validation with 97% accuracy. Immunohistochemistry confirmed high expression of cytokeratin 7 in class 1 tumors and of topoisomerase IIα in class 2 tumors. We report two molecular subclasses of PRCC, which are biologically and clinically distinct and may be readily distinguished in a clinical setting.

Introduction The spread of coronavirus disease 2019 (COVID-19) in the spring of 2020 resulted in the temporary suspension of elective dental procedures and clinical dental education in academic institutions. This study describes the use of the Tufts University School of Dental Medicine emergency dental clinic during the peak surge in COVID-19 cases in Massachusetts, highlighting the number of endodontic emergencies. Methods Aggregate data from clinical encounters and call records to an emergency triage phone line from March 30 through May 8, 2020, were used to describe the characteristics of dental emergencies, clinical encounters, and procedures performed. Results A total of 466 patient interactions occurred during this period, resulting in 199 patients advised by phone and 267 clinical encounters. The most common dental emergencies were severe dental pain from pulpal inflammation (27.7% of clinical encounters) followed by a surgical postoperative visit (13.1%). The most frequent procedures were extractions (13.9% of clinical encounters) and surgical follow-up (13.5%); 50.2% of the clinical encounters were categorized as aerosol generating, and 86.1% of encounters would have required treatment in a hospital emergency department if dental care was not available. There were no known transmissions of severe acute respiratory syndrome coronavirus-2 among clinic providers, patients, or staff during this period. Conclusions These results highlight the importance of endodontic diagnosis and treatment in the provision of emergency dental care during a pandemic and demonstrate that dental treatment can be provided in a manner that minimizes the risk of viral transmission, maintaining continuity of care for a large patient population.

Introduction Radiography has played a fundamental role in the advancement of nonsurgical root canal therapy (NSRCT), allowing for more accurate diagnosis and treatment. Typically, providers choose to perform NSRCT using periapical (PA) radiographs alone or, often in more difficult cases, in conjunction with cone-beam computed tomographic (CBCT) imaging. This study aimed to evaluate the outcomes of NSRCT based on imaging modality selection for the initial treatment of maxillary first molars. Methods A retrospective chart review was conducted using 1385 cases of NSRCT on maxillary first molars. Charts were reviewed for patient demographics and treatment outcomes. Based on the imaging modality used, patients were stratified into 2 groups (PA radiographs alone or PA radiographs + CBCT imaging). Those who required additional treatment(s) after the completion of NSRCT were classified as having “posttreatment disease.” Statistical analysis was performed to assess the differences between groups. Results After the completion of primary endodontic therapy, 5.8% (n = 81) of the entire sample had posttreatment disease. CBCT imaging was used in 13.4% (n = 185) of NSRCTs. Although not significant, cases that were difficult enough to require the use of CBCT imaging had a higher rate of posttreatment disease compared to those that could be completed with PA radiographs alone (8.6% vs 5.4%, P > .05). Results from a multivariable logistic regression model showed that the need for CBCT imaging had a nonsignificant positive association with posttreatment disease (P > .05). Conclusions The decision to use CBCT imaging appears to serve as a proxy for case complexity and the associated increase in risk of posttreatment disease. This is important to keep in mind when assessing treatment prognosis.

The use of cone-beam computed tomography (CBCT) in endodontics has increased in recent years. In clinical application of small field of view (FOV) CBCTs, these scans are not reviewed routinely by a radiologist. Studies of large FOV CBCT scans show the prevalence of incidental findings to be greater than 90%. The purpose of this study was to evaluate the prevalence of missed findings by endodontic residents as compared with a radiologist on small FOV CBCT scans.Two hundred three small FOV CBCTs obtained for endodontic purposes were analyzed by an endodontic resident and a medical radiologist. The reported findings of each practitioner were compared to evaluate for missed incidental findings by the endodontic resident.The radiologist reported abnormalities in 176 of the 203 subjects (87%), with a total of 310 abnormalities reported. The endodontic resident reported abnormalities in 102 of the 203 subjects (50%), with a total of 126 abnormalities reported. The percentage of scans with any abnormality reported by the radiologist was significantly greater than the endodontic resident (P .001). There was no significant difference between jaw locations in percentage of missed findings for the 3 most common types of finding-rarefying osteitis, sinusitis/mucosal lining thickening, and excess restorative material in the periapical area. Rarefying osteitis was missed significantly less than the other 2 types of findings (P .001).A radiologist is significantly more likely to identify incidental findings in small FOV CBCT scans than an endodontic resident. Scan location had no significant association with the rate of missed findings.

Meningiomas are the most common primary intracranial tumors. The current diagnosis and treatment of meningioma is dependent on computed tomography and magnetic resonance imaging, with follow-up management relying mainly on magnetic resonance imaging. The limitations of these structural imaging modalities include delineation of the tumor extent, tumor grade, and differentiation from other meningioma mimickers, especially in or around the skull base. Because studies with positron emission tomography (PET) have shown that PET is able to fulfill some of these gaps, the use of PET for meningiomas has been steadily increasing. Fluciclovine, also known as anti-1-amino-3-[We present 3 cases of meningioma with avid uptake of fluciclovine. In each of these cases, the meningioma was incidentally found during surveillance using PET imaging in patients with prostate cancer.These cases illustrate that this new radiotracer has the potential to be a complementary tool in the meningioma workup, treatment, and follow-up, especially for skull base lesions.

Introduction Vestibular schwannoma, also called acoustic neuroma, is a tumor composed of Schwann cells that most commonly involves the vestibular division of the 8th cranial nerve. A thorough medical and dental history and properly conducted diagnostic testing and radiographic evaluation are essential in differentiating odontogenic tooth pain from tooth pain of a nonodontogenic origin. Methods This report discusses a case of acoustic neuroma mimicking odontogenic pain. A 61-year-old man presented with pain in the lower left quadrant. Medical history revealed peripheral neuropathy and prior exposure to Agent Orange. Diagnostic testing on teeth #19, #20, and #21 ruled out an odontogenic cause for the pain. Brushing of a specific region of the face elicited pain that resembled the patient's chief concern. The patient was referred to a craniofacial pain center with the tentative diagnosis of trigeminal neuralgia. Treatment for trigeminal neuralgia was not successful, prompting referral to the neurosurgery department where magnetic resonance imaging was performed. Results Magnetic resonance imaging revealed a moderate-size, lobular, left cerebellopontine angle mass lesion consistent with acoustic neuroma with compression of the left trigeminal nerve secondary to the lesion. Conclusions Acoustic neuroma can cause tooth pain secondary to compression of the trigeminal nerve.

Introduction Salivary leakage after root canal therapy is of great concern and can lead to failure of the endodontic therapy. The aim of this study was to investigate whether the use of a rubber dam (RD) during post placement impacts the success of root canal–treated teeth. Methods Retrospective chart reviews of 185 patients with an average recall of 2.7 years were assessed for the incidence of a new periapical lesion (periapical index score >2) after root canal therapy and post placement. The patients were divided into 2 groups based on the presence or absence of an RD clamp in the verification radiograph during post placement. Results Twenty-six patients (30 teeth) had a post placed with the use of an RD, and 159 patients (174 teeth) had a post placed without an RD. In the non-RD group, 128 (73.6%) teeth were considered successful at follow-up. In the RD group, 28 (93.3%) teeth were considered successful at follow-up. Based on the bivariate GEE model, the difference in success between these 2 groups was statistically significant ( P = .035). Conclusions The use of an RD during prefabricated post placement provides a significantly higher success rate of root canal–treated teeth. Using an RD is already considered a standard of care for nonsurgical root canal therapy; in addition, using an RD during restorative procedures that involve open teeth should also become a standard of care.

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PURPOSE: The efficacy of interferon alfa has been established in treating advanced melanoma and renal cell carcinoma (RCC) patients. We conducted a phase I/II study to determine the maximum-tolerated dose (MTD), the safety and tolerability, and the preliminary efficacy of once-weekly pegylated interferon alfa-2b (IFNα-2b) in patients with advanced solid tumors (primarily RCC). PATIENTS AND METHODS: To determine the MTD, 35 patients with a variety of advanced solid tumors received 0.75 to 7.5 μg/kg/wk of pegylated IFNα-2b by subcutaneous injection for 12 weeks. An additional 35 previously untreated RCC patients received 6.0 and 7.5 μg/kg/wk for up to 12 weeks. Patients with a response or stable disease after 12 weeks were eligible for the extension protocol and were treated for up to 1 year or until disease progression. RESULTS: The MTD for pegylated IFNα-2b at 12 weeks was 6.0 μg/kg/wk. One year of 6.0 μg/kg/wk was well tolerated with appropriate dose modification; no grade 3 or 4 fatigue occurred, and safety was comparable with that with nonpegylated IFNα-2b. The most common nonhematologic adverse events included mild to moderate nausea, anorexia, and fatigue. Six patients had grade 3 or 4 hematologic toxicity. Twenty-nine patients continued on the extension protocol. Four patients had a complete response, and five patients had a partial response. Among 44 previously untreated RCC patients, the objective response rate was 14%. Median survival for all RCC patients was 13.2 months. CONCLUSION: Pegylated IFNα-2b was active and well tolerated in patients with metastatic solid tumors, including RCC, at doses up to 6.0 μg/kg/wk.

BACKGROUND The incidence of testicular carcinoma in the United States has increased significantly over the last two decades. Germ cell tumors form the majority of malignant testicular tumors. With advances in diagnosis and therapeutic approaches, germ cell tumors are now highly sensitive to treatment, providing long-term survival. It has been speculated that the incidence of bilateral germ cell tumors may increase due to the improved survival of patients with unilateral germ cell tumors. In this report, the authors present a study of bilateral germ cell tumors of the testis in men who were treated at The University of Texas M. D. Anderson Cancer Center over a 20-year period with emphasis on their incidence, histologic features, and clinical features. METHODS Between 1978 and 1999, 2431 patients with testicular germ cell tumors were treated at The University of Texas M. D. Anderson Cancer Center. Among these, 24 patients with bilateral germ cell tumors were identified. Clinical records and all available pathology slides of the tumors were reviewed. RESULTS The overall incidence of bilateral germ cell tumors in the patients with testicular germ cell tumors was 1% (24 of 2431 patients). The incidence was 1.8% (14 of 776 patients) in patients with seminoma and 0.6% (10 of 1655 patients) in patients with nonseminomatous germ cell tumors. Patients with seminoma who were age ≤ 30 years at the time of initial diagnosis had a higher incidence of bilateral tumors compared with older men. Twenty of 24 patients with bilateral germ cell tumors had metachronous tumors, and 4 patients had synchronous tumors. Among the patients with metachronous tumors, 70% of second tumors occurred within 5 years; the longest interval between the first and second tumors was 15 years. The outcome of patients with bilateral germ cell tumors was excellent; only 1 of 24 patients died of metastatic disease. CONCLUSIONS The overall incidence of bilateral testicular germ cell tumors was 1% in patients who were treated at The University of Texas M. D. Anderson Cancer Center over the past two decades. The incidence of bilateral germ cell tumors was related to the histologic type of the initial tumor and to the patient's age at initial presentation in patients with seminoma. Thus, patients in the second or third decade of life who presented with seminomas as their initial tumor were more likely to develop a second germ cell tumor compared with patients in the fourth or fifth decade of life. These findings have potentially important implications for clinical management by identifying a population of patients with germ cell tumors who are at risk of developing a second tumor and also for studying risk factors of bilateral germ cell tumors of the testis. Cancer 2002;95:1228–33. © 2002 American Cancer Society. DOI 10.1002/cncr.10804

Vestibular schwannoma, also called acoustic neuroma, is a tumor composed of Schwann cells that most commonly involves the vestibular division of the 8th cranial nerve. A thorough medical and dental history and properly conducted diagnostic testing and radiographic evaluation are essential in differentiating odontogenic tooth pain from tooth pain of a nonodontogenic origin.This report discusses a case of acoustic neuroma mimicking odontogenic pain. A 61-year-old man presented with pain in the lower left quadrant. Medical history revealed peripheral neuropathy and prior exposure to Agent Orange. Diagnostic testing on teeth #19, #20, and #21 ruled out an odontogenic cause for the pain. Brushing of a specific region of the face elicited pain that resembled the patient's chief concern. The patient was referred to a craniofacial pain center with the tentative diagnosis of trigeminal neuralgia. Treatment for trigeminal neuralgia was not successful, prompting referral to the neurosurgery department where magnetic resonance imaging was performed.Magnetic resonance imaging revealed a moderate-size, lobular, left cerebellopontine angle mass lesion consistent with acoustic neuroma with compression of the left trigeminal nerve secondary to the lesion.Acoustic neuroma can cause tooth pain secondary to compression of the trigeminal nerve.

BACKGROUND Patients with metastatic renal cell carcinoma have a poor prognosis and no standard therapy is available. The authors performed a Phase II trial of the novel agent bryostatin-1 in this patient population. METHODS In all, 30 patients with measurable, previously untreated metastatic renal cell carcinoma were studied. Patients had excellent physiologic reserve and preserved performance status. Bryostatin-1 (25 μg/m2) was given in the PET (polyethyleneglycol, ethanol, and Tween 80) formulation as a 30-minute intravenous infusion on Days 1, 8, and 15 of each 28-day cycle. In general, treatment was continued until disease progression. RESULTS Two patients had significant objective responses, although methodologic problems made interpretation difficult. The median time to progression for all patients was 2.1 months; the median overall survival was 13.1 months. The treatment was generally well tolerated. Myalgia was the most common adverse event. One patient died while on study. This was a sudden death for a patient receiving a 15th cycle of therapy. Aside from this patient (for whom the correlation of study drug to death was not clear), no Grade 4 nonhematologic toxicity was encountered in more than 150 treatment courses delivered. CONCLUSIONS There is minimal, if any, clinically relevant single-agent activity of bryostatin-1 at this dose and schedule for patients with metastatic renal cell carcinoma. Cancer 2000;89:615–8. © 2000 American Cancer Society.

Sinonasal undifferentiated carcinoma (SNUC) is a rare and highly malignant tumor that occurs in the nasal cavity and/or paranasal sinuses. Prognosis is poor despite multimodality treatment. Currently, there is no optimal standard of treatment, partially due to a lack of research defining the biology of such tumors. This report discusses two SNUC cases where patients received a novel chemotherapeutic approach using cisplatin, etoposide, Adriamycin (doxorubicin), metformin, and adjuvant melatonin therapies based on morphoproteomic-guidance, followed by consolidation with chemoradiation therapy. This resulted in excellent and objective tomographic and magnetic resonance imaging and clinical responses including complete responses in the induction phase utilizing morphoproteomic-guided therapies. Later, endoscopic excision of the tumor bed failed to reveal any residual tumor. Morphoproteomics helped to define the biology of these SNUC tumors and provided targets for the agents employed, creating a new treatment paradigm for such tumors. This treatment regimen poses a new effective regimen to treat SNUC.

BACKGROUND Intraabdominal desmoplastic small cell tumor is a rare malignancy that has only recently been described. In the adult population, it is usually seen in young males. The tumor appears to arise as a dominant mass or masses in the abdominal cavity, particularly in the pelvic region, without a clear visceral origin. Multiple small tumor nodules may be found attached to the peritoneal surface. Visceral metastases occur late in the clinical course, ultimately leading to the patient's death. Five young adults with intraabdominal desmoplastic small cell tumors were treated with aggressive chemotherapy. METHODS Charts of five patients treated between 1990 and 1995 were reviewed. The diagnosis of desmoplastic small cell tumor was made on the basis of typical clinical and radiographic findings, light microscopy showing hyperchromatic cells surrounded by a desmoplastic stroma, and immunohistochemistry demonstrating markers of epithelial and mesenchymal differentiation. Patients were treated with aggressive combination chemotherapy consisting of alternating regimens similar to those used as testis cancer salvage therapy. RESULTS Four of the five patients demonstrated a partial response to chemotherapy. Two of the responding patients had surgery with the intent of removing all residual disease, but this was successful in only one case. All patients have died from their cancer. CONCLUSIONS Intraabdominal desmoplastic small cell tumors are sensitive to combination chemotherapy. It appears that treatment offers good palliation and may prolong survival in isolated cases. However, even the patients managed with the most aggressive medical and surgical approaches are not cured and ultimately die of their disease. Cancer 1996;78:845-51.

The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by epithelial cancer cells. To identify novel regulators of EMT, we carried out cDNA screens that covered 500 human kinases. Subsequent characterization of candidate kinases led us to uncover cyclin-dependent kinase-like 2 (CDKL2) as a novel potent promoter for EMT and breast cancer progression. CDKL2-expressing human mammary gland epithelial cells displayed enhanced mesenchymal traits and stem cell-like phenotypes, which was acquired through activating a ZEB1/E-cadherin/beta-catenin positive feedback loop and regulating CD44 mRNA alternative splicing to promote conversion of CD24-high cells to CD44-high cells. Furthermore, CDKL2 enhanced primary tumor formation and metastasis in a breast cancer xenograft model. Notably, CDKL2 is expressed significantly higher in mesenchymal human breast cancer cell lines than in epithelial lines, and its over-expression/amplification in human breast cancers is associated with shorter disease-free survival. Taken together, our study uncovered a major role for CDKL2 in promoting EMT and breast cancer progression. Citation Format: Linna Li, Mohit Hulsurkar, Robert Amato, Jeffrey Chang, Guangwei Du, Wenliang Li. CDKL2 promotes epithelial-mesenchymal transition and breast cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr B34.

More than 100,000 new cases of bone metastases are diagnosed each year, and they present an important clinical problem. They cause significant morbidity and quality-of-life issues in cancer patients. Conventional external-beam radiotherapy is currently the most common method to treat these metastases, with several randomized controlled trials showing no difference in effectiveness between multiple- and single-dosing treatment regimens. A newer technology to treat bone metastases is stereotactic body radiotherapy (SBRT), a radiation delivery method that allows for a large ablative dose to be accurately given to the target over one to a few fractions. This review details the role of SBRT in painful bone metastases, primarily in the vertebral column, but in other bony sites as well, its unique advantages and disadvantages, and its role in the treatment of tumors traditionally deemed radioresistant. Toxicity to surrounding normal tissues and patterns of local failures are also addressed.

Conditionally replicating (oncolytic) herpes simplex viruses (HSVs) have shown clear potential as effective agents for the treatment of solid tumors such as renal cell carcinoma (RCC). To enhance the oncolytic capabilities of first-generation HSVs, we recently developed two new constructs. Synco-2D is derived from HSV-1 and contains two mechanisms to induce cell membrane fusion. FusOn-H2 is derived from HSV-2. It selectively targets the activated Ras signaling pathway in tumor cells and also has the ability to induce cell membrane fusion and apoptosis. We studied the in vitro and in vivo antitumor effects of both Synco-2D and FusOn-H2 against RCC. Both Synco-2D and FusOn-H2 lysed human RCC cells in vitro much more readily than did Baco-1. For in vivo studies, the oncolytic viruses were administered either intratumorally or intravenously to nude mice bearing xenografted human RCC, and the tumor growth rate and animal survival were monitored after treatment. In most instances, the results were compared with those for a first-generation non-fusogenic oncolytic HSV (Baco-1). A single intratumoral injection of either Synco-2D or FusOn-H2 produced a striking effect against xenografted human RCC, in contrast to Baco-1, which produced only moderate antitumor activity. Two intravenous injections of Synco-2D also inhibited the growth of human RCC xenografts, while Baco-1 injections via the same route lacked any measurable antitumor effect. These data demonstrate that the newly constructed oncolytic HSVs have potent activity against established RCC in animal models. Clinical trials to validate these results in cancer patients appear warranted.

Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

Forty-two patients with metastatic renal cell carcinoma who were participating in a Phase II clinical trial were randomly assigned to an expressive writing (EW) or neutral writing (NW) group. Patients in the EW group wrote about their cancer, and patients in the NW group wrote about health behaviors. No statistically significant group differences were found in symptoms of distress, perceived stress, or mood disturbance, except for the Vigor subscale of the Profile of Mood States. However, patients in the EW group reported significantly less sleep disturbance, better sleep quality and sleep duration, and less daytime dysfunction compared with patients in the NW group. The results suggest that EW may have sleep-related health benefits in terminally ill cancer patients.

BACKGROUND Previous research has found that cancer patients often overestimate the likelihood that they will achieve a positive response in Phase I trials. However, maintaining optimistic expectations may help patients cope with a poor prognosis and uncertain outcome. The authors prospectively examined the association between treatment-specific optimism and mental health among patients participating in a Phase I/b trial. METHODS Twenty-four patients with metastatic renal cell carcinoma and 22 patients with metastatic melanoma completed an assessment battery at the beginning of treatment and 3 weeks later, on the final day of treatment. Patients completed measures of treatment-specific optimism (e.g., beliefs regarding the treatment working), depressive symptomatology, mood disturbance, and overall distress. RESULTS The majority of patients believed that the treatment would either cure them (87%) or stop cancer progression (85%). Regression analyses revealed that the level of treatment-specific optimism (e.g., “The treatment I am receiving may cure me”) was associated negatively with baseline measures of depressive symptoms (P < 0.006), mood disturbance (P < 0.001), and symptoms of distress (P < 0.0001) after controlling for age, number of metastases, and time since diagnosis. Patients with symptoms of clinical depression at baseline reported significantly lower levels of treatment-specific optimism than patients without symptoms (P < 0.03). Treatment-specific optimism also was associated negatively with symptoms of depression at the end of treatment (P < 0.003), controlling for symptoms of depression at the beginning of treatment. CONCLUSIONS The results of the current study suggest that high levels of treatment-specific optimism are associated with better mental health outcomes at both the beginning and end of treatment. Cancer 2001;91:1949–55. © 2001 American Cancer Society.

Rabbit alveolar macrophages were exposed in culture medium to asbestos, beryllium sulfate, and beryllium oxide. The specific activities of the lysosomal hydrolases, acid phosphatase beta-N-acetylglucosaminidase and beta-glucuronidase plus the glycolytic enzyme, phosphohexose isomerase were determined in the medium, whole-cell homogenates, mitochondrial fractions, and supernatant. These hydrolases increased significantly in the medium but not in the mitochondrial fraction of cells exposed to dusts. Asbestos and beryllium sulfate were highly cytotoxic for alveolar macrophages in vitro and the data suggested that these agents were not associated with an increase in enzyme synthesis but rather a direct cytotoxic effect at the macrophage membrane level. For induction of enzyme release in vitro, a higher concentration of beryllium oxide was needed when compared with asbestos and beryllium sulfate. The cytotoxicity and enzyme release induced by these agents may represent an important nonspecific mechanism by which they induce inflammation and perhaps local proliferation of fibroblasts.

In a study designed to assess the potential sensitizing and granulomagenic capacities of selected metallic salts, rabbits were inoculated intradermally with zirconium aluminum glycinate (ZAG), sodium zirconium lactate (NZL), aluminum chlorhydrate (ACH), BeSO 4 , and ovalbumin (OVA) by single and multiple injections. Animals immunized with BeSO 4 and with OVA developed delayed skin reactivity as well as antigen-specific alveolar macrophage migration inhibition. Neither single nor multiple injections of ZAG or ACH resulted in clear-cut positive skin reactivity, macrophage migration inhibitory factor (MIF) production, or lymphocyte stimulation. Rabbits inoculated with multiple injections of NZL (500 μg) showed some marginally positive macrophage migration inhibition and skin reactivity. Histologically, ZAG and ACH were found to induce well-organized foreign-body granulomas after intradermal injection in both normal and inoculated rabbits. NZL and BeSO 4 also induced skin granulomas, but these were less organized and distinct. Cell viability and ultrastructural studies indicated that BeSO 4 was highly toxic for isolated alveolar macrophages in vitro at concentrations above 10 μg/ml, but NZL and ZAG did not exert such an effect at these dose levels. BeSO 4 also depressed lymphocyte stimulation in sensitized animals which demonstrated delayed skin reactivity and macrophage migration inhibition.