Absence of lung tumor promotion with reduced tumor size in mice after inhalation of copper welding fumes.

Welding fumes are a Group 1 (carcinogenic to humans) carcinogen as classified by the International Agency for Research on Cancer. The process of welding creates inhalable fumes rich in iron (Fe) that may also contain known carcinogenic metals such as chromium (Cr) and nickel (Ni). Epidemiological evidence has shown that both mild steel (Fe-rich) and stainless steel (Fe-rich + Cr + Ni) welding fume exposure increases lung cancer risk, and experimental animal data support these findings. Copper-nickel (CuNi) welding processes have not been investigated in the context of lung cancer. Cu is intriguing, however, given the role of Cu in carcinogenesis and cancer therapeutics. This study examines the potential for a CuNi fume to induce mechanistic key characteristics of carcinogenesis in vitro and to promote lung tumorigenesis, using a two-stage mouse bioassay, in vivo. Male A/J mice, initiated with 3-methylcholanthrene (MCA; 10 µg/g), were exposed to CuNi fumes or air by whole-body inhalation for 9 weeks (low deposition-LD and high deposition-HD) and then sacrificed at 30 weeks. In BEAS-2B cells, the CuNi fume-induced micronuclei and caused DNA damage as measured by γ-H2AX. The fume exhibited high reactivity and a dose-response in cytotoxicity and oxidative stress. In vivo, MCA/CuNi HD and LD significantly decreased lung tumor size and adenomas. MCA/CuNi HD exposure significantly decreased gross-evaluated tumor number. In summary, the CuNi fume in vitro exhibited characteristics of a carcinogen, but in vivo, the exposure resulted in smaller tumors, fewer adenomas, less hyperplasia severity, and with HD exposure, less overall lung lesions/tumors.

Lung toxicity profile of inhaled copper-nickel welding fume in A/J mice.

Objective: Stainless steel welding creates fumes rich in carcinogenic metals such as chromium (Cr). Welding consumables devoid of Cr are being produced in an attempt to limit worker exposures to toxic and carcinogenic metals. The study objective was to characterize a copper-nickel (Cu-Ni) fume generated using gas metal arc welding (GMAW) and determine the pulmonary deposition and toxicity of the fume in mice exposed by inhalation. Materials and Methods: Male A/J mice (6-8 weeks of age) were exposed to air or Cu-Ni welding fumes for 2 (low deposition) or 4 (high deposition) hours/day for 10 days. Mice were sacrificed, and bronchoalveolar lavage (BAL), macrophage function, and histopathological analyses were performed at different timepoints post-exposure to evaluate resolution. Results and Discussion: Characterization of the fume indicated that most of the particles were between 0.1 and 1 µm in diameter, with a mass median aerodynamic diameter of 0.43 µm. Metal content of the fume was Cu (∼76%) and Ni (∼12%). Post-exposure, BAL macrophages had a reduced ability to phagocytose E. coli, and lung cytotoxicity was evident and significant (>12%-19% fold change). Loss of body weight was also significant at the early timepoints. Lung inflammation, the predominant finding identified by histopathology, was observed as a subacute response early that progressively resolved by 28 days with only macrophage aggregates remaining late (84 days). Conclusions: Overall, there was high acute lung toxicity with a resolution of the response in mice which suggests that the Cu-Ni fume may not be ideal for reducing toxic and inflammatory lung effects.

Pentoxyfilline as a treatment for subcorneal pustular dermatosis.

Subcorneal pustular dermatosis (SPD) is a rare pustular neutrophilic dermatosis in which groups of sterile pustules appear in the superficial (subcorneal) skin. This chronic condition can be associated with significant morbidity and decreased quality of life. Dapsone is the first-line therapy for SPD, but some patients fail to respond or cannot tolerate it. In these instances, patients may be treated with second-line therapies such as phototherapy, topical corticosteroids, or systemic agents including glucocorticoids, acitretin, immunosuppressive, or biologic medications. These therapies may not always be efficacious and can be associated with intolerable adverse effects. Here, we report a case of a patient who sustained long-term remission and no side effects with the novel use of pentoxifylline, a tumor necrosis factor-alpha inhibitor, as monotherapy. Pentoxifylline should be considered as a possible therapy in patients with SPD intolerant to dapsone.

Inhalation of gas metal arc-stainless steel welding fume promotes lung tumorigenesis in A/J mice.

Epidemiologic studies suggest an increased risk of lung cancer with exposure to welding fumes, but controlled animal studies are needed to support this association. Oropharyngeal aspiration of collected "aged" gas metal arc-stainless steel (GMA-SS) welding fume has been shown by our laboratory to promote lung tumor formation in vivo using a two-stage initiation-promotion model. Our objective in this study was to determine whether inhalation of freshly generated GMA-SS welding fume also acts as a lung tumor promoter in lung tumor-susceptible mice. Male A/J mice received intraperitoneal (IP) injections of corn oil or the chemical initiator 3-methylcholanthrene (MCA; 10 µg/g) and 1 week later were exposed by whole-body inhalation to air or GMA-SS welding aerosols for 4 h/d × 4 d/w × 9 w at a target concentration of 40 mg/m3. Lung nodules were enumerated at 30 weeks post-initiation. GMA-SS fume significantly promoted lung tumor multiplicity in A/J mice initiated with MCA (16.11 ± 1.18) compared to MCA/air-exposed mice (7.93 ± 0.82). Histopathological analysis found that the increased number of lung nodules in the MCA/GMA-SS group were hyperplasias and adenomas, which was consistent with developing lung tumorigenesis. Metal deposition analysis in the lung revealed a lower deposited dose, approximately fivefold compared to our previous aspiration study, still elicited a significant lung tumorigenic response. In conclusion, this study demonstrates that inhaling GMA-SS welding fume promotes lung tumorigenesis in vivo which is consistent with the epidemiologic studies that show welders may be at an increased risk for lung cancer.

Systemic Sarcoidosis Presenting in a Scar.

While most forms of sarcoidosis of the skin do not require treatment, 40% of patients initially diagnosed with cutaneous sarcoidosis are found to have an asymptomatic disease involving other organ systems. It is the involvement of the lungs, heart, eyes, and nervous system which most often contributes to morbidity/mortality. An early and accurate diagnosis of sarcoidosis is difficult because patients may be asymptomatic, initial presentations may vary, and there is no single reliable diagnostic test except biopsy. We present a case of scar sarcoidosis which led to the diagnosis of stage II pulmonary sarcoidosis in a woman in her 50s. Her scar sarcoidosis presented as well-circumscribed, reddish-brown macules surrounding an atrophic scar from a prior skin graft on the right leg. Biopsy revealed scattered, well-formed, non-necrotizing granulomas of the dermis composed of epithelioid histiocytes and multinucleated giant cells, surrounded by a sparse infiltrate of lymphocytes and histiocytes. A CT chest demonstrated extensive hilar lymphadenopathy, leading to a diagnosis of stage II pulmonary sarcoidosis with cutaneous involvement. This case illustrates the interesting presentation of scar sarcoidosis and underscores the importance of a broad differential including sarcoidosis for skin changes around scars and underscores the need for early biopsy. Prompt cutaneous diagnosis leads to earlier systemic evaluation, therapeutics, and better outcomes.

Hydroxychloroquine-induced repetitive atypical pustular drug eruptions in the same patient separated by 12 years.

Hydroxychloroquine (HCQ) has been reported to cause pustular drug eruptions such as acute generalized exanthematous pustulosis (AGEP) and putular psoriasis (PP). Clinical differentitation of these entities is often difficult. This case emphasizes characteritics of AGEP and PP as well as the need for clinicans to proactively follow-up these patients to monitor for the more aggressive outcome of PP.

Rapid isolation of human stem cells (connective progenitor cells) from the distal femur during arthroscopic knee surgery.

PURPOSE: (1) To safely obtain bone marrow aspirates from the distal femur during arthroscopic knee surgery, (2) to purify and efficiently concentrate connective tissue progenitor cells (CTPs) in the operating room (OR), and (3) to confirm that these are CTPs through their ability to differentiate into bone cells. METHODS: Bone marrow aspirates were harvested from the distal femur during arthroscopic knee surgery in 26 patients. Twenty-five matched control subjects were selected to evaluate for increased incidence of complications. CTPs were isolated using a rapid method designed for use in the OR compared with 2 accepted methods. Cytochemical and molecular analysis was used to assess osteogenic potential. RESULTS: Osteogenic potential of the CTPs was confirmed by reverse transcription polymerase chain reaction analysis and cellular staining. Bone marrow was successfully aspirated in 25 cases, with 3 incidences of stiffness in the aspirate group compared with 2 in the control group, 1 incidence of a wound irregularity in the aspirate group compared with 1 in the control group, and 3 incidences of hemarthrosis/persistent effusion in the aspirate group compared with 1 in the control group. The rate of complications for the aspirate group was 36% compared with 25% in the control group. CONCLUSIONS: Our intention was to develop a technique for extracting and purifying bone marrow so that the orthopaedic surgeon would have a simple, safe, and efficient process by which to isolate CTPs during arthroscopic knee surgery. This method of aspiration did not lead to a significant increase in complications. Further bone marrow aspirate was successfully purified in the OR, with only a slight increase in surgery time, and resulted in a fractionated layer rich with CTPs. These cells showed osteogenic potential, as evidenced by their osteoblastic differentiation. These CTPs may have future use in enhancing the incorporation of the graft into the bone. LEVEL OF EVIDENCE: Level III, matched case-control study.

Tumorigenic response in lung tumor susceptible A/J mice after sub-chronic exposure to calcium chromate or iron (III) oxide.

Iron oxides are Group 3 (not classifiable as to its carcinogenicity to humans) according to the International Agency for Research on Cancer (IARC). Occupational exposures during iron and steel founding and hematite underground mining as well as other iron predominant exposures such as welding are Group 1 (carcinogenic to humans). The objective of this study was to investigate the potential of iron as iron (III) oxide (Fe2O3) to initiate lung tumors in A/J mice, a lung tumor susceptible strain. Male A/J mice were exposed by oropharyngeal aspiration to suspensions of Fe2O3 (1 mg) or calcium chromate (CaCrO4; 100 µg; positive control) for 26 weeks (once per week). Shams were exposed to 50 µL phosphate buffered saline (PBS; vehicle). Mice were euthanized 70 weeks after the first exposure and lung nodules were enumerated. Both CaCrO4 and Fe2O3 significantly increased gross-observed lung tumor multiplicity in A/J mice (9.63 ± 0.55 and 3.35 ± 0.30, respectively) compared to sham (2.31 ± 0.19). Histopathological analysis showed that bronchiolo-alveolar adenomas (BAA) and carcinomas (BAC) were the primary lung tumor types in all groups and were increased in the exposed groups compared to sham. BAC were significantly increased (146 %) in the CaCrO4 group and neared significance in the Fe2O3 group (100 % increase; p = 0.085). BAA and other histopathological indices of toxicity followed the same pattern with exposed groups increased compared to sham control. In conclusion, evidence from this study, in combination with our previous studies, demonstrate that exposure to iron alone may be a potential risk factor for lung carcinogenesis.

Pulmonary toxicity and lung tumorigenic potential of surrogate metal oxides in gas metal arc welding-stainless steel fume: Iron as a primary mediator versus chromium and nickel.

In 2017, the International Agency for Research on Cancer classified welding fumes as "carcinogenic to humans" (Group 1). Both mild steel (MS) welding, where fumes lack carcinogenic chromium and nickel, and stainless steel (SS) increase lung cancer risk in welders; therefore, further research to better understand the toxicity of the individual metals is needed. The objectives were to (1) compare the pulmonary toxicity of chromium (as Cr(III) oxide [Cr2O3] and Cr (VI) calcium chromate [CaCrO4]), nickel [II] oxide (NiO), iron [III] oxide (Fe2O3), and gas metal arc welding-SS (GMAW-SS) fume; and (2) determine if these metal oxides can promote lung tumors. Lung tumor susceptible A/J mice (male, 4-5 weeks old) were exposed by oropharyngeal aspiration to vehicle, GMAW-SS fume (1.7 mg), or a low or high dose of surrogate metal oxides based on the respective weight percent of each metal in the fume: Cr2O3 + CaCrO4 (366 + 5 µg and 731 + 11 µg), NiO (141 and 281 µg), or Fe2O3 (1 and 2 mg). Bronchoalveolar lavage, histopathology, and lung/liver qPCR were done at 1, 7, 28, and 84 days post-aspiration. In a two-stage lung carcinogenesis model, mice were initiated with 3-methylcholanthrene (10 µg/g; intraperitoneal; 1x) or corn oil then exposed to metal oxides or vehicle (1 x/week for 5 weeks) by oropharyngeal aspiration. Lung tumors were counted at 30 weeks post-initiation. Results indicate the inflammatory potential of the metal oxides was Fe2O3 > Cr2O3 + CaCrO4 > NiO. Overall, the pneumotoxic effects were negligible for NiO, acute but not persistent for Cr2O3 + CaCrO4, and persistent for the Fe2O3 exposures. Fe2O3, but not Cr2O3 + CaCrO4 or NiO significantly promoted lung tumors. These results provide experimental evidence that Fe2O3 is an important mediator of welding fume toxicity and support epidemiological findings and the IARC classification.