The Role of 18F-FDG PET/CT on Staging and Prognosis in Patients with Small Cell Lung Cancer.

BACKGROUND: We evaluated 18F-FDG PET/CT in small cell lung cancer (SCLC) staging and assessed metabolic (SUVmax, MTV and TLG) and morphologic (CTvol) variables as predictors for overall survival (OS) and progression-free survival (PFS). METHODS: Patients with newly diagnosed, histopathology-confirmed SCLC, who underwent 18F-FDG PET/CT were evaluated. A Cox proportional hazard model was used to determine the association between the primary tumour SUVmax, MTV, TLG and CTvol with OS and PFS. Similar evaluations were performed when hilar/mediastinal lymphadenopathy was included [total SUVmax (TSUVmax), total MTV (TMTV) and total TLG (TTLG)]. RESULTS: 55 patients were included. 18F-FDG PET/CT changed staging in 6/55 (10.9%) patients who were upstaged to extensive disease. TTLG (>443.8) was a significant variable for OS with HR=2.1 (CI 1.14-3.871, p=0.017). Patients with TTLG>443.8 had a median OS of 13.4 months compared to 25.7 months in patients with TTLG<443.8 (p=0.018). TMTV (>72.4) was significant for PFS with HR=2.3 (CI 1.11-4.8, p=0.025). A median PFS of 12.1 and 26.2 months was found with TMTV greater and less than 72.4, respectively (p=0.005). CONCLUSIONS: 18F-FDG PET/CT improved staging of patients with SCLC, and TTLG and TMTV can be used as prognostic variables for OS and PFS, respectively. KEY POINTS: • Identifying variables that predict the prognosis of patients with SCLC is important. • 18F-FDG PET/CT influences staging of patients with SCLC. • Metabolic parameters could be used as predictors for PFS and OS.

Monoclonal antibody CM-H-9 detects circulating placental isoferritin in the serum of patients with visceral metastases of breast cancer.

The aim of the current pilot study was to determine whether placental isoferritin (PLF) can be detected in the serum of patients with metastatic breast cancer. Sera were obtained from breast cancer patients with metastatic disease (n = 100), from breast cancer with no evidence of disease (n = 70) and from healthy female controls (n = 34). PLF and total serum ferritin levels were independently measured using specific monoclonal antibody ELISAs in a double-blind study. It was found that the mean serum PLF levels were significantly elevated only in patients with visceral metastases (lung, liver, brain) compared with the levels of patients with non-visceral metastases (bone, skin) or with healthy controls. Contrary to this, analysis of total serum ferritin levels did not reveal significant differences between these groups. Considering 0-10 units/ml as a PLF negative result, it was found that PLF was negative in 87.5% of healthy controls and in 96% of breast cancer patients with no evidence of disease. In contrast, PLF was positive in 73% of the patients with visceral metastases and in 29.7% of those with non-visceral metastases. The striking difference between visceral and non-visceral metastases is not yet understood. It could result from a difference in the degree of vascularisation or, alternatively, a difference in the cell types and genes expressed by cells metastasizing to visceral or non-visceral organs.

Endometrial pathology in postmenopausal tamoxifen treatment: comparison between gynaecologically symptomatic and asymptomatic breast cancer patients.

AIMS: To evaluate whether endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic rather than in gynaecologically asymptomatic postmenopausal breast cancer patients with tamoxifen treatment; and to evaluate the possible influence of various clinical factors on the incidence of endometrial pathology. METHODS: Endometrial histological findings, transvaginal ultrasonographic endometrial thickness, demographic characteristics, health habits, and risk factors for endometrial cancer were compared between 14 gynaecologically symptomatic (group I) and 224 gynaecologically asymptomatic (group II) postmenopausal breast cancer patients with tamoxifen treatment. RESULTS: Overall, 28.6% of the study population had endometrial pathology. The incidence of overall positive endometrial histological findings was significantly higher in group I than in group II (92.9% v 24.6%, p < 0.0001). Atrophic endometrium was more common in group II than in group I (75.3% v 7.1%, p < 0.0001). Most other endometrial pathology was significantly more common in group I than in group II (endometrial hyperplasia, 35.7% v 5.6%, p < 0.0001; endometrial polyps, 35.7% v 13.4%, p < 0.0111; endometrial carcinoma, 21.5% v 0.9%, p < 0.0001). Endometrial pathology appeared considerably later in the gynaecologically asymptomatic patients than in gynaecologically symptomatic patients (p = 0.0002). Vaginal bleeding or spotting occurred exclusively in group I. The incidence of endometrial pathology in the entire study population was consistent with that reported elsewhere, and higher than that reported for healthy postmenopausal women. CONCLUSIONS: Endometrial pathology is more likely to be diagnosed in gynaecologically symptomatic postmenopausal breast cancer patients with tamoxifen treatment, and after a shorter duration of time, than in gynaecologically asymptomatic patients.

Antiandrogen withdrawal syndrome with cyproterone acetate.

OBJECTIVES: To determine whether the antiandrogen withdrawal syndrome occurs with the steroidal antiandrogen cyproterone acetate. METHODS: Cyproterone acetate was withheld in 12 patients with progressing androgen-independent metastatic prostate cancer. Eight patients had been receiving cyproterone acetate concomitant with androgen ablation, and in 4 patients it was prescribed after failure of androgen suppression. Time to response and to disease progression were defined by serum prostate-specific antigen (PSA) levels and imaging studies. RESULTS: PSA levels decreased in 5 of the 1 2 patients; in 4 of them (33%), the decrease exceeded 50%. The decline lasted a median of 24 weeks (range 9 to 37.8). All 5 patients had received initial concomitant exposure to androgen ablation and cyproterone acetate. CONCLUSIONS: We recommend that the steroidal antiandrogen cyproterone acetate be added to the list of agents capable of inducing antiandrogen withdrawal syndrome.

[Combination chemotherapy with M-VAC protocol in metastatic urothelial cancer].

The treatment of metastatic urothelial cancer is based on the combination of cisplatin, methotrexate, vinblastine and adriamycin (M-VAC). From November 1994 to May 1997 we treated 25 patients (51 men, 3 women, aged 50-77) with M-VAC. The tumor originated from the urinary bladder in 14 (56%) and the upper urinary tract in 11 (44%). Disease sites included: primary--5 (25%), lymph nodes--17 (68%), lungs--10 (40%), bones--8 (32%), pelvic mass and liver each--4 (16%), with an overall median of 2 (1-5) sites per patient. 9 patients (38%) had complete responses and 8 (32%) had partial responses, for an overall response rate of 68% (95% CI 48.5%-85%). The median duration of response was 15.3 (1.6-29.6+) months. Median survival of responders was 19.1 (4.8-35.7+) months compared to 6.2 (0.7-11.2) for the non-responders (p < 0.05). 13 (52%) of patients are alive, of whom 8 (32%) are free of disease and 5 with a single metastatic site on presentation at follow-up. In the 118 treatment cycles we observed grade III-IV toxicity: myelosuppression 53 (45%), thrombocytopenia 4 (3%), stomatitis 8 (6.7%), diarrhea 3 (2.5%). There were 22 infectious episodes and 1 patient died of sepsis. We achieved a high response rate with the combination M-VAC. However, only a third had long-term disease-free states and treatment was associated with excessive toxicity. Therapeutic approaches with new agents are required to improve the response rate and toxicity.

Solitary conjunctival extramedullary plasmacytoma.

We describe two patients with different adnexal locations of localized extramedullary plasmacytomas, one under the conjunctiva of the caruncle and the other under the tarsal conjunctiva. In both general physical examination and ancillary tests, including bone marrow aspiration, were normal. Because immunohistochemical studies of the tumor showed no immunoglobulin secretion and electrophoresis and immunoelectrophoresis of the serum and urine were normal, we diagnosed solitary conjunctival extramedullary plasmacytoma in each case.

Genetic analysis of the APC gene regions involved in attenuated APC phenotype in Israeli patients with early onset and familial colorectal cancer.

The genetic basis for the majority of early onset or non-syndromic "familial" colorectal cancer (CRC) is unknown. Attenuated APC phenotype is characterized by relatively few colonic polyps, early age at onset of colon cancer compared with the general population, and inactivating germline mutations within specific regions of the APC gene. We hypothesized that germline mutations within these APC gene regions, might contribute to early onset or familial CRC susceptibility. To test this notion, we analysed 85 Israeli patients with either early onset (< 50 years at diagnosis) or familial CRC for harbouring mutations within the relevant APC gene regions: exons 1-5, exon 9 and a region within exon 15 (spanning nucleotides c.3900 to c.4034; codons 1294 to 1338) using denaturing gradient gel electrophoresis (DGGE), and all of exon 15 employing protein truncation test (PTT). No inactivating, disease-associated mutations were detected in any patient. A novel polymorphism in intron 5 was detected in 16 individuals, 8 patients were carriers of the 11307K variant, a mutation prevalent among Jewish individuals with colorectal cancer, and 4 displayed the E1317Q variant. We conclude that in Israeli individuals with early onset or familial CRC, truncating mutations in the APC gene regions associated with attenuated APC phenotype probably contribute little to disease pathogenesis.

The rate of the 6174delT founder Jewish mutation in BRCA2 in patients with non-colonic gastrointestinal tract tumours in Israel.

Inherited predisposition occurs in 5-10% of all gastrointestinal (GI) cancer patients, but with the exception of colorectal cancer (CRC), the genes involved in conferring genetic susceptibility remain largely unknown. Indirect evidence indicates that germline mutations in BRCA2 might be associated with an increased risk for various GI malignancies. A single mutation (6174delT) occurs in the BRCA2 gene in high-risk breast ovarian cancer families of Jewish Ashkenazi origin, in about 1% of the general Ashkenazi population, and rarely in non-Ashkenazi Jews. In order to assess the contribution of this germline mutation to non-CRC GI cancer in Jewish Israeli patients, we tested 70 unselected, consecutive Jewish Ashkenazi patients with gastrointestinal malignancies for this mutation by PCR amplification and modified restriction enzyme digests. Patients' age range was 38-90 years (mean 65.8+/-11.8 years). The most common malignancies were gastric cancer (n = 35) and exocrine pancreatic cancer (n = 23). Overall, 6 mutation carriers were detected: 3/23 (13%) of the patients with pancreatic cancer, 2/35 (5.7%) of patients with gastric cancer and 1/4 (25%) of patients with bile duct cancer. The 8.6% mutation carrier rate among patients is a rate significantly higher than that of the general Ashkenazi population (1.16%, P = 0.0002). We conclude that the rate of the predominant Jewish BRCA2 mutation in patients with gastric and pancreatic cancer significantly differ from that of the general population of the same ethnic origin. Thus, BRCA2 mutations probably contribute to gastrointestinal tumorigenesis other then colon cancer, and the surveillance scheme for mutation carriers should incorporate this information.

Long-term transvaginal ultrasonographic endometrial follow-up in postmenopausal breast cancer patients with tamoxifen treatment.

OBJECTIVE: The aim of this study was to evaluate changes in transvaginal ultrasonographic endometrial thickness with increased duration of tamoxifen treatment in postmenopausal breast cancer patients. MATERIAL AND METHODS: In this prospective study we evaluated the changes (mean +/- SD) of endometrial thickness measured by transvaginal ultrasonography in 181 postmenopausal breast cancer patients, according to the duration of tamoxifen treatment. According to our protocol, the ultrasonographic evaluations were performed every 6 months for the first 2 years of the follow-up and every 12 months thereafter. Two such subsequent ultrasonographic evaluations were performed in 181 patients following 35.1 +/- 41.7 months of tamoxifen treatment, three studies in 127 patients following 44.7 +/- 47.98 months of treatment, four studies in 75 following 54.2 +/- 61.7 months of treatment, five studies in 51 patients following 65.3 +/- 74.4 months of treatment, and six studies in 27 patients following 79.5 +/- 98.8 months of treatment. RESULTS: The measured endometrial thickness detected varied from 8.84 +/- 4.66 to 10.61 +/- 12.35 mm. There were no significant changes in mean +/- SD of endometrial thickness following various durations of tamoxifen treatment. CONCLUSIONS: Extension of duration of tamoxifen treatment in postmenopausal breast cancer patients up to 79.48 +/- 98.79 consecutive months does not cause a significant increase in transvaginal ultrasonographic endometrial thickness.

Successful co-treatment with LHRH-agonist for ovarian over-stimulation and cystic formation in premenopausal tamoxifen exposure.

The present study evaluates the potential beneficial effect of co-treatment with LHRH-agonist in resolving premenopausal tamoxifen's induced supraphysiological serum 17beta estradiol levels and persistent ovarian cysts. Ultrasonographic and serum hormonal evaluations were performed before, during, and following three consecutive injections of long acting LHRH-agonist administered to 14 premenopausal breast cancer patients treated with tamoxifen, who had supraphysiological serum 17beta estradiol levels and simultaneous persistent ovarian cysts. Within 3 weeks of the first LHRH-agonist injection, all patients had menopausal serum estradiol levels. Ovarian cysts completely disappeared within 2 months following the first injection. Following the discontinuation of LHRH-agonist co-treatment, serum estradiol levels remained in physiological levels and the ovaries remained a normal size in 64.3% of the patients for 13.3 +/- 11.5 months. 28.6% of the patients had a gradual reappearance of high serum estradiol levels and of ovarian cysts, and were, therefore, treated with a second course of LHRH-agonist. Following the second course, serum estradiol levels remained in physiological levels and the ovaries remained a normal size for 8-15 months. It is concluded that short duration of co-treatment with long acting LHRH-agonist administered to premenopausal breast cancer patients treated with tamoxifen, successfully resolved the tamoxifen-induced supraphysiological serum 17beta estradiol levels and the ovarian cysts.

Local recurrence after low anterior resection using the EEA stapling device.

Fifty-five patients underwent curative stapled low anterior resection for rectal adenocarcinomas located 5 to 15 cm from the anal verge. Two patients (3.7 percent) died postoperatively. The mean follow-up for the remaining 53 patients was 40 months. Local recurrence was diagnosed in 17 patients (32 percent), in most (88 percent) within the first two years after surgery. Most local recurrences appeared in patients classified as Dukes' C1 and C2 but, surprisingly, no significant difference was found between rectal tumors of high and low location as regards recurrence. The high rate of recurrence in this series may be attributable to the large number of patients with advanced tumors, and poorly differentiated carcinoma, or both.

Low PSA metastatic androgen- independent prostate cancer.

OBJECTIVES: To describe the clinical parameters of low PSA, progressive metastatic androgen-independent prostate cancer. METHODS: From April 1995 to May 1999, we selected 18 patients with clinically progressive androgen-independent prostate cancer and low PSA (

Combination chemotherapy following adrenal suppression in androgen- independent prostate cancer.

OBJECTIVES: Recent trials with modern chemotherapy have demonstrated activity in androgen-independent prostate cancer, but all focused on patients with progression following androgen suppression or antiandrogen withdrawal. Limited data are available on the activity of chemotherapy in androgen-independent, hormone-refractory (progressing following adrenal suppression) prostate cancer. We evaluated the activity of estramustine combined with vinblastine in this subset of androgen-independent prostate cancer. METHODS: From January 1995 until April 1999, 19 patients with hormone-refractory prostate cancer received estramustine 140 mg p.o., three times daily along with weekly vinblastine 5 mg/m(2). RESULTS: A decrease in prostate-specific antigen of 50% or more was noted in 12 patients (63.1%, 95% CI 38.3-83.7%). The median decrease in prostate-specific antigen was 71.2% (range 50.5-85.2%). None of the 7 patients with measurable soft-tissue disease showed an objective response. The median survival from onset of chemotherapy was 6 (range 1.4-27.7) months and from initiation of adrenal suppression 16.9 (range 3.8-40. 5) months. CONCLUSIONS: The combination of estramustine and vinblastine is capable of inducing activity in androgen-independent prostate cancer progressing after adrenal suppression. In our small sample, the survival rate was low, and we obtained no response in soft-tissue sites. Future prospective trials are needed to determine the benefit of sequential versus simultaneous incorporation of adrenal suppression with chemotherapy in the management of androgen-independent prostate cancer.

Ultrasonographic measurement of endometrial changes following discontinuation of tamoxifen treatment in postmenopausal breast cancer patients.

OBJECTIVE: To assess whether there is a decrease in endometrial thickness following discontinuation of tamoxifen treatment as measured by ultrasound. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynaecology, Sapir Medical Centre, Kfar-Saba, Israel. POPULATION: Fifty-eight postmenopausal women with breast cancer who were treated with tamoxifen. METHODS: Transvaginal ultrasonographic measurements of endometrial thickness. MAIN OUTCOME MEASURES: Evaluation of the changes of endometrial thickness and the frequency the endometrium reached a thickness of < or = 5 mm at different time intervals after stopping tamoxifen treatment. RESULTS: There was a significant decrease in median thickness of the endometrium, within six months after stopping tamoxifen, from 7.75 mm measured at the last ultrasonographic study performed before tamoxifen discontinuation down to 5.2 mm (P = 0.002). There were no further reductions in endometrial thickness, and it remained constantly low in subsequent ultrasonographic studies which were performed at various times up to 30 months following the discontinuation of tamoxifen treatment. While taking tamoxifen, only 25-9% of the women had an endometrial thickness of < or = 5 mm. This proportion doubled in their first six months after stopping. CONCLUSIONS: Median thickness of endometrial thickness significantly reduced within six months following tamoxifen discontinuation, and remained constantly low thereafter. This finding may support use of ultrasonographic imaging for the measurement of tamoxifen's effect on the endometrium of postmenopausal breast cancer patients.

Phenotypic characteristics of colo-rectal cancer in I1307K APC germline mutation carriers compared with sporadic cases.

The I1307K APC germline mutation is associated with an increased risk to colo-rectal cancer (CRC). Whether and to what extent the phenotype of CRC in mutation carriers differs from sporadic cases, remains unknown. To gain insight into this issue, we analysed 307 unselected Israeli patients with CRC, who were treated in a single medical centre, for harbouring the I1307K mutation. Twenty-eight mutation carriers (9.1%) were detected. Two of 28 mutation carriers (7.1%) and 93/277 (33.6%) of non-carriers, were of non-Ashkenazi origin (P < 0.01). In 74/278 (26.6%) of the sporadic cases, and only 1/28 (3.6%) of mutation carriers (3.6%) the tumour was located in the right colon (P < 0.01). Mutation carriers had a more advanced disease stage (14/28 - 50% Dukes C), as compared with 60 (19.5%) of non-carriers (P = 0.02). The mean age at diagnosis was similar: 65 (+/- 9.7) years and 66.3 (+/- 11.6) years, for mutation carriers and non-carriers, respectively. No statistical differences were noted between the two groups in sex distribution, tumour grade, and family history of cancer. We conclude that early age at diagnosis and family history of cancer cannot be used to predict who is likely to harbour the I1307K APC germline mutation carriers. However, the tumours in patients with this mutation appear different than those without, are less likely to be proximal and more likely to be advanced than tumours in non-carriers.

Dose-dependent effect of tamoxifen therapy on endometrial pathologies in postmenopausal breast cancer patients.

To assess whether a higher cumulative tamoxifen dose is associated with increased incidence of various types of endometrial pathologies, we compared cumulative dose of tamoxifen treatment as well as demographic characteristics, risk factors for endometrial cancer, transvaginal ultrasonographic endometrial thickness, and various treatments for the primary breast cancer between 159 postmenopausal breast cancer tamoxifen-treated patients without endometrial pathologies (group I) and 67 similar patients with endometrial pathologies (group II). A similar comparison was made between group I patients and similar patients with proliferative endometrium (group IIa), with endometrial hyperplasia (group IIb), with endometrial polyps (group IIc), and with endometrial cancer (group IId). Overall cumulative tamoxifen dose was significantly higher in group II as compared to group I (27.4+/-33.4 and 17.4+/-20.2, respectively; P<0.0252). Transvaginal ultrasonographic endometrial thickness was significantly higher in group II than in group I patients (16.3+/-11.3 mm and 12.1+/-6.3 mm, respectively; P<0.0147). The frequency of diabetes mellitus, of previous postmenopausal bleeding, and of previous exposure to hormone replacement therapy was significantly higher in group II than in group I patients (P<0.001, P<0.0001 and P<0.001, respectively). There were no significant differences in all parameters tested between group I, group IIa, group IIb, group IIc, and group IId. However, there was an obvious trend for higher cumulative tamoxifen dose in patients with benign endometrial pathologies as compared to those without endometrial pathologies or to those with endometrial cancer (Group I = 17.4+/-20.2 g, group IIa = 22.5+/-18.5 g, group IIb = 28.1+/-20.3 g, group IIc = 31.4+/-42.7 g and group IId = 10.4+/-12.6 g). Endometrial pathologies, except for endometrial cancer, are associated with a high cumulative dose of tamoxifen in postmenopausal breast cancer patients.