Phase I trial of gemcitabine (Gemzar), 24 h infusion 5-fluorouracil and folinic acid in patients with inoperable pancreatic cancer

Gemcitabine (Gemzar) has a significant impact upon survival and quality of life for patients with pancreatic cancer, compared with 5-fluorouracil (5-FU). This phase I study was initiated to define the recommended dose of 5-FU delivered as a 24 h infusion in combination with gemcitabine (1000 mg/m2) and folinic acid (200 mg/m2) in patients with inoperable pancreatic cancer, treated on an outpatient basis. Drugs were administered weekly for 4 weeks out of 6 weeks. Sixteen chemonaive patients (median age 59 years, range 51-66) were enrolled, 15 had stage IV and one stage III disease. The median Karnofsky performance score (KPS) was 70 (range 60-80). Six patients received 5-FU 750 mg/m2, eight received 5-FU 1000 mg/m2 and two received 5-FU 1250 mg/m2. The maximum tolerated dose of 5-FU was 1000 mg/m2. Hepatotoxicity was dose limiting. One patient who received 5-FU 1250 mg/m2 died as a result of hepatorenal failure. There was one partial response, nine patients had stable disease for more than 3 months and 13 patients had improved KPS. The median time to progressive disease was 31 weeks (range 5-50 weeks). A phase 11 trial is underway to further assess the activity of this combination at the recommended dose of 750 mg/m2 5-FU.     

Serum p53 autoantibodies in patients with minimal lesions of ductal carcinoma in situ of the breast

Five of 43 patients (11.6%) with ductal carcinoma in situ of the breast presented with p53 autoantibodies at diagnosis. Three seropositive patients demonstrated tumour sizes of < or = 5 mm. There was no association of p53 autoantibody status with age, clinical presentation, histological subtype, tumour size, grading, p53 immunohistochemistry or hormone receptor status.     

Post-traumatic stress disorder in cancer: a review

The stressor criterion for Post-Traumatic Stress Disorder (PTSD) has been recently modified to include life-threatening illnesses, such as cancer, as precipitating traumatic events. We sought to examine the empiric evidence for cancer's inclusion as a traumatic stressor. Nine published studies assessing PTSD in cancer survivors and/or family members were identified in the literature. The studies were predominantly small (n<100) and cross-sectional. Study target groups included one or more of the following: children cancer survivors, parents of pediatric survivors and adult cancer survivors. There was considerable inter- and intra-study variability in the type and stage of cancer diagnosed and in the type of treatment regimens participants had undergone. Only three studies utilized a validated PTSD diagnostic tool to evaluate the disorder. Evidence of full-blown PTSD was found for adults and parents, and for children in all but one instance. These results suggest that a PTSD symptom assessment provides valuable clinical information concerning the post-treatment adjustment of cancer survivors and their immediate family members.     

Cervical cysts: Cancer until proven otherwise?

A cystic neck mass can be either malignant or benign; 22% of patients (4/18) admitted with the tentative diagnosis of branchial cyst in a recent 2-year period (1977-1979) had metastatic carcinoma: epidermoid, thyroid or salivary gland. Preoperative fine needle aspiration was diagnostic in 1 instance and unhelpful in 2. Frozen section analysis of the gross specimen invariably provided the correct diagnosis. All patients with malignancies had subclinical primary disease and in 1 instance random biopsies identified its origin. The prudent surgeon will avoid untoward results if he approaches a neck cyst in an adult as if it were malignant. Guidelines he can follow to prevent the inadvertent removal of a metastasis under the misapprehension that it is a benign neck cyst include: 1. Prior to operation, perform a thorough head and neck examination to identify a primary carcinoma; 2. Do a fine needle aspiration of the mass for cytology. A negative report must be considered inconclusive; 3. Make a gross examination in the operating room of the opened cyst and frozen section processing of suspicious areas; 4. Follow with a panendoscopy and random biopsies of appropriate areas and omplete the neck dissection on the involved side, after a metastatic deposit has been recognized. The preoperative procurement of contingency consent for these procedures is understood.     

MRI with Gd-DTPA in tumours of larynx and hypopharynx

Twenty-eight patients with tumours of the larynx, divided into supraglottic, glottic, and subglottic lesions, and of the hypopharynx were examined by different MRI techniques using the paramagnetic contrast medium Gd-DTPA. The results of preoperative MRI were compared with clinical laryngoscopy and the pathological tumour classification. The examinations were carried out using plain T1-wand T2-weighted and Gd-DTPA enhanced T1-weighted sequences. Most studies included three slice orientations for optimal assessment of different tumour locations. The most accurate diagnostic information was given by Gd-DTPA-enhanced sequences. The combination of plain images, contrast-enhanced images and subtraction enabled precise assessment of deep infiltration. T2-weighted and proton density sequences conveyed more information about cartilage invasion and liquid-filled structures, but gave more artefacts than T1-weighted images. Laryngoscopy had advantages in T1-classified tumors, as the extent of the tumor could be seen, and offered histological information via biopsy. Diagnostic findings of MRI correlated in 85.7% with the pathologist's report, and laryngoscopy provided exact classification in only 64.3% of patients. Gd-DTPA-enhanced MRI is an important adjunct to non-contrast MR studies, and forms an ideal diagnostic supplement to laryngoscopy. Offprint requests to: T. Vogl     

Parotid gland: plain and gadolinium-enhanced MR imaging

The purpose of this study was to show the typical appearance of lesions of the parotid gland with plain MR imaging and MR imaging enhanced with gadopentetate dimeglumine. Seventeen patients with inflammatory changes and 43 with benign and malignant tumors were studied. The examinations were carried out with plain T1-weighted sequences with a repetition time (TR) of 500 msec and an echo time (TE) of 25 msec (TR/TE = 500/25), T2-weighted sequences (1,600/90), and gadolinium-enhanced T1-weighted sequences in axial, coronal, and sagittal orientations. For identifying normal anatomic structures such as the facial nerve and the main duct, the administration of gadopentetate dimeglumine was helpful. In inflammatory changes, gadolinium-enhanced images showed no diagnostic advantages. Gadopentetate dimeglumine proved helpful in delineating tumorous lesions and in differentiating benign and malignant lesions. However, an exact differentiation of the different histologic types was not possible. Post-operative fibrosis could be differentiated from recurrent tumors after administration of gadolinium. If a question regarding infiltration or definition of the boundaries of a lesion cannot be answered with non-enhanced MR imaging, gadopentetate dimeglumine administration is advised. However, for routine imaging of the parotid gland, its use is not recommended.     

Phase II trial of misonidazole (MISO) and cyclophosphamide (CYC) in metastatic renal cell carcinoma

In animal models pre-treatment with misonidazole, a hypoxic cell radiosensitizer, enhances the antineoplastic effects of alkylating agent chemotherapy. Laboratory data suggest that hypoxic tumor cells may be more resistant to chemotherapy because of suboptimal drug delivery, reduced rates of cell division, or because hypoxia confers relative drug resistance. The therapeutic potential depends on the tumor type, doses of radiosensitizer and alkylating agent, the time interval between drug administration, and the ratio of sensitization of normal and malignant tissues. A Phase II trial of misonidazole and cyclophosphamide was initiated by the Eastern Cooperative Oncology Group to determine the response rate and toxicity in patients with metastatic renal cell cancer. Patients received 5 gm/m2 of misonidazole intravenously two hr before 1200 mg/m2 of cyclophosphamide every 3 wk. Patients with prior chemotherapy or radiotherapy received 1000 mg/m2 of cyclophosphamide. Misonidazole was discontinued after a total dose of 15 gm/m2. The median total misonidazole dose was 23.5 gm (range 4.5-34.5 gm). The median number of cyclophosphamide cycles was 2 (range 1-12). Of the 30 patients evaluable for response, only one patient had an objective partial response. Twenty-nine patients had stable or progressive disease. One patient remains on cyclophosphamide after 9 mo. Estimated median survival is 4.8 mo. There have been no lethal toxicities; however, 9 patients (25%) experienced life-threatening leukopenia and an additional 42% experienced severe hematologic toxicity. Eight patients had WBC less than 1000 on days 7-14 of cycle 1. Thrombocytopenia and grade 3 anemia occurred in 1 and 2 patients, respectively. Moderate or severe nausea and vomiting occurred in 47% and 19% of patients, respectively. Only 3 patients experienced severe neurotoxicity. Four additional patients had moderate neurotoxicity. In summary, misonidazole in this dosing schedule does not enhance the antitumor activity of cyclophosphamide in renal cell carcinoma.     

Cell size and shape changes in the myoepithelium of the mammary gland during differentiation

We have studied changes in myoepithelial cell size and shape during different stages of mouse mammary gland differentiation by using the fluorescent probe for actin NBD-phallacidin. Pieces of mammary tissue were fixed, mounted on slides, permeabilized with cold acetone (-20 degrees C), and then treated with nitrobenzoxadiazole-phallacidin. Myoepithelial cells lining ducts of glands at all stages of development are spindle-shaped structures oriented parallel to the long axis of the duct at the base of the luminal epithelium. In virgin animals, myoepithelial cells also occur as linear tracts oriented parallel to the long axis of small projections along the sides of ducts and terminal end buds. In early pregnancy, small stellate-shaped cells begin to appear around presumptive secretory units. By late pregnancy, larger star-shaped units of intense fluorescence appear at the base of alveoli. During lactation, both cell bodies and cell processes further enlarge as these interlacing stellate-shaped cells encompass the expanded alveoli. In regressing glands, cell size decreases and the processes appear to retract. Although alveoli are virtually absent in the multipartate resting gland, myoepithelial cells remain around lateral buds of ducts. These myoepithelial cells have two distinct shapes: small star-shaped cells capping the buds and spindle-shaped cells oriented parallel to the long axis of the buds. A comparison of myoepithelial cell shape in virgin mice and nulliparous women indicates a more developed cell in the human gland at this stage of development. Intact segments of mammary gland combined with NBD-phallacidin as a probe for actin provide an ideal system for future studies of the control of myoepithelial cell size and shape and their influence on cell functions.