Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial

BACKGROUND: Gefitinib has demonstrated activity in patients with non-small cell lung cancer (NSCLC). Clinical trials have not demonstrated a relationship between response to gefitinib and over-expression of the epidermal growth factor receptor (EGFR). Although, EGFR is not over-expressed in small cell lung cancer (SCLC), we postulated that gefitinib might affect tumor growth through other mechanisms. Agents that are active in NSCLC usually are also effective in SCLC. METHODS: The primary objective was to assess the clinical control rate: complete response (CR) partial response (PR) and stable disease (SD > 90 days), of gefitinib in patients with chemo-resistant and chemo-sensitive small cell cancers. Eligibility criteria included pathologic proof of a neuroendocrine tumor, especially small cell cancer, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, prior treatment with one or two prior chemotherapy regimens and adequate end-organ function. Patients received gefitinib, 250 mg p.o. daily until disease progression or intolerable side effects. RESULTS: From April 2003 to March 2004, 19 patients were enrolled. Small cell lung cancer accounted for 18 of the 19 patients and one patient had metastatic Merkel cell carcinoma. Twelve patients (63%) had chemo-sensitive disease, defined as progression greater than three months from completion of prior chemotherapy; 7 (37%) had chemo-refractory disease; 13 (68%) had one prior chemotherapy regimen. Other patient characteristics: mean age 64 years (range 52-79 years); ECOG PS 0/1/2 = 7/9/3, M:F = 9:10. Grade 3 toxicities included: fatigue in three patients (15.8%), pulmonary toxicities in three (15.8%) and one patient (5.3%) each with hyperglycemia or pain. Four patients had grade four toxicities: one patient (5.3%) with fatigue and three patients (15.8%) with dyspnea. There were no patients with grade 3 or 4 rash or diarrhea. Two patients had stable disease (<90 days) and 17 had progressive disease as their best response. This study was a two-stage design and because the continuing criterion for stage one was not met, stage 2 was not performed. Median time to progression (TTP) was 50 days (95% CI = 21-58 days). One year overall survival (OS) was 21% (95% CI = 6-45.6%). CONCLUSION: Although gefitinib has activity in select patients with NSCLC, this study failed to demonstrate benefit in patients with small cell lung cancer.     

Ifosfamide: an active drug in the treatment of adenocarcinoma of the pancreas

From April 1982, until February 1984, 29 patients with biopsy-proven and measurable adenocarcinoma of the pancreas were treated with ifosfamide. Ifosfamide was administered at a dose of 1.25 to 1.5 g/m2 daily for five consecutive days with courses repeated every three weeks. If no serious toxicity was noted, subsequent dosages were escalated to a maximum of 2.0 g/m2/d. In addition, N-acetylcysteine (NAC) (8 to 12 g/d) was administered (in divided daily doses days 1 through 7) as a urothelial protective agent. Nausea and vomiting occurred in the majority of the treated patients. Other toxicities noted were mild myelo-suppression, CNS toxicity, and one case of acute renal failure. One complete response (CR) and five partial responses (PR) were observed in 27 evaluable patients (CRs and PRs = 22%). Ifosfamide has definite activity against pancreatic adenocarcinoma. Doses greater than 1.2 g/m2 for days 1 through 5 can be administered without significant toxicity in the majority of patients. Further trials with ifosfamide alone and/or with other agents are warranted.     

Dose distribution in 42 MV roentgen irradiation of cervical carcinoma.

The dose distribution obtained with two different techniques for external irradiation of cervical carcinoma is described. The dose to the central area is somewhat higher with the multiple beam technique compared with the newly introduced shielding block technique. The difference between the calculated CRE values for the two techniques is small. When the shielding block is not placed over the area corresponding to the position of the applicators from the previous intracavitary treatment the considerable difference in absorbed dose between the two techniques does not correspond to the difference in the calculated CRE values. A comparison of the relative distributions laterally, in total dose and CRE, shows that for central volumes the relative CRE is much higher than the relative dose, when the normalization is made at the pelvic wall.     

Analysis of the DND1 gene in men with sporadic and familial testicular germ cell tumors

A base substitution in the mouse Dnd1 gene resulting in a truncated Dnd protein has been shown to be responsible for germ cell loss and the development of testicular germ cell tumors (TGCT) in the 129 strain of mice. We investigated the human orthologue of this gene in 263 patients (165 with a family history of TGCT and 98 without) and found a rare heterozygous variant, p. Glu86Ala, in a single case. This variant was not present in control chromosomes (0/4,132). Analysis of the variant in an additional 842 index TGCT cases (269 with a family history of TGCT and 573 without) did not reveal any additional instances. The variant, p. Glu86Ala, is within a known functional domain of DND1 and is highly conserved through evolution. Although the variant may be a rare polymorphism, a change at such a highly conserved residue is characteristic of a disease-causing variant. Whether it is disease-causing or not, mutations in DND1 make, at most, a very small contribution to TGCT susceptibility in adults and adolescents.     

Anabolic Agents and Bone Quality

Background  

The definition of bone quality is evolving particularly from the perspective of anabolic agents that can enhance not only bone mineral density but also bone microarchitecture, composition, morphology, amount of microdamage, and remodeling dynamics.