ABSTRACT
BACKGROUND: Adhesive capsulitis is a relatively common condition that can develop in cancer patients during treatment. Positron emission tomography - computed tomography (PET-CT) is routinely performed as a follow-up study in cancer patients after therapy. Being aware of PET-CT findings to suggest shoulder adhesive capsulitis may help to alert clinicians for the diagnosis of unsuspected shoulder capsulitis. AIM: To assess the association of shoulder adhesive capsulitis with cancer/therapy type and symptoms in cancer patients undergoing PET-CT. METHODS: Our prospective study received Institutional Review Board approval. Written informed consent was obtained from all patients, who answered a questionnaire regarding shoulder pain/stiffness at the time of PET-CT study, between March 2015 and April 2019. Patients with advanced glenohumeral arthrosis, metastatic disease or other mass in the shoulder, or shoulder arthroplasty were excluded. Patterns of shoulder capsule 18F-fluorodeoxyglucose (FDG) uptake were noted. Standard Uptake Value (SUV)max and SUVmean values were measured at rotator interval (RI) and deltoid muscle in bilateral shoulders. Normalized SUV (SUV of RI/SUV of deltoid muscle) was also calculated. We assessed if SUV values are different between symptomatic and asymptomatic patients in both shoulders. Covariates were age, gender, and therapy type (surgery, chemotherapy, radiation). Wilcoxon rank sum tests were used to compare unadjusted marginal differences for age, SUV measurements between symptomatic and asymptomatic patients. Multiple linear regression models were used to examine the relationship between right or left shoulder SUV measurements and symptom status, after adjusting for covariates. Statistical significance level was set at P < 0.05. RESULTS: Of 252 patients initially enrolled for the study (mean age 66 years, 67 symptomatic), shoulder PET-CT data were obtained in 200 patients (52 were excluded due to exclusion criteria above). The most common cancer types were lymphoma (n = 61), lung (n = 54) and breast (n = 53). No significant difference was noted between symptomatic and asymptomatic patients in terms of age, gender, proportion of patients who had surgical therapy and radiation therapy. A proportion of patients who received chemotherapy was higher in patients who were asymptomatic in the right shoulder compared to those symptomatic in the right shoulder (65% vs 48%, P = 0.012). No such difference was seen for the left shoulder. In both shoulders, SUVmax and SUVmean were higher in symptomatic shoulders than asymptomatic shoulders (Left SUVmax 2.0 vs 1.6, SUVmean 1.6 vs 1.3, both P < 0.002; Right SUVmax 2.2 vs 1.8, SUVmean 1.8 vs 1.5, both P < 0.01). For lung cancer patients, bilateral RI SUVmax and SUVmean values were higher in symptomatic shoulders than asymptomatic shoulders. For other cancer patients, symptomatic patients had higher left RI SUVmax/mean than asymptomatic patients after adjustment. CONCLUSION: In symptomatic patients metabolic activities in RI were higher than asymptomatic patients. Adhesive capsulitis should be considered in cancer patients with shoulder symptoms and positive FDG uptake in RI.
ABSTRACT
PURPOSE: Erlotinib, a small molecule inhibitor of the tyrosine kinase (TK) domain of epidermal growth factor receptor (EGFR), increases survival of advanced non-small cell lung cancer patients who failed standard chemotherapy (Phase III study). We evaluated whether erlotinib is also effective at an early stage of primary lung tumorigenesis in a carcinogen-induced lung tumor model in mice. METHODS: Sixteen weeks after carcinogen (urethane) injection, when small self-contained adenomas are evident, male and female A/J mice were treated IP with 10 mg/kg erlotinib or Captisol vehicle daily over 3.5 weeks (15 mice per group). The efficacy, metabolism and mechanism of action of erlotinib were evaluated. RESULTS: Erlotinib reduced tumor burden in males by twofold compared to vehicle (12.7 +/- 1.2 vs 26.2 +/- 2.5 mg, respectively; p < 0.0001), while tumor burden in erlotinib-treated females slightly increased compared to vehicle by 21% (15.1 +/- 1.2 vs 11.9 +/- 0.9 mg, respectively; p < 0.05). Tumor multiplicity, in contrast, was unaffected by erlotinib. The levels of erlotinib that accumulated in plasma, lung tumor tissue and adjacent uninvolved (UI) lung were comparable in males and females. Males, however, accumulated more OSI-420, an active and pharmacologically equipotent metabolite of erlotinib, than females in plasma, lung tumors, and UI lung. In both genders, 80% of tumors contained Kras mutations at codon 61, but no EGFR mutations were detected. The cellular distribution and concentration of EGFR were also similar between genders. In control mice, however, phosphorylated EGFR (pEGFR) levels were nearly 2.5-fold higher in males compared to females in UI lungs and sevenfold higher in lung tumors. Further, erlotinib decreased the contents of pEGFR in UI lungs and lung tumors, particularly in males. CONCLUSIONS: Adenomas from male mice in this early lung cancer model are responsive to erlotinib treatment, possibly because of a greater dependence of male tumor growth on the EGFR pathway compared to females. Importantly, these results indicate that small lung adenomas from male mice that utilize EGFR signaling but also harbor Kras mutations shrink in response to erlotinib, suggesting that erlotinib may be beneficial for some patients very early during lung cancer progression.
