Gallbladder cancer is a rare malignancy of the biliary tract with a poor prognosis, frequently presenting at an advanced stage. While rare in the United States overall, gallbladder cancer has an elevated incidence in geographically distinct locations of the globe including Chile, North India, Korea, Japan and the state of New Mexico in the United States. People with Native American ancestry have a much elevated incidence of gallbladder cancer compared to Hispanic and non-Hispanic white populations of New Mexico. Gallbladder cancer is also one of the few bi-gendered cancers with an elevated female incidence compared to men. Similar to other gastrointestinal cancers, gallbladder cancer etiology is likely multi-factorial involving a combination of genomic, immunological, and environmental factors. Understanding the interplay of these unique epidemiological factors is crucial in improving the prevention, early detection, and treatment of this lethal disease. Previous studies have failed to identify a distinct genomic mutational profile in gallbladder cancers, however, work to identify promising clinically actionable targets is this form of cancer is ongoing. Examples include, interest in the HER2/Neu signaling pathway and the recognition that chronic inflammation plays a crucial role in gallbladder cancer pathogenesis. In this review, we provide a comprehensive overview of gallbladder cancer epidemiology, risk factors, pathogenesis, and treatment with a specific focus on the rural and Native American populations of New Mexico. We conclude this review by discussing future research directions with the goal of improving clinical outcomes for patients of this lethal malignancy.
A retrospective review of 240 patients with T1/T2 squamous cell carcinomas of the larynx was performed. Seventy-two per cent had glottic primaries, 27 per cent had supraglottic tumours and one per cent had subglottic disease. Sixty-nine per cent presented with T1 disease and 31 per cent had T2 staged tumours. All patients were treated with definitive radiotherapy between 1973 and 1997. With a median follow-up of 68 months, 68 patients (28 per cent) have developed 72 other cancers. Ten of 68 presented with synchronous primaries (15 per cent). Thirty per cent of glottic patients and 25 per cent of the supraglottic/subglottic patients developed second cancers. The most frequent second malignancy was lung cancer: 28/72 (39 per cent). Fifteen patients developed second head and neck cancers (21 per cent). Other second primary sites included oesophagus (eight), prostate (six), colorectal (five), breast (two) and others (eight). The median time from radiotherapy until the development of a second cancer was 31 months. The Kaplan-Meier survival estimate at five years was significantly less for those patients developing second cancers (55 per cent) compared to those not developing second malignancies (70 per cent), (p<0.05). The median survival from the development of a second cancer was 14 months. More died as a result of a second cancer (41 patients) than their primary laryngeal cancer (40 patients). Second cancers are common and deadly in patients with early stage laryngeal carcinoma.
Lessons Learned.
Colorectal cancers exhibit a high level of cyclooxygenase‐2 (COX‐2) expression with strong preclinical rationale for improved clinical outcomes with COX‐2 inhibition. Celecoxib is a COX‐2 inhibitor and we have shown that it can be safely combined with capecitabine and oxaliplatin as part of neoadjuvant treatment with radiation therapy (RT) in rectal cancer.There was a significant improvement in skin toxicity with this combination as compared with historical data. Considering the field has moved on to single‐agent capecitabine, we believe future trials with capecitabine and celecoxib hold potential.Background.Improved survival is seen among patients with rectal cancer who achieve pathologic complete response (pCR) after neoadjuvant therapy. Cyclooxygenase‐2 (COX‐2) expression is increased in gastrointestinal malignancies and it may serve as a target to enhance pathologic response. A trial combining chemoradiation and COX‐2 inhibition was conducted to evaluate the pCR rate, surgical outcomes, survival, and treatment toxicity.Methods.Patients with resectable (T3‐4, N1‐2) rectal cancer within 12 cm of the anal verge were included in this phase II clinical trial. The neoadjuvant treatment consisted of capecitabine 850 mg/m2 b.i.d. Monday through Friday for 5 weeks, weekly oxaliplatin 50 mg/m2 intravenous (IV), celecoxib 200 mg b.i.d. daily, along with concurrent 45 gray radiation therapy in 25 fractions.Results.Thirty‐two patients were included in the final analysis. The primary endpoint was pCR: 31% (95% confidence interval [CI]: 16%–50%). Secondary endpoints were surgical downstaging (SD): 75% (95% CI: 57%–89%) and sphincter‐sparing surgery (SSS): 56% (95% CI: 38%–74%). Common grade >3 toxicities were diarrhea and abnormal liver function tests (9% each). Grade 0 and 1 toxicities included radiation dermatitis (59% and 34%, respectively) and proctitis (63% and 28%, respectively). At 3 years, disease‐free survival and overall survival (OS) were 84% (95% CI: 65%–93%) and 94% (95% CI: 77%–98%), respectively.Conclusion.Chemoradiation with celecoxib in rectal cancer was well tolerated and demonstrated high rates of pCR, SD, and SSS. Improvement in skin toxicity (34% grade 1 and no grade 3/4) as compared with historical results (43%–78% grade 3/4) seems to be a significant improvement with addition of celecoxib to neoadjuvant chemotherapy.
Summary
Familial cerebral cavernous malformations are autosomal dominant conditions that can result in significant morbidity. A two-hit mechanism is accepted as likely responsible for formation of these malformations. We present 2 patients with this disease who received therapeutic radiation and developed very high numbers of malformations within the radiation ports, supporting radiation as an accelerator of lesion formation and suggesting implications for risks of radiation in this disease.
mTOR inhibitors are emerging as important anti-neoplastic agents with a wide range of clinical applications. The topoisomerase I inhibitor irinotecan is a potent DNA damaging drug, with a broad spectrum of anticancer activities. mTOR appears to enhance cancer cell survival following DNA damage, thus the inhibition of mTOR after irinotecan could theoretically show synergistic activities in patients. Both mTOR inhibitors and irinotecan have been used as single agents in soft tissue sarcomas with limited efficacy. We completed a phase I trial of the combination of the mTOR inhibitor, temsirolimus, and irinotecan in patients with advanced soft tissue sarcoma. Seventeen patients were recruited. The Phase II recommended dose is 20 mg of temsirolimus and 80 mg/m2 of irinotecan administered on weekly basis for three out of four weeks. Most frequently encountered toxicities include cytopenias, fatigue, and gastrointestinal toxicities. Two patients (one with leiomyosarcoma and one with high grade undifferentiated sarcoma) had stable disease for more than 12 months.
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