Other Primary Malignancies Among Women With Adult-Type Ovarian Granulosa Cell Tumors.

OBJECTIVE: The aim of this study was to determine the incidence of new primary malignancies after adult-type granulosa cell tumor (AGCT) and the incidence of AGCT after breast and uterine cancer using nationwide population-based registry data. METHODS: We used the Finnish Cancer Registry to identify all patients diagnosed with AGCT in 1968 to 2013 (n = 986). The number of subsequent primary malignancies among women with AGCT and the number of AGCTs in women with previous breast or uterine cancer were compared with the expected number of cases and expressed as standardized incidence ratios (SIRs). RESULTS: There were 122 cases of subsequent cancers diagnosed at least 6 months after the primary diagnosis of AGCT (SIR, 1.09; 95% confidence interval [CI], 0.91-1.3). In particular, the observed number of cancers of the soft tissue (SIR, 4.13; 95% CI, 1.33-12.8), thyroid (SIR, 3.42; 95% CI, 1.54-7.62), and leukemia (SIR, 2.67; 95% CI, 0.98-5.82) exceeded the number of expected cases. The SIR for breast cancers after AGCT was 1.26 (95% CI, 0.92-1.73), and the SIR for AGCT after breast cancer was 1.59 (95% CI, 1.04-2.29). The risk for subsequent AGCT was more than 2-fold in breast cancer patients younger than 50 years, and over 15 years after primary diagnosis. CONCLUSIONS: There is an increased risk for thyroid and soft tissue cancer as well as leukemia after AGCT, which may be associated with late effects of carcinogenic treatments and possibly shared risk factors. After breast cancer, the risk for AGCT was higher, which may indicate a shared hormonal etiology.

Cancer risk of Lichen planus: A cohort study of 13,100 women in Finland.

The association between Lichen planus (LP) and cancer has been under debate for decades. We studied the connection via population-based Finnish register data. All women with the diagnosis of LP (n = 13,100) were identified from the Finnish Hospital Discharge Registry from 1969-2012. These patients were linked with subsequent cancer diagnoses from the Finnish Cancer Registry until 2014. Standardized incidence ratios (SIRs) were counted for different cancers by dividing the observed numbers of cancers by expected numbers, which were based on national cancer incidence rates. In total, 1,520 women with LP were diagnosed with cancer (SIR 1.15, 95% confidence interval [CI] 1.09-1.20). LP was associated with an increased risk of cancer of lip (SIR 5.17, 95% CI 3.06-8.16), cancer of tongue (SIR 12.4, 95% CI 9.45-16.0), cancer of oral cavity (SIR 7.97, 95% CI 6.79-9.24), cancer of esophagus (SIR 1.95, 95% CI 1.17-3.04), cancer of larynx (SIR of 3.47, 95% CI 1.13-8.10) and cancer of vulva (SIR 1.99, 95% CI 1.18-3.13). The risk of cancer was not increased in other locations where LP manifests (pharynx and skin). Patients with diagnosed LP have an increased risk of developing cancer of lip, tongue, oral cavity, esophagus, larynx and vulva. These data are important when considering treatment and follow-up of patients with LP diagnosis.

Pain Sensation During Colposcopy and Cervical Biopsy, With or Without Local Anesthesia: A Randomized Trial.

OBJECTIVE: The aim of the study was to determine whether an injection of a local anesthetic is more painful than a cervical punch biopsy without local anesthesia. MATERIALS AND METHODS: The study was a randomized controlled trial, conducted at the Helsinki University Central Hospital. It consisted of 204 women referred for colposcopic assessments. Half of them were randomized to receive local anesthesia before their cervical punch biopsies. After the injection of the local anesthetic, the cervical punch biopsy, and the endocervical curettage, the women scored their actual pain using a 10-cm visual analog scale (VAS).To measure the difference in VAS scores between two groups, a linear regression model was used. Binomial regression model was applied for comparing the probability of experiencing unbearable pain between the groups. Applying modeling approach allowed also for proper adjustment for other potential risk factors. RESULTS: The mean VAS score for the injection of the local anesthetic was 2.7, the VAS score for the cervical punch biopsy without local anesthesia was 3.5, and the difference was 0.8 (p = .017; 95% CI = 0.1-1.5). The mean VAS for the biopsy with local anesthesia was 0.8, which was significantly lower than the mean VAS for the biopsy without local anesthesia (difference = 2.7; p < .001; 95% CI = 2.2-3.3). The relative risk for experiencing moderate or severe pain (VAS ≥ 5) was 0.6 (p = .03; 95% CI = 0.3-0.9) for the injection of local anesthetic versus the biopsy without local anesthesia. CONCLUSIONS: Injection of a local anesthetic for colposcopy is less painful than biopsies without local anesthesia, and local anesthesia decreases the pain perceived.

Lichen sclerosus and risk of cancer.

Malignant potential of lichen sclerosus (LS) has been suspected, but evidence is sparse. We used the population-based Finnish Cancer Registry data to further study this connection. We identified all women with the diagnosis of LS (n = 7,616) listed in the Finnish Hospital Discharge Registry from 1970 to 2012. The cohort was followed through the Finnish Cancer Registry for subsequent cancer diagnoses until 2014. Standardized incidence ratios (SIRs) were calculated for different cancers by dividing the observed numbers of cancers by expected ones. The expected numbers were based on national cancer incidence rates. During the follow-up period, we found 812 cancers among patients with LS (SIR: 1.13, 95% CI 1.05-1.21). LS was associated with an increased risk of vulvar (182 cases, SIR: 33.6, 95% CI 28.9-38.6) and vaginal cancer (4 cases, SIR: 3.69, 95% CI 1.01-9.44). The risk of cancers of the uterine cervix and lung was significantly decreased. LS is associated with an increased risk for vulvar and vaginal cancer. These data are important when designing the care of women diagnosed with LS.

Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells.

OBJECTIVE: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs. METHODS: The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells. RESULTS: Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression. CONCLUSIONS: We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options.

FOXL2 402C>G Mutation Can Be Identified in the Circulating Tumor DNA of Patients with Adult-Type Granulosa Cell Tumor.

Adult granulosa cell tumors (AGCTs) of the ovary are molecularly characterized by the pathognomonic FOXL2 402C>G (C134W) mutation. To improve diagnostics and follow-up, we developed a specific digital droplet PCR (ddPCR) assay to detect the FOXL2 mutation in the circulating tumor DNA (ctDNA) of AGCT patients. Optimization of the ddPCR assay was performed using a TaqMan primer/probe with the RainDance RainDrop digital PCR system. The ddPCR assay was performed on circulating cell-free DNA extracted from 120 serial plasma samples collected prospectively from 35 AGCT patients. The ddPCR assay included a preamplification step that is sensitive and specific for detecting the FOXL2-mutated ctDNA at levels as low as 0.05%. FOXL2 ctDNA mutations were detected in the plasma of 12 of 33 AGCT patients (36%), with both primary (6 of 17, 35%) and recurrent (6 of 31, 19%) tumors. The median tumor size was significantly larger in ctDNA mutation-positive compared with mutation-negative samples (13.5 cm versus 7.5 cm; P = 0.003). The ctDNA FOXL2 mutation was detected in four patients without clinical disease, of which one relapsed during follow-up. As proof of concept, we established that specific molecular diagnosis of AGCT and detection of AGCT recurrence can be achieved noninvasively using ctDNA FOXL2 mutation testing. Further studies are needed to determine the clinical value of ctDNA mutation testing.

Characteristics and outcome of recurrence in molecularly defined adult-type ovarian granulosa cell tumors.

OBJECTIVE: Adult-type ovarian granulosa cell tumors (AGCTs) have an unpredictable tendency to relapse. In a carefully validated patient cohort, we evaluated the prognostic factors related to AGCT recurrence. METHODS: We identified all patients diagnosed with AGCT during 1956-2014 in Helsinki University Hospital, with a minimum follow-up of one year (n=240). After a histological review supplemented with FOXL2 (402C-G) mutation status analysis, we analyzed the clinical data for association with relapse. RESULTS: The final cohort included 164 (68%) molecularly defined AGCTs (MD-AGCTs). The majority of the women were postmenopausal (63%), and 92% of tumors were stage I. The median follow-up time was 15.5years. Fifty-two (32%) patients developed tumor recurrence, of whom 55% had successive recurrences. Multiple-site recurrences were common, and nearly half of the recurrences were asymptomatic. The median time to the first relapse was 7.4years, and 75% of relapses occurred within ten years after primary diagnosis. The median disease-free survival was 11.3years. Premenopausal status at initial diagnosis, FIGO stage Ic versus Ia, and tumor rupture associated with relapse. However, tumor rupture was the only independent predictive factor. Of the relapsed patients, 48% died of AGCT in a median time of 15.3years. CONCLUSION: Tumor rupture is the strongest predictive factor for recurrence, and these patients might benefit from a more aggressive initial treatment approach. AGCT requires active follow up for 10 to 15years after primary diagnosis, since recurrences may develop late, asymptomatically and in multiple anatomical locations.

Randomised trial on treatment of vaginal intraepithelial neoplasia-Imiquimod, laser vaporisation and expectant management.

Vaginal intraepithelial neoplasia (VAIN) is associated with human papillomavirus (HPV) infection. The most common treatment modality is laser vaporisation, but recurrences are common. Imiquimod is an immune response modulator which is used for the treatment of external condylomas and other HPV-related genital neoplasias. The aim of the study was to evaluate the efficacy and tolerability of vaginally administered imiquimod in comparison with laser vaporisation and expectant management of high-grade VAIN. This proof of principle pilot study was a prospective 16-week randomised trial. We enrolled 30 patients with histologically confirmed VAIN 2 or 3 into three study arms: vaginally administered imiquimod, laser vaporisation and expectant management. Follow-up colposcopy visits included high-risk human papillomavirus (hrHPV) testing, cytology and punch biopsies. At baseline 77% (n = 20/26) of the patients were hrHPV positive. HPV clearance was significantly higher in the imiquimod arm (63%, n = 5/8) than in the laser arm (11%, n = 1/9) (p = 0.05) or in the expectant management arm (17%, n = 1/6) (p = 0.138). At baseline 25 patients (83%) had VAIN 2 and five (17%) had VAIN 3. None of the lesions progressed during the follow-up. Histological regression (≤VAIN 1) was observed in 80% (n = 8/10) of patients in the imiquimod arm, 100% (n = 10/10) of the laser arm (p = 0.474) and 67% (n = 6/9) of the expectant management arm (p = 0.628). Vaginal imiquimod appears to be as effective as laser treatment in high-grade VAIN.

Clinical characteristics and survival of patients with an adult-type ovarian granulosa cell tumor: a 56-year single-center experience.

OBJECTIVE: The objective of this study was to evaluate clinical prognostic factors and survival of patients with ovarian granulosa cell tumors (GCTs) in a long-term follow-up study. METHODS: A total of 240 adult-type GCTs diagnosed in Helsinki University Central Hospital from 1956 to 2012 were histologically reevaluated. Data were analyzed for several clinical factors in relation to major developments in imaging, surgery, and chemotherapy: the old era (1956-1983) and the new era (1984-2012). Prognostic factors for survival were evaluated in the univariate and multivariate analyses. RESULTS: The original diagnosis was confirmed in 187 (77.9%) patients. The International Federation of Gynecology and Obstetrics stage I disease was present in 89.2%; stage II, in 7.0%; stage III, in 3.8%; and stage IV, in 0% of cases. The mean age at diagnosis (52.9 years) and the mean tumor size (10.8 cm) did not change significantly over time. The most common presenting symptom was abnormal bleeding, but 14% were asymptomatic. The mean follow-up period was 15.7 years. Recurrence rate was similar in both eras. The GCT-specific 5-, 10-, and 20-year survival rates were 95.6%, 88.1%, and 79.8% in the old era as well as 97.2%, 94.8%, and 94.8% in the new era, respectively. In the univariate analyses, old era, patient age older than 60 years, tumor size greater than 10 cm, advanced stage, residual tumor, and use of hormonal adjuvant treatment were associated with GCT-related deaths. Prior use of oral contraceptives and history of infertility improved survival rates. In the multivariate analysis, stage was the only independent prognostic factor for GCT-specific survival. CONCLUSIONS: An accurate histological diagnosis of GCT is essential. Stage IV disease is an extreme rarity. However, tumor stage overcomes other possible clinical prognostic factors for GCT-specific survival. Fertility-sparing surgery, the use of oral contraceptives, or hormonal replacement therapy seems not to be risk factors for survival.

Loop electrosurgical excision procedure and the risk for preterm delivery.

OBJECTIVE: To estimate whether the severity of cervical intraepithelial neoplasia (CIN) and the loop electrosurgical excision procedure (LEEP) increase the risk for preterm delivery, and to evaluate the role of repeat LEEP and time interval since LEEP. METHODS: This was a retrospective register-based study from Finland from 1997 to 2009. We linked Hospital Discharge Register and Finnish Medical Birth Register data. Case group women consisted of 20,011 women who underwent LEEP during the study period and their subsequent singleton deliveries in 1998-2009. Control population included women from the Medical Birth Register with no LEEP (n=430,975). The main outcome measure was preterm delivery before 37 weeks of gestation. RESULTS: The risk for preterm delivery increased after LEEP. Women with previous LEEP had 547 (7.2%) preterm deliveries, whereas the control population had 30,151 (4.6%) preterm deliveries (odds ratio [OR] 1.61, confidence interval [CI] 1.47-1.75, number needed to harm 38.5). The overall preterm delivery rate in the study period was 4.6% for singleton deliveries. Repeat LEEP was associated with an almost threefold risk for preterm delivery (OR 2.80, CI 2.28-3.44). The severity of CIN did not increase the risk for preterm delivery. However, with LEEP for carcinoma in situ or microinvasive cancer, the risk for preterm delivery was higher (OR 2.55, CI 1.68-3.87). The increased risk also was associated with non-CIN lesions (OR 2.04, CI 1.46-2.87). Similarly, the risk was increased after diagnostic LEEP (OR 1.39, 95% CI 1.16-1.67). Time interval since LEEP was not associated with preterm delivery. Adjusting for maternal age, parity, socioeconomic or marital status, urbanism, and previous preterm deliveries did not change the results. CONCLUSION: The risk for preterm delivery was increased after LEEP regardless of the histopathologic diagnosis. The risk was highest after repeat LEEP, which should be avoided, especially among women of reproductive age. LEVEL OF EVIDENCE: II.

Erythropoietin is detectable in the ascitic fluid in patients with ovarian tumors.

BACKGROUND AND OBJECTIVE: Erythropoietin (Epo) is a glycoprotein that stimulates proliferation and migration of human endothelial cells and promotes angiogenesis, which are crucial phenomena in cancer biology. The objective of this study was to investigate whether Epo is detectable in the ascitic fluid of patients with ovarian tumors. PATIENTS AND METHODS: We investigated the presence of Epo in the ascitic fluid of 100 women undergoing laparotomy for an ovarian tumor. Epo concentration was quantitated with an immunochemiluminometric assay. RESULTS: Ten women had a benign tumor, 13 women had a borderline tumor, and 77 women had ovarian cancer. Epo was detected in all ascitic fluid samples, in similar amounts as in corresponding serum samples. Ascitic fluid Epo concentration did not differ between the 3 study groups (P = 0.081), but in multiple comparisons, ascitic fluid Epo was higher in the women with cancer than in the women with a benign tumor (P = 0.006). Ascitic fluid Epo concentration correlated positively with serum Epo (P < 0.0001) and the volume of ascites (P < 0.0001). In regression analyses, serum Epo, volume of ascites, blood hemoglobin, plasma CA125, tumor stage, tumor grade, and the presence of residual tumor after surgery had no significant independent effect on ascitic fluid Epo. CONCLUSION: Considerable amounts of Epo are present in the ascitic fluid of women with ovarian tumors. The origin of Epo in the ascitic fluid of women with ovarian tumors as well as the clinical relevance of our finding remain to be clarified.

Primary fallopian tube carcinoma risk in users of postmenopausal hormone therapy in Finland.

OBJECTIVE: Primary fallopian tube carcinoma (PFTC) is a rare malignancy and only sparse data exist on its possible association with postmenopausal hormone therapy (HT). We therefore studied this association in a nationwide cohort of Finnish HT users. METHODS: All women> 50 years using systemic estradiol-only therapy (ET) (n=117,820 hysterectomized women) or estradiol-progestin therapy (EPT) (n=247,781 nonhysterectomized women) for ≥ 6 months during 1994-2008 were identified from the national medical reimbursement register. The incidence of PFTC in HT users was compared to that in the comparable background population (standardized incidence ratio, SIR, with 95% confidence interval, CI). RESULTS: A total of 160 cases of PFTC were encountered in users of ET (n=34) or EPT (n=126). The use of EPT ≥ 5 years was accompanied by an increased risk for PFTC (SIR 2.15; 95% CI 1.66-2.72). The SIR increased further to 3.36 (95% CI 2.02-5.24) when EPT use lasted ≥ 10 years. The EPT-related risk for PFTC was restricted to the sequential EPT and it was not seen for continuous EPT. Two leading progestins in EPT, norethisterone acetate and medroxyprogesterone acetate, associated with comparable risk elevations. ET use was not associated with the risk for PFTC. CONCLUSIONS: The long-term, sequential use of EPT associates with an increased risk for PFTC. In absolute terms, 4 additional cases of PFTC would be detected in 10-year follow-up of 10,000 women who have used EPT for at least 5 years.

Determinants of incidence of primary fallopian tube carcinoma (PFTC).

Primary fallopian tube carcinoma (PFTC) is a rare malignancy, but its incidence has been rising during the last decades and varies between 2.9/1,000,000 and 5.7/1,000,000. The epidemiology of PFTC has been sparsely studied. In Finland, the incidence rate has been rising during the last decades. The rise has been highest in the cities, in higher social classes, and in certain specific occupations. Parity gives protection against this disease, as does a previous sterilization procedure. Earlier thoughts of a previous salpingitis as a possible promoter of PFTC seem not to hold. Previous infections such as Chlamydia trachomatis infections or human papillomavirus infections cannot be regarded as risk factors. In this chapter, we clarify the possible epidemiological factors behind this disease.

Updating on primary fallopian tube carcinoma.

Primary fallopian tube carcinoma (PFTC) is rare, constituting about 1% of female genital tract malignancies, and little is known about its etiological, protective, risk or prognostic factors. Earlier, such factors were thought to be similar to those seen in ovarian cancer. The incidence of PFTC has been rising during the last decades, especially in higher social classes and among women in certain occupations. Parity is a strong protective factor for PFTC, with a lower incidence associated with an increasing number of deliveries. Previous sterilisation seems to offer some protection. Earlier suggestions of previous genital infections as risk factors appear not to hold. Previous cancers are frequent among PFTC patients, especially breast cancer. Second primary cancers after PFTC are also frequent, especially non-lymphoid leukemia, colorectal, breast, bladder and lung cancer. Only 4% of primary fallopian carcinomas are correctly diagnosed before operation. Treatment consists of aggressive cytoreductive surgery and adjuvant chemotherapy with a platinum-taxane combination. A high preoperative serum hCGss is a strong prognostic factor for worse prognosis. The 5-year survival rates vary between 22 and 57%.

Second primary malignancies in females with primary fallopian tube cancer.

Primary fallopian tube cancer (PFTC) is a rare disease, and its aetiological factors are poorly understood. Studies on PFTC in the setting of 2nd primary malignant neoplasms can provide clues on aetiology and also define the possible side effects of different treatment modalities for PFTC. A cohort of 2,084 cases with first PFTC was extracted from the data from 13 cancer registries from Europe, Canada, Australia and Singapore and followed for second primary cancers within the period 1943-2000. Standardized incidence ratios (SIRs) were calculated and Poisson regression analyses were done to find out the RRs related to age at, period of and time since the PFTC diagnosis. There were 118 cancer cases observed after first PFTC (SIR 1.4, 95%CI 1.1-1.6). Elevated SIRs were seen for colorectal cancer (1.7, 95%CI 1.0-2.6), for breast cancer (1.5, 95%CI 1.1-2.2), for bladder cancer (2.8, 95%CI 1.0-6.0), for lung cancer (1.8, 95% CI 0.9-3.2) and for nonlymphoid leukaemia (3.7, 95%CI 1.0-9.4). Significant risk increases were detected for colorectal cancer during the 2nd to 5th year after the first PFTC diagnosis, for breast cancer in follow-up 10+ and for nonlymphoid leukaemia during the 2nd to 10th year. The clustering of cancers of the lung and bladder in PFTC patients may suggest shared smoking aetiology. The excess of colorectal and breast cancers after PFTC may indicate a genetic aetiology.

Parity, tubal sterilization, hysterectomy and risk of primary fallopian tube carcinoma in Finland, 1975-2004.

We studied the possible relationship among parity, female sterilization, hysterectomy and the risk of primary fallopian tube carcinoma (PFTC) in a case-control study in Finland in cases occurring between 1975 and 2004. A total of 573 PFTC cases were identified from the Finnish Cancer Registry, and 10 age-matched controls per case were randomly selected from the Finnish Central Population Registry. In multivariate analysis (including 189 PFTC cases and 1764 controls) parity was protective: the odds ratio (OR) for 1-2 deliveries was 0.63 (95% CI 0.44-0.91) and for > or =3 deliveries, 0.32 (95% CI 0.19-0.52). The OR for sterilization was 0.74 (95% CI 0.42-1.30) and for hysterectomy 1.27 (95% CI 0.73-2.21). Our findings suggest a possible hormonal background as regards the development of PFTC.

Sociodemographic determinants of incidence of primary fallopian tube carcinoma, Finland 1953-97.

Primary fallopian tube carcinoma is very rare. In Western countries, it accounts for about 1% of all female genital malignant tumors. Its etiology remains poorly known, but high parity is considered to be protective. We studied determinants of incidence of primary fallopian tube carcinoma in Finland. Incidence rates for primary fallopian tube carcinoma, according to the population based Finnish Cancer Registry, from 1953- 97 were assessed by age, year of diagnosis, and type of residential area. Standardized incidence ratios (SIRs) for the years 1971- 95 were calculated by occupation and social class variables taken from the 1970 Population Census. There were 485 cases of primary fallopian tube carcinoma registered during 45 years. The age-adjusted incidence rate increased from 1.2/1000000 in 1953-57 to 5.4/1000000 in 1993-97. This 4.5-fold increase in incidence rate corresponds to a 7-fold increase in the number of new cases. The increase is attributable to the age group beyond 55 years, the peak incidence occurring between 60-64 years. Although the relative increase in incidence rate has been larger in rural areas than in cities, the rate in the latter remains 2-fold. Women in the 2 highest social classes had a 1.8-fold incidence (95% CI = 1.2-2.6) as compared to the lowest social class. Women in agriculture and those not working outside the home had only half the cancer incidence of those in academic or clerical occupations. The incidence of primary fallopian tube carcinoma increases in Finland. Evidently, the incidence has increased simultaneously with the affluence of urban life. Part of the variation in incidence correlates with variation in parity.

Synthesis of R-(-)-imperanene from the natural lignan hydroxymatairesinol.

A convenient and high yielding method for the synthesis of R-(-)-imperanene, starting from the readily available natural lignan hydroxymatairesinol from Norway spruce, was developed. Hydroxymatairesinol was degraded in strongly basic aqueous conditions to (E)-4-(4-hydroxy-3-methoxyphenyl)-2-(4-hydroxy-3-methoxyphenylmethyl)but-3-enoic acid, which was esterified and then reduced by LiAlH(4) to afford R-(-)-imperanene. The configuration at the crucial stereocenter was preserved in the synthesis, and the obtained product was identified by optical rotation measurements and chiral HPLC analyses as the R-(-)-enantiomer (ee 86-92%).