Buccal Epithelium, Cigarette Smoking, and Lung Cancer: Review of the Literature.

Lung cancer is currently the leading cause of cancer-related mortality among men and women in the United States, and optimal screening methods are still lacking. The field effect is a well-supported phenomenon wherein a noxious stimulus triggers genetic, epigenetic and molecular changes that are widespread throughout the entire exposed organ system. The buccal epithelium is an easily accessible part of the respiratory tree that has good potential of yielding a surrogate marker for the field effect in cigarette smokers, and thus, a noninvasive, reliable lung cancer screening method. Herein, we review the literature on the relationship between the buccal epithelium, cigarette smoking, and lung cancer.

Pericardial Metastasis From Recurrent Squamous Cell Carcinoma of Hypopharynx in a Living Patient.

Cardiac metastatic disease is a rare finding and is usually diagnosed incidentally postmortem; it has been commonly reported in patients with cancers of lung, esophagus, breast, and melanoma. We present a case of a 62-year-old male with a history of squamous cell carcinoma of the pyriform sinus who presented with shortness of breath for one day. He underwent tumor resection followed by chemotherapy and radiotherapy seven months before this presentation. Computed tomography (CT) of the chest revealed pericardial nodular soft tissue that was consistent with the diagnosis of metastatic carcinomatosis. Further imaging with a transthoracic echocardiogram (TTE) showed a likely metastatic pericardial mass. The patient had presented with shortness of breath three months prior to this admission and TTE had demonstrated pericardial effusion. However, pericardial fluid cytology was negative for malignancy, and the repeat TTE had revealed resolution of the pericardial effusion. On the current admission, CT of the neck demonstrated local recurrence of the tumor in the resection bed with scattered regional lymph nodes enlargement. Thus, we report a case of a recurrent laryngopharyngeal tumor with very rarely reported pericardial metastasis.

Isolated Enteric Myeloid Sarcoma as a Rare Etiology of Small Bowel Obstruction in a Young Female Patient.

Myeloid sarcoma (MS) is an extra-medullary solid tumor consisting of myeloid blasts or immature myeloid cells. MS is usually associated with acute myeloid leukemia (AML) and other myeloproliferative neoplasms or myelodysplastic disorders. Isolated MS is a rare clinical entity, and the small bowel is a rare phenomenon for the occurrence of MS. A 30-year-old African American female patient with a past medical history of asthma presented with acute abdominal pain and vomiting for 3 days. Imaging revealed small bowel obstruction with a transition point at a suspicious mass in the distal ileum mimicking carcinoid tumors. She underwent an uneventful laparoscopic resection of this mass with primary bowel anastomosis. Histopathology of the resected mass revealed immature myeloid cells that stained positive for myeloperoxidase and CD34/CD117, in keeping with a small bowel MS. A bone marrow examination was negative for concurrent AML. Cytogenetic analysis revealed MYH11/CBFB fusion and an inversion 16 chromosomal aberration which are rarely associated with myeloid disorders. The patient was commenced on systemic chemotherapy to achieve remission and prevent progression to AML. The literature is reviewed, and all cases of small bowel MS are presented in this report. Non-leukemic small bowel MS is an exceptional presentation. We described a case of isolated enteric MS, which was associated with a rare MYH11/CBFB fusion and inversion 16 chromosomal aberration. The diagnosis of small bowel MS can be extremely challenging due to the rarity of the disease and non-specific nature of clinical and radiological features. A histopathological examination with immunohistochemistry staining is imperative to establish an accurate diagnosis. Isolated small bowel MS deserves special attention as it warrants systemic chemotherapy to prevent transformation into AML.

Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2.

PURPOSE: Preclinical studies indicate that gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE), an orally active epidermal growth factor receptor tyrosine kinase inhibitor, may enhance antitumor efficacy of cytotoxics, and combination with paclitaxel and carboplatin had acceptable tolerability in a phase I trial. Gefitinib monotherapy demonstrated unparalleled antitumor activity for a biologic agent, with less toxicity than docetaxel, in phase II trials in refractory, advanced non-small-cell lung cancer (NSCLC). This phase III, randomized, placebo-controlled, double-blind trial evaluated gefitinib plus paclitaxel and carboplatin in chemotherapy-naive patients with advanced NSCLC. PATIENTS AND METHODS: Patients received paclitaxel 225 mg/m(2) and carboplatin area under concentration/time curve of 6 mg/min/mL (day 1 every 3 weeks) plus gefitinib 500 mg/d, gefitinib 250 mg/d, or placebo. After a maximum of six cycles, daily gefitinib or placebo continued until disease progression. End points included overall survival, time to progression (TTP), response rate (RR), and safety evaluation. Results A total of 1,037 patients were recruited. Baseline demographic characteristics were well balanced. There was no difference in overall survival (median, 8.7, 9.8, and 9.9 months for gefitinib 500 mg/d, 250 mg/d, and placebo, respectively; P =.64), TTP, or RR between arms. Expected dose-related diarrhea and skin toxicity were observed in gefitinib-treated patients, with no new significant/unexpected safety findings from combination with chemotherapy. Subset analysis of patients with adenocarcinoma who received > or = 90 days' chemotherapy demonstrated statistically significant prolonged survival, suggesting a gefitinib maintenance effect. CONCLUSION: Gefitinib showed no added benefit in survival, TTP, or RR compared with standard chemotherapy alone. This large, placebo-controlled trial confirmed the favorable gefitinib safety profile observed in phase I and II monotherapy trials.

EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-Expressing Breast Cancer.

PURPOSE: Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression. PATIENTS AND METHODS: Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigator's choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3). RESULTS: Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC. CONCLUSION: Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.

A phase II multicenter study of L-alanosine, a potent inhibitor of adenine biosynthesis, in patients with MTAP-deficient cancer.

OBJECTIVE: Methylthioadenosine phosphorylase (MTAP)-deficient tumors are dependent on the de novo purine synthesis pathway. These cancers are potential targets for selective chemotherapy with inhibitors of de novo adenine synthesis such as L-alanosine [L-2-amino-3-(N-hydroxy-N-nitrosamino) propionic acid]. This phase II study was designed to evaluate the efficacy and safety of L-alanosine in patients with MTAP-deficient solid tumors. METHODS: Patients with mesothelioma, non-small cell lung cancer (NSCLC), soft tissue sarcoma, osteosarcoma, or pancreatic cancer whose tumors were MTAP deficient by immunohistochemistry were eligible. Patients received L-alanosine at a starting dose of 80 mg/m(2) by continuous intravenous infusion daily for 5 days every 21 days. Computed tomography scans or magnetic resonance imaging were performed every 3 cycles. RESULTS: 65 patients (16 mesothelioma, 13 NSCLC, 15 soft tissue sarcoma, 7 osteosarcoma, 14 pancreatic cancer) were enrolled at 19 centers; 55 were evaluable for response. There were no objective responses; 24% had s disease, including 2 patients with mesothelioma who had prolonged stable disease lasting 7.5 and 15.2 months, respectively. Grade 3/4 toxicities included mucositis 11%, fatigue 6%, nausea 3%, and renal failure 1.5%. CONCLUSION: At this dose and schedule, L-alanosine was ineffective in patients with advanced MTAP-deficient tumors.

Phase I study of a novel pro-apoptotic drug R-etodolac in patients with B-cell chronic lymphocytic leukemia.

R-etodolac is a novel pro-apoptotic agent with potential antitumor activity against B-cell chronic lymphocytic leukemia (B-CLL). This phase I clinical trial was conducted to determine the tolerability, safety, and maximum tolerated dose (MTD) of R-etodolac, administered orally twice a day (BID), in patients with B-CLL. Secondary objectives included evaluating clinical response, pharmacodynamic activity (reduction of lymphocytes), and pharmacokinetic (PK) profile. Forty-three patients were enrolled in the study. The most frequently reported adverse events were diarrhea, rash, pruritus, and headache. Increases in alanine aminotransferase (ALT) were also observed. Adverse events were generally mild and self-limiting, although in an apparent dose-response relationship, grade 2 and 3 gastrointestinal toxicities and grade 3 skin toxicities were reported with the highest dose regimens (1,800 and 2,400 mg BID). Hematologic toxicity was rare. The MTD was determined to be 1,200 mg BID. PK results indicated that oral absorption of R-etodolac was rapid (time to maximum concentration ranged from 2 to 4 h), and the half-life ranged from 5 to 7 h. The increase in maximum concentration, however, was not proportional to the increase in dose. R-etodolac significantly reduced absolute lymphocyte count (ALC) in B-CLL patients in a dose-dependent manner up to 1,800 mg BID and caused partial responses in 2 patients. Further study of R-etodolac as a possible new maintenance therapy or as a part of combination therapy of B-CLL appears warranted.

A randomized controlled trial of darbepoetin alfa administered as a fixed or weight-based dose using a front-loading schedule in patients with anemia who have nonmyeloid malignancies.

BACKGROUND: The effect of using fixed versus weight-based doses for erythropoietic agents has not been reported previously. To investigate this issue, the authors conducted a randomized Phase II study of darbepoetin alfa administered as either a fixed dose or a weight-based dose using an accelerated correction and maintenance dosing regimen (front-loading). METHODS: During the correction phase, patients with anemia (hemoglobin < 11.0 g/dL) who had nonmyeloid malignancies and who were receiving chemotherapy were given darbepoetin alfa at a fixed dose of 325 microg (n = 122) or at a weight-based dose of 4.5 microg/kg (n = 120) once weekly until they achieved a hemoglobin concentration > or = 12.0 g/dL. Patients then received darbepoetin alfa (325 microg or 4.5 microg/kg) once every 3 weeks for the remainder of the 16-week treatment period (maintenance phase). RESULTS: Darbepoetin alfa resulted in high Kaplan-Meier rates of hematopoietic response (> or = 2 g/dL increase from the baseline level or a hemoglobin level > or = 12 g/dL) in both the fixed-dose group (86%; 95% confidence interval [95% CI], 78- 94%) and the weight-based dose group (84%; 95% CI, 76-92%). The median time to hematopoietic response was 34 days (95% CI, 28-44 days) for the fixed-dose group and 36 days (95% CI, 30-45 days) for the weight-based dose group. Hemoglobin concentrations were maintained at target levels for up to 16 weeks in both groups. Darbepoetin alfa was well tolerated, and no clinically significant differences between fixed doses and weight-based doses were observed. CONCLUSIONS: Darbepoetin alfa was effective when administered as either a fixed dose or a weight-based dose using a front-loading approach to rapidly correct anemia and effectively maintain hemoglobin levels in patients with anemia who had malignant disease.