John H. Kearsley

Merkel cell tumor. A chemosensitive skin cancer.

The clinical courses of six patients treated with cytotoxic chemotherapy for recurrent Merkel cell tumor of the skin are reported. All patients experienced prompt clinical responses to chemotherapy five complete response [CR], one partial response [PR] and three patients (50%) have achieved long‐term disease‐free remission. The report highlights (1) the aggressive nature of Merkel cell skin cancer, (2) the highly chemosensitive nature of the disease, and (3) some practical problems in administering chemotherapy to elderly patients.

A comparison of epidermal growth factor receptor (EGFR) and c-erbB-2 oncogene expression in head and neck squamous cell carcinomas.

Summary The proto‐oncogenes c‐erbB‐2 and epidermal growth factor (EGF) receptor which encode 2 closely homologous transmembrane glycoproteins have been found amplified and/or overexpressed in a range of epithelial malignancies. In a series of 46 head and neck squamous cell cancers (SCCs), immunohistochemical reactivity for the EGF receptor was detected in all cases, particularly at the invading edge of cellular islands of SCC and in the basal cells of normal adjacent squamous epithelium. Southern blot analysis demonstrated EGF receptor gene amplification in 3 cases. In contrast, strong membrane staining for the c‐erbB‐2 oncoprotein was not detected in any sample, and there were no cases of c‐erbB‐2 gene amplification. Despite a close structural and (presumed) functional homology between these 2 receptor‐oncoproteins in the development of malignancy, we report that their expression in SCCs is markedly different. Furthermore, unlike the situation for breast cancer, quantitation of the c‐erbB‐2 or EGF receptor oncoproteins is unlikely to yield important prognostic information in this group of patients.

Prognostic significance of tumor ploidy in patients with advanced ovarian carcinoma

Abstract Fresh tumor specimens obtained from 53 consecutive patients with FIGO Stage III ovarian carcinoma were analyzed by flow cytometry. All patients were treated by a standard protocol: maximal tumor excision and cisplatin/cyclophosphamide/adriamycin chemotherapy, and followed-up for at least 24 months. Thirty-two percent of tumors were diploid (DNA index=1.00) and 68% aneuploid (DNA index > 1.00), with more aneuploid tumors being associated with larger residual tumor and poor cellular differentiation. Patients with diploid tumors were found to survive significantly better than those with aneuploid tumors, in terms of survival rate (65% versus 31%), median survival time (33 months versus 13 months), and mean disease-free interval (17.8 months versus 8.2 months). The influence of the amount of residual tumor after primary surgery on survival was only significant in patients with diploid tumors. Our results support previous findings that tumor ploidy is an important prognostic indicator in ovarian cancer. We found aneuploidy to be associated with a poorer clinical outcome in Stage III disease, regardless of the amount of residual tumor after primary surgery and the degree of cellular differentiation.

Serial D-dimer levels in the assessment of tumor mass and clinical outcome in ovarian cancer

D-dimer (DD)--an end product of fibrinolysis--was measured in serum by enzyme immunoassay using a monoclonal antibody to the gamma gamma crosslink in patients with ovarian cancer, before primary surgery and during chemotherapy for 12 months or more. Serial DD levels were found to have a high sensitivity for the detection of tumor in patients with subclinical disease (91%) as well as for predicting progression of disease (100%). As determined by a careful second-look laparotomy in patients with complete clinical remission the DD marker was highly predictive of tumors less than 1 cm. The negative predictive value (82%) was higher than the positive predictive value (69%). However, there were 31% of the patients who showed a false-positive result; a close examination of the clinical data of these 9 patients failed to reveal an explanation for the positive DD levels. Despite the lack of specificity (50% in the present series), the findings support the use of DD in the assessment of patients with ovarian cancer, especially those with subclinical disease.

Chemosensitivity testing of primary cultures of Merkel cell cancer.

Twenty-seven tumor specimens from patients with Merkel cell carcinoma (MCC) were tested for chemosensitivity against a battery of nine cytotoxic drugs in a short-term antimetabolic assay measuring inhibition of thymidine incorporation. Dose-response curves were constructed by plotting drug concentration in μg/ml versus % control [3H]thymidine incorporation. Specimens were considered ‘sensitive’ to a drug if, at the approximate peak plasma concentration (PPC), the inhibition of [3H]thymidine was greater than 50% when compared with untreated control primary cultures. The assay revealed a ‘sensitive’ tumor in 19 of 20 specimens and 16 of 17 patients had a tumor that was ‘sensitive’ to at least one drug tested in the assay system. The highest sensitivity in order of frequency was found with doxorubicin, epirubicin, cyclophosphamide, etoposide and cisplatin. At least 40% of the tumors were ‘sensitive’ to these five drugs. Cyclophosphamide was chosen as the most active drug (at PPC) in 10 of 19 assays (53%), etoposide in seven of 17 (41%), doxorubicin in four of 19 (21%), chlorambucil in one of 12 (8%) and cisplatin in one of 18 (5%) of assays. Though our results are preliminary, we have identified for the first time a range of cytotoxic drugs which appear effective against MCC in vitro. Our main task now is to determine whether our in vitro predictive assay will correlate with clinical benefit to the patient.

HPV DNA in oropharyngeal squamous cell cancers: comparison of results from four DNA detection methods

&NA; Oropharyngeal squamous cell cancers (SCCs) were examined for human papillomavirus (HPV) related DNA sequences. The techniques employed were Southern blotting under stringent and non stringent conditions, dot blotting, primer directed gene amplification using the polymerase chain reaction (PCR), and in‐situ hybridization. HPV 16 DNA was found in 4 of 30 tumor samples using PCR. HPV 16 DNA was found in 2 further tumors using in‐situ hybridization. No HPV DNA could be found by Southern blot or dot blot in any tumor sample. The Southern blot assays were sensitive enough to detect clonally integrated HPV 16 DNA of length greater than 250 bp in the tumors. While HPV DNA is present in some oropharyngeal SCCs, there is no molecular evidence to support a causal association of HPV 16 gene products with continued tumor growth in oropharyngeal cancer.

Antiemetic superiority of lorazepam over oxazepam and methylprednisolone as premedicants for patients receiving cisplatin-containing chemotherapy

Lorazepam, oxazepam, and methylprednisolone were compared for antiemetic efficacy in patients receiving cisplatin chemotherapy. Three consecutive courses of cisplatin‐containing chemotherapy were administered at equal doses so that each patient acted as his own control. Of 100 patients randomized, 85 received at least two of the three agents and were evaluable for analysis. Lorazepam significantly reduced the number of patients with more than ten vomits compared to either oxazepam (P < 0.05) or methylprednisolone (P < 0.001). Lorazepam also significantly reduced the number of patients with the most severe degrees of vomiting compared to either oxazepam or methylprednisolone (both P < 0.005). The duration of vomiting was reduced significantly after the first 48 hours postchemotherapy for those patients receiving lorazepam over those receiving methylprednisolone (P < 0.05). Lorazepam significantly reduced the number of patients with severe nausea compared to both oxazepam and methylprednisolone (both P < 0.05), but there were no significant differences in duration of nausea among the groups. The results of linear analogue self‐assessment scores indicated a strong patient preference for lorazepam over both oxazepam and methylprednisolone. Drowsiness was significantly more common with both lorazepam and oxazepam compared to methylprednisolone (both P < 0.001). Patients who received lorazepam or oxazepam also experienced significantly more severe drowsiness than those patients receiving methylprednisolone (both P < 0.01). Lack of recall was significantly more common with lorazepam than with oxazepam and methylprednisolone (both P < 0.001) and was more profound when lorazepam was compared with oxazepam (P < 0.05) and with methylprednisolone (P < 0.001). Methylprednisolone was administered with minimal side effects. The results of this randomized cross‐over study indicate that, in the dosage/schedule used, lorazepam is a significantly superior premedicant than is either oxazepam or methylprednisolone in alleviating the distress of cytotoxic‐induced emesis in patients receiving cisplatin‐containing chemotherapy.

A clinical and flow cytometric analysis of patients with nasopharyngeal cancer

Abnormal cellular DNA content, a hallmark of malignancy, is known to be an important prognostic factor in many human solid tumors; however, no data have been published on whether cellular DNA content carries prognostic significance for patients with nasopharyngeal cancer (NPC). Archival, formalin‐fixed, paraffin‐embedded pathology specimens representing pretreatment tissue biopsies from 55 patients (41 men and 14 women) with NPC were analyzed for cellular DNA content in a retrospective fashion from 1968 to 1988. Individual tumors were classified as either lymphoepithelioma, squamous cell, or anaplastic carcinoma, and were staged according to International Union Against Cancer (UICC) criteria. All patients were treated with curative intent using a 4 to 6 MeV linear accelerator to total doses ranging from 50 to 60 Gy in 4 to 6 weeks. The overall 5‐year actuarial survival for all 55 patients was 44.4% (men, 41%; women, 52%). Survival by T stage was as follows: T1, 65%; T2, 51%; T3, 36%; and T4, 27%. Similarly, the 5‐year survival rate declined as the bulk of nodal metastases increased: NO, 62%; N2, 50%; N3, 37%; and N1, 25%. Patients who had anaplastic carcinoma had a 5‐year survival of 73%, those with lymphoepithelioma had a 60% survival, and those with squamous cell cancer (SCC) had a 30% survival. There was a statistically significant difference in 5‐year survival between patients with SCC and those with nonkeratinizing histologies (P < 0.05). In addition, there was a significant association between patients older than 40 years of age with SCC and patients younger than 40 years of age with nonkeratinizing malignancies (P < 0.01). Of the 55 tumors successfully analyzed, 22 (40%) were diploid and 33 (60%) were aneuploid. The mean coefficient of variation (CV) of all 55 samples was 6.17%. There was no significant difference in 5‐year survival between patients with diploid and those with aneuploid tumors (48% versus 42%). Furthermore, there was no statistically significant survival difference between aneuploid and diploid tumors within any one histologic subgroup. There was also no significant survival difference related to the DNA index. The results indicate that the extent of local tumor spread is still the most important prognostic factor for patients treated with radiotherapy for NPC. The data support the conclusion that patients with lymphoepithelioma and anaplastic carcinomas have a superior survival to patients with squamous cell carcinoma. Although the authors were unable to demonstrate a significant prognostic influence of cellular DNA content on outcome for patients with NPC, the study was relatively small and should be repeated with larger, ideally Chinese‐based data bases.

Measurement of tumor cell activity in short-term primary culture: Clinical significance in women with ovarian cancer

In vitro activity was determined by primary culture of tumor samples obtained at surgery from 63 patients with Stage III ovarian cancer. These patients had completed at least 24 months of follow‐up. Proliferative activity was measured after 3‐hour culture by 3H‐thymidine incorporation and metabolic activity by 3H‐uridine incorporation. A large range of individual tumor activity was found; no correlation was present between proliferative and metabolic activity in the same tumor, the distribution of tumors with high and low activity was similar between histologic types, and the activity was not higher in undifferentiated tumors. There was a strong association between in vitro activity of the tumor and patient outcome (both clinical status and survival). On the basis of in vitro activity, a subset of patients was identified within subgroups with known amount of residual tumor; proliferative activity was a better predictor of good outcome in patients with no residual disease, whereas metabolic activity was better in those with more extensive disease. In these patients, a tumor showing high proliferative and/or metabolic activity (>5000 cpm) was associated with poor survival.