Congenital hyposomatotropism in a domestic shorthair cat presenting with congenital corneal oedema.

A six-month-old, female, domestic shorthair cat was presented with a history of failure to grow and bilateral corneal opacity caused by corneal oedema. Congenital hyposomatotropism and possible secondary hypothyroidism were diagnosed on the basis of fasting serum levels of insulin-like growth factor-1 and thyroxine levels, respectively. These endocrinopathies are rare in the cat and have not been reported to cause ocular signs. The cat died during investigation of these diseases, and histopathological examination of the eyes showed significantly reduced corneal endothelial cell density and number of corneal epithelial cell layers when compared with age-matched healthy control corneas. These changes were implicated in the development of the corneal oedema.

Canine keratoconjunctivitis sicca: disease trends in a review of 229 cases.

OBJECTIVES: To investigate the disease patterns in dogs with keratoconjunctivitis sicca referred to the University of Glasgow Small Animal Hospital. METHODS: A retrospective study of 229 cases was carried out. RESULTS: There were 44 breeds in the study, with four breeds, English cocker spaniels, cavalier King Charles spaniels, West Highland white terriers and shih-tzus, making up 58 per cent of the cases. Among these four breeds, two breed-dependent disease patterns, one chronic and one acute, were identified. English cocker spaniels and West Highland white terriers had a mean age at onset of clinical signs of five years and one month and five years and six months, respectively, with more females affected than males. Clinical signs consisted predominantly of conjunctival hyperaemia and mucopurulent discharge, with a relatively low incidence of ulcerative keratitis. In contrast, cavalier King Charles spaniels and shih-tzus showed a more acute disease pattern with a biphasic age distribution at 0 to less than two years of age, and four to less than six and six to less than eight years of age, respectively, with more males affected than females and a significantly higher incidence of ulcerative keratitis in some cases resulting in corneal perforation. CLINICAL SIGNIFICANCE: The study reveals interbreed differences with respect to sex, age and risk of ulcerative keratitis which have not been detailed previously in a referral population.

Randomized trial comparing aminoglutethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma.

A total of 218 postmenopausal patients were entered in a prospective randomized trial comparing aminoglutethimide (AG) and high-dose medroxyprogesterone acetate (MPA) as second-line hormonal therapy for advanced breast carcinoma. All responses were assessed by the criteria of the International Union Against Cancer. The response rates were 27% (29 of 106 patients) for AG and 31% (35 of 112) for MPA, but if stabilization of previously progressive disease is included, then the overall response rates were 51% (54 of 106) and 54% (61 of 112) for patients receiving AG or MPA, respectively. There was no difference in response to the two drugs at any site of disease, and the durations of response and survival were identical for the two drugs. The time to response was significantly shorter for patients treated with MPA (median, 8.7 wk) than for those treated with AG (median, 15.3 wk) (chi 2 = 9.96, 1 df, P = .0016). The percentage of patients experiencing toxic effects was equivalent in both arms, although the patterns and time courses of these effects were different.

Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer.

We report a phase II study of bleomycin, ifosfamide, and cisplatin (BIP) in cervical cancer. Our aims were to assess response rate, toxicity, and survival in women treated with this combination. Among 49 patients, 34 objective responses (69%) were seen, with 10 complete responses (20%). Toxic effects were assessed in 186 treatment cycles. All patients had alopecia and nausea and vomiting. Other effects included myelosuppression, infection, reduction in renal function, and disturbance of consciousness. These data indicate that BIP is highly active against advanced and recurrent cervical cancer.

Cisplatin, etoposide, and radiotherapy in regional inoperable squamous cell carcinoma of the bronchus.

Thirty-three ambulatory patients with limited stage, inoperable, squamous cell carcinoma of the bronchus were administered cisplatin (60 mg/m2 IV on day 1) and etoposide (VP-16) (400 mg/m2 orally in divided doses over days 3, 4, and 5). This regimen was repeated every 28 days for a maximum of six courses. Radiotherapy was given to patients who did not respond to chemotherapy for urgent relief of local symptoms, or as adjuvant to chemotherapy in responding patients. Response to chemotherapy was assessable in 28 patients. Patients experiencing early death were included in the evaluation. Ten patients (36%) had progressive disease and nine (32%) had stable disease during chemotherapy. Eight patients achieved radiologically verified partial response (PR) and one, a complete response (CR) verified bronchoscopically, yielding an overall response rate of 32%. Of responding patients who proceeded to radiotherapy, one patient showing PR was converted to a CR; another patient with PR improved, although not to CR. The median survival of 33 patients was 49 weeks. There were two deaths among nine responding patients (at 38 and 48 weeks), and nine deaths among 19 nonresponders (six before the 27th week). The principle toxic reactions were nausea and vomiting, which were serious (greater than grade 2) in 29 of 33 patients. All patients receiving more than one course of chemotherapy suffered total alopecia. Cisplatin/etoposide is an effective combination in some patients with regional, squamous cell lung cancer, but randomized trials comparing it to radiotherapy alone are required to establish real survival benefit.

The role of ifosfamide in cervical cancer.

A series of phase II studies using ifosfamide as a single agent and in combination with cisplatin and bleomycin (BIP) in advanced and recurrent cervical cancer were coordinated at the West Midlands Cancer Research Campaign Clinical Trials Unit, Birmingham, UK. The aim of these studies was to identify single agents and combination regimens that might be of value for palliation and have potential for neoadjuvant and adjuvant therapy in primary treatment. Ninety-eight patients were studied. Seventy-nine patients with disease not amenable to radical local therapy were treated with single-agent ifosfamide or the BIP combination. In 30 patients treated with single-agent ifosfamide, ten objective responses (33%) were seen, with one complete response. In 49 patients treated with BIP, 34 objective responses (69%) were seen, with ten complete responses (20%). Eleven (79%) of 14 patients with primary inoperable disease had at least a 50% reduction in tumor bulk before radical local radiotherapy. Toxicity resulted in alopecia, nausea and vomiting, myelosuppression, infection, reduction in renal function, and disturbance of consciousness. There was no evidence that neoadjuvant chemotherapy enhanced the acute toxic effects of pelvic radiotherapy. These data indicate that ifosfamide is highly active in cervical cancer and that in combination with bleomycin and cisplatin, it can be used for effective palliation and cytoreduction in around 70% of patients. Ifosfamide-containing regimens have potential for use as neoadjuvant and adjuvant therapy in patients at high risk of recurrence with conventional treatment. These hypotheses are currently being tested in prospective randomized trials.

Glycoprotein patterns in normal and malignant cervical tissue.

Glycoproteins from normal and malignant human cervix were studied using an organ culture system and compared by gel electrophoresis and autoradiography. Five glycoproteins of 178 kDa, 95 kDa, 93 kDa, 82 kDa and 38 kDa and 1 glycolipid (46 kDa) were detected more frequently in squamous carcinomas. Certain glycoproteins were shown to be oncofoetal and some had affinity for Concanavalin A (Con A). The 82 kDa glycoprotein was present in 16/17 squamous carcinomas but in only 1/13 normal cervices. This band represented a glycoprotein containing glucosamine, mannose, small quantities of methionine and no fucose. These preliminary results suggest that these glycoproteins and in particular the 82-kDa glycoprotein are worthy of further investigation and characterisation.

A phase II study of ifosfamide in endometrial cancer.

Around 32% of all patients with endometrial carcinoma relapse after primary therapy. The outlook for these patients is poor. Ifosfamide (IFX) has activity in a number of gynaecological malignancies and was selected for evaluation in this disease. The aims of this study were to assess the activity and toxicity of IFX in recurrent endometrial carcinoma no longer amenable to radical local treatment. In all, 16 evaluable patients with symptomatic advanced metastatic or recurrent disease entered a phase II study of this drug. Patients received IFX (5 g/m2) as a 24-h infusion, with mesna (8 g/m2) given during and for 12 h following IFX to prevent urothelial toxicity. Treatment was repeated every 21 days. Two patients showed evidence of response [one complete response (CR) of 3 months and one partial response (PR) lasting 5 months]. Most patients experienced nausea and vomiting, and WHO grade 3/4 alopecia invariably occurred after two or more cycles. Four patients developed severe (grade 3/4) IFX/mesna CNS toxicity, and four other patients had mild (grade 1/2) CNS toxicity. Significant myelosuppression was seen in 3/41 cycles. Haematuria was uncommon and invariably mild. There were two toxic deaths (one due to grade 4 CNS toxicity and one due to septicaemia). IFX has activity in endometrial carcinoma, but responses are of limited duration and toxicity is considerable.

Neoadjuvant bleomycin, ifosfamide and cisplatin in cervical cancer.

Patients with advanced and bulky early-stage cancer of the cervix have an unfavourable prognosis, which may be improved by initial neoadjuvant, cytoreductive chemotherapy. In a phase II study, coordinated at the West Midlands CRC Clinical Trials Unit, Birmingham, using ifosfamide (IFX) in combination with cisplatin and bleomycin (BIP) in advanced and recurrent cervical cancer, we demonstrated a response rate of 69%. This regimen produces rapid responses with acceptable toxicity and has potential for use as neoadjuvant therapy prior to radical radiotherapy in patients presenting with advanced and bulky early-stage disease. In an initial pilot study of this approach, 13 of 19 patients (68%) with primary inoperable disease showed significant tumour regression prior to radical local radiotherapy. Interim analysis of the first 66 patients entered into a randomized study evaluating the value of this approach has shown complete clinical tumour resolution after radical radiotherapy in 24/32 patients (75%) treated with up to three cycles of BIP prior to radiotherapy vs 19/34 patients (56%) treated with radiotherapy alone. There was no evidence that neoadjuvant chemotherapy enhances the acute toxic effects of pelvic radiotherapy. This approach has the potential for improving the outlook in patients with poor-prognosis primary disease.

Phase II study of combination 4'-epidoxorubicin and mitomycin C in recurrent epithelial ovarian cancer.

Thirty-three evaluable patients who had epithelial ovarian cancer that had not responded to treatment were entered into a phase II study of combination epirubicin and mitomycin C. Epirubicin (65 mg/m2) and mitomycin C (4 mg/m2) were administered separately, each as an i.v. bolus every 4 weeks. Ten patients (30%) had a complete or partial responses. The median duration of response was 20 weeks (range, 9-53). The regimen was well tolerated. Myelotoxicity occurred in four patients requiring hospitalization for septicaemia. Eleven patients had a blood transfusion. Alopecia was common, and nausea and vomiting, though frequent, usually mild. Cardiological toxicity was observed in one patient only. She developed congestive cardiac failure after an acute myocardial infarction. This regimen is active in advanced ovarian cancer that has not responded to prior treatment and warrants further study combination with other active drugs as a first-line regimen for ovarian cancer.

Phase II studies of ifosfamide alone and in combination in cancer of the cervix.

A series of phase II studies using ifosfamide (IFX) as a single agent and in combination with cisplatin and bleomycin (BIP) in advanced and recurrent cervical cancer have been coordinated at the West Midlands CRC Clinical Trials Unit (Birmingham, UK). The aims of these studies were to identify single agents and combination regimens that may be of value for palliation and have potential for use as neoadjuvant and adjuvant therapy at the time of primary treatment. A total of 79 patients with disease non-amenable to radical local therapy were treated with single-agent IFX or the BIP combination. In 30 patients treated with single-agent IFX, 10 objective responses (30%) were seen, with 1 complete response. In 49 patients treated with BIP, 34 objective responses (69%) were seen, with 10 complete responses (20%). Toxicity included alopecia, nausea and vomiting, myelosuppression, infection, reduction in renal function and disturbance of consciousness. These data indicate that IFX is highly active in cervix cancer and, in combination with bleomycin and cisplatin, can be used for effective palliation and cytoreduction in greater than 70% of patients. IFX-containing regimens have potential for use as neoadjuvant and adjuvant therapy in patients at high risk of recurrence with conventional treatment. These hypotheses are currently being tested in prospective randomised trials.

Survival after negative second-look laparotomy.

Complete pathological responses, as defined by multiple negative intraperitoneal biopsies at second-look laparotomy, were recorded in 22 of 120 patients with epithelial ovarian cancer. Patients had been previously treated with either high-dose single agent cisplatinum (19) or total abdominal and pelvic irradiation (3). Nine of 21 (43%) evaluable patients developed recurrent disease after 'negative' second-look laparotomy. The median time to relapse was 15 months (3-19) and the median survival after relapse, 4 months (1-6). One patient remains alive with evidence of disease.

Carboplatin and retroperitoneal fibrosis.

A patient treated for ovarian epithelial cancer by total abdominal hysterectomy (TAH), bilateral salpingo-oophorectomy (BSO), total omentectomy and five courses of single agent carboplatin chemotherapy, developed retroperitoneal fibrosis. This was diagnosed at exploratory laparotomy 6 months after completing treatment. No predisposing drug history existed in this patient. We believe that there have been no previous reports of an association between retro peritoneal fibrosis and carboplatin treatment.

A randomized trial comparing whole abdominal radiotherapy with chemotherapy following cisplatinum cytoreduction in epithelial ovarian cancer. West Midlands Ovarian Cancer Group Trial II.

The potential role of consolidation therapy has been tested in a randomized trial in ovarian cancer. Patients were randomized to receive either whole abdominal radiotherapy using the moving strip technique (n = 56) or one year of chlorambucil (n = 53) following primary surgery, five courses of cisplatinum 100 mg/m2, and second look laparotomy. Overall survival at two years was 35%. There was no significant difference in survival between the two groups, and in spite of the observation that approximately 50% of the patients were optimally debulked prior to consolidation, no subgroups in either arm could be identified who might benefit from consolidation therapy. Toxicity was considerable in both arms, and almost 50% of patients were unable to complete the planned treatment in both arms. These results suggest that after primary surgery and cisplatinum chemotherapy, there is no indication for consolidation therapy with either radiotherapy or alkylating agents.

The West Midlands epithelial ovarian cancer adjuvant therapy trial.

In a multicentre prospective randomized controlled trial, single agent cisplatinum was compared with whole abdomino-pelvic moving strip radiotherapy in the management of Stage IC-III epithelial ovarian cancer patients who had no macroscopic residual disease after primary surgery. Over a 6-year period 40 eligible patients were recruited, 15 of whom had Stage III disease. The overall 5-year survival was 60% with no significant survival difference between the treatment groups. Acute toxicity was common in both arms and six (11%) patients experienced significant long term disability.