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Quality of life in patients with chronic hepatitis C (HCV) during high dose induction interferon (IFN) treatment
April 1998 the cooperative effect of other epigenetic factors, namely radiation, is probably necessary for the phenotypic expression of thyroid carcinoma. [1] Cetta F. et al. Histopathology, 1997; 31: 231-236. [2] Cetta F. J. Clin. Endocrinol. Metab. 1997; 82: 1650. • L0091
MUTATIONS OF C-Ki-ras IN GALLBLADDER CARCINOMAS ASSOCIATED WITH GALLSTONES AND IN THOSE ASSOCIATED WITH CYSTIC BILE DUCT DILATATION. Cetta F., Montalto G., *Petracci M., Zuckermann M., Baldi C., Piro P., **Civeli L., °Cariati A., °~l'omono H., °*Nimura Y. Institute of Surgical Clinics, *Ophthalmology and **Radiology, University of Siena; °Institute of Surgical Anatomy, University of Genoa, Italy; °°First Department of Surgery, University of Nagoya, Japan. Cystic bile duct dilatation (CBDD) is usually related to the presence of an abnormal pancreatico-choledoch0-ductal junction (PCDJ) and may be accompanied later not only by cholangiocarcinoma (CHC) limited to the choledochal cyst, but also by gallbladder carcinoma (GBC). To determine whether atypical epithelium may be precancerous, the DNA sequence of the Ki-ras genes at codon 12 was examined in 9 patients with CBDD removed at Nagoya University Hospital (3 M - 6 F; mean age 47, range 35-58) (7 with GBC, 1 with bile duct carcinoma and 1 with atypical adenoma) and in 11 patients (2 M - 9 F; mean age 67, range 49-85), who underwent surgery for GBC at Siena University Hospital. In the latter group CBDD was absent and GBC was associated with gallstones in 8 of 11 patients. Histotypes in specimens from Nagoya were papillary (PAP) in 2 cases, tubulary adenocarcinoma (ADC) in 4 (moderately differentiated ADC in 3, well differentiated in 1), poorly differentiated in 2 and undifferentiated in the last case (1). Histotypes in specimens from Siena were ADC in 5 cases (moderately differentiated in 3, well differentiated in 2), PAP in 3 including 1 case with papillary adenoma with severe dysplasia, squamous cell carcinoma (SCC) in 2 and adenosquamous in the last case. Tumors were isolated by microdissection. DNA was amplified by a two-step PCR then directly sequenced. RESULTS Age difference between the 2 groups was significantly lower in patients with CBDD (p<0.05). Patients with SCC were more frequently associated with large, long lasting stones than those with differentiated ADC (p=0.002), while no stone was found in the 2 patients from Nagoya and the 3 from Siena with PAP. Two of the latter 3 patients had increased biliary trypsin values suggesting pancreatobiliary reflux (PBR), even in the absence of evident CBDD. C-Ki-ras point mutations at codon 12 were found in 6 of 9 patients with associated CBDD. In particular, they included the 2 patients with PAP and those with ADC, while the 3 patients with poor or undifferentiated carcinomas didn't show Ki-ras mutations, neither in the tumor not in the atypical epithelium, when available. The mutation from the wild type ACC was ACG in 4 cases, ADC and ACC in the 2 last cases. ACG point mutations were also found in 3 out of 3 patients with PAP (and without stones) from Siena. On the contrary, only 2 of 5 ADC and 1 of the 3 SQC from Siena had Ki-ras mutations. Present data are preliminary. They suggest that: (i) the genetic behaviour of PAP carcinoma (associated with PBR, but not associated with gallstones) from the Siena series is similar to that of PAP carcinomas associated with CBDD from the Nagoya series (high rate of Ki-ras mutation), whereas SQC and ADC associated with gallstones showed less frequently Ki-ras mutation; (ii) present data further support previous suggestions from epidemiologic studies that GBCs associated with longlasting gallstones have a different pathogenesis from those associated with APDJ in the absence of gallstones. The former are more frequently SQC or ADC, the latter more frequently PAP. They also support the view that the basic factor in most of PAP GBCs is increased PBR, either in the presence or in the absence of evident CBDD. [1] Tomono H. et al. Am. J. Gastroenterol. 1996; 91:1211-1214. • L0092 THE WILD TYPE APC ALLELE IS NOT LOST IN FAP-ASSOCIATED THYROID TUMORS, SHOWING ACTIVATION OF THE CHIMERIC ONCOGENE ret-PTC. Cetta F., Montalto G., Petracci M., Gori M., Baldi C., *Curia M.C., *Battista P., *Cama A., *Mariani Costantini R. Institute of Surgical Clinics, University of Siena; *Department of Pathology, University of Chieti, Italy. Thyroid carcinomas (THYRC) are observed with an increased frequency in some FAP kindreds, but the molecular bases for this occurrence are still obscure. Definitive proof that thyroid tumors are integral to FAP could be obtained following the demonstration of double-hit inactivation of the APC gene in FAP-associated thyroid neoplasms. In fact, somatic inactivation of the residual allele of the APC gene occurs early in FAP- associated colorectal adenomas. Biallelic inactivation of the APC gene has also been documented
AASLD A1221 in hepatomas and hepatoblastomas. We have recently shown that a similar mechanism plays a key role in the pathogenesis of FAP associated desmoids (1). Caspari et al. initially suggested that desmoids occur more frequently in patients with germ-line mutations beyond codon 1444 (2). Studies from our laboratory showed that in patients with desmoids the germ-line mutation can also occur before codon 1444, but in these cases the somatic mutation always occurs beyond codon 1444 (1). Therefore, if somatic mutation also play a role in thyroid tumors, it is important to determine whether these mutations cluster in a specific region of the gene. The aim of the present study has been to verify whether somatic inactivation of the APC gene also occurs in FAP asssociated thyroid tumors. This could also yield a better insight into the function of the APC protein. We have recently studied 2 kindreds with FAP associated THYRC: in the former THYRC was found 3 of 7 affected membres, in the latter in one of two. Interestingly, 3 of the 4 patients with THYRC had ret-PTC activation. On the contrary, no germ-line mutation of ret gene could be detected. The analysis of the entire spectrum of somatic APC mutations in tumoral thyroid tissue showed no somatic inactivation of the APC gene in these 4 patients. Because ret-PTC activation is a frequent finding after X-ray radiation (Chemobyl disaster), it is suggested that in the occurrence of thyroid carcinoma, APC gene mutation could play a minor role as compared to colonic adenomas, hepatoblastomas or desmoids, in which biallelic inactivation of the APC gene has frequently been found. On the contrary, environmental factors, namely radiation (3), but also sex related factors, could play an important cooperative role. even if the exact mechanism of this cooperation has not yet been elucidated. [1] Palmirotta et al. Hum. Mul. 1995; 10:1979-1981; [2] Caspari R. et al. Hum, Mol. Genet. 1995; 4:337-340; [3] Cetta F. J. Clin. Endocrinol. Metab. 82:2015-2017; 1997. • L0093 QUALITY OF LIFE IN PATIENTS WITH CHRONIC HEPATITIS C (HCV) DURING HIGH DOSE INDUCTION INTERFERON (IFN) TREATMENT. JW Cha, TJ Layden*, NP Lam. Depts of Pharmacy Practice and Medicine*, University of Illinois, Chicago, IL. We reported in recent studies (Gastroenterology 1997;112(4):A1312) that daily, high doses of IFN (5-15 mlU) for 2 weeks (wks) led to a significant decrease in HCV levels at the end of the induction treatment (tx). A concern, however, is the effect of high doses of IFN on the health related quality of life (HRQOL) of these patients (pts) and how well pts can tolerate such doses during tx. Aim: The purpose of this study was to evaluate the effect of various daily, high doses of IFN on the HRQOL of HCV pts at the end of a 2-wk induction tx, and to assess the tolerability to such dosing regimens. Methods: Twenty-one pts with HCV who were enrolled in a viral kinetic study participated. The different daily dosing regimens of IFN were 5 mlU, 10 mlU, and 15 mlU. To assess the HRQOL, the SF-36 HRQOL survey was administered to these pts before and at the end of the induction tx. The SF-36 reports a score for the physical component summary (PCS) and the mental component summary (MCS). A score of 50 is considered as the US population mean for each summary. The PCS consists of scales to measure bodily pain (BP), general health (GH), physical functioning (PF) and role limitations due to physical problems (RP). The MCS consists of scales to measure mental health (MH), role limitations due to emotional problems (RE), social functioning (SF), and vitality (VT). All scales range between 0 and 100. The higher the scores, the better the HRQOL. The changes (A) in the PCS and MCS, and individual scale were assessed for all pts and compared between the various dosing regimens. Results: Compared to the US population mean, the mean PCS (45.8 -+ 12.2) and MCS (48.2 _ 10.1) were slightly lower in pts with HCV. High daily doses (5-15 mIU) of IFN have most impact on the pts' perception of role limitations due to physical (ARP=-44.1-+ 53.6) or emotional problems (ARE=-31.8 -+44.1), and least impact on physical functioning (APF=-2.9 +- 36.5) and mental health (AMH=-7.1-4- 17.9). Overall, IFN reduced the score of MCS (-8.1 -+ 9.7) more than PCS (-4.9 +_.10.2). The mean PCS score reduction was not significantly different between the 3 doses of IFN. The mean MCS score reduction was most significant with 10 mlU as compared to 5 or 15 mlU. However, none of the pts withdrew because of side effects (SE). Only 2 pts who received 10 mlU and 1 pt who received 15 mlU required dosage adjustment due to SE. In Summary: Daily, high doses of IFN for 2 wks reduced HRQOL of pts, with more impact on mental components as opposed to physical components, and there was no dose-dependent effect on the reductions of HRQOL of pts. Overall, the induction treatment with IFN was well-tolerated. This research was funded by Schering Plough, Kenilworth, NJ.
MUTATIONS OF C-Ki-ras IN GALLBLADDER CARCINOMAS ASSOCIATED WITH GALLSTONES AND IN THOSE ASSOCIATED WITH CYSTIC BILE DUCT DILATATION. Cetta F., Montalto G., *Petracci M., Zuckermann M., Baldi C., Piro P., **Civeli L., °Cariati A., °~l'omono H., °*Nimura Y. Institute of Surgical Clinics, *Ophthalmology and **Radiology, University of Siena; °Institute of Surgical Anatomy, University of Genoa, Italy; °°First Department of Surgery, University of Nagoya, Japan. Cystic bile duct dilatation (CBDD) is usually related to the presence of an abnormal pancreatico-choledoch0-ductal junction (PCDJ) and may be accompanied later not only by cholangiocarcinoma (CHC) limited to the choledochal cyst, but also by gallbladder carcinoma (GBC). To determine whether atypical epithelium may be precancerous, the DNA sequence of the Ki-ras genes at codon 12 was examined in 9 patients with CBDD removed at Nagoya University Hospital (3 M - 6 F; mean age 47, range 35-58) (7 with GBC, 1 with bile duct carcinoma and 1 with atypical adenoma) and in 11 patients (2 M - 9 F; mean age 67, range 49-85), who underwent surgery for GBC at Siena University Hospital. In the latter group CBDD was absent and GBC was associated with gallstones in 8 of 11 patients. Histotypes in specimens from Nagoya were papillary (PAP) in 2 cases, tubulary adenocarcinoma (ADC) in 4 (moderately differentiated ADC in 3, well differentiated in 1), poorly differentiated in 2 and undifferentiated in the last case (1). Histotypes in specimens from Siena were ADC in 5 cases (moderately differentiated in 3, well differentiated in 2), PAP in 3 including 1 case with papillary adenoma with severe dysplasia, squamous cell carcinoma (SCC) in 2 and adenosquamous in the last case. Tumors were isolated by microdissection. DNA was amplified by a two-step PCR then directly sequenced. RESULTS Age difference between the 2 groups was significantly lower in patients with CBDD (p<0.05). Patients with SCC were more frequently associated with large, long lasting stones than those with differentiated ADC (p=0.002), while no stone was found in the 2 patients from Nagoya and the 3 from Siena with PAP. Two of the latter 3 patients had increased biliary trypsin values suggesting pancreatobiliary reflux (PBR), even in the absence of evident CBDD. C-Ki-ras point mutations at codon 12 were found in 6 of 9 patients with associated CBDD. In particular, they included the 2 patients with PAP and those with ADC, while the 3 patients with poor or undifferentiated carcinomas didn't show Ki-ras mutations, neither in the tumor not in the atypical epithelium, when available. The mutation from the wild type ACC was ACG in 4 cases, ADC and ACC in the 2 last cases. ACG point mutations were also found in 3 out of 3 patients with PAP (and without stones) from Siena. On the contrary, only 2 of 5 ADC and 1 of the 3 SQC from Siena had Ki-ras mutations. Present data are preliminary. They suggest that: (i) the genetic behaviour of PAP carcinoma (associated with PBR, but not associated with gallstones) from the Siena series is similar to that of PAP carcinomas associated with CBDD from the Nagoya series (high rate of Ki-ras mutation), whereas SQC and ADC associated with gallstones showed less frequently Ki-ras mutation; (ii) present data further support previous suggestions from epidemiologic studies that GBCs associated with longlasting gallstones have a different pathogenesis from those associated with APDJ in the absence of gallstones. The former are more frequently SQC or ADC, the latter more frequently PAP. They also support the view that the basic factor in most of PAP GBCs is increased PBR, either in the presence or in the absence of evident CBDD. [1] Tomono H. et al. Am. J. Gastroenterol. 1996; 91:1211-1214. • L0092 THE WILD TYPE APC ALLELE IS NOT LOST IN FAP-ASSOCIATED THYROID TUMORS, SHOWING ACTIVATION OF THE CHIMERIC ONCOGENE ret-PTC. Cetta F., Montalto G., Petracci M., Gori M., Baldi C., *Curia M.C., *Battista P., *Cama A., *Mariani Costantini R. Institute of Surgical Clinics, University of Siena; *Department of Pathology, University of Chieti, Italy. Thyroid carcinomas (THYRC) are observed with an increased frequency in some FAP kindreds, but the molecular bases for this occurrence are still obscure. Definitive proof that thyroid tumors are integral to FAP could be obtained following the demonstration of double-hit inactivation of the APC gene in FAP-associated thyroid neoplasms. In fact, somatic inactivation of the residual allele of the APC gene occurs early in FAP- associated colorectal adenomas. Biallelic inactivation of the APC gene has also been documented
AASLD A1221 in hepatomas and hepatoblastomas. We have recently shown that a similar mechanism plays a key role in the pathogenesis of FAP associated desmoids (1). Caspari et al. initially suggested that desmoids occur more frequently in patients with germ-line mutations beyond codon 1444 (2). Studies from our laboratory showed that in patients with desmoids the germ-line mutation can also occur before codon 1444, but in these cases the somatic mutation always occurs beyond codon 1444 (1). Therefore, if somatic mutation also play a role in thyroid tumors, it is important to determine whether these mutations cluster in a specific region of the gene. The aim of the present study has been to verify whether somatic inactivation of the APC gene also occurs in FAP asssociated thyroid tumors. This could also yield a better insight into the function of the APC protein. We have recently studied 2 kindreds with FAP associated THYRC: in the former THYRC was found 3 of 7 affected membres, in the latter in one of two. Interestingly, 3 of the 4 patients with THYRC had ret-PTC activation. On the contrary, no germ-line mutation of ret gene could be detected. The analysis of the entire spectrum of somatic APC mutations in tumoral thyroid tissue showed no somatic inactivation of the APC gene in these 4 patients. Because ret-PTC activation is a frequent finding after X-ray radiation (Chemobyl disaster), it is suggested that in the occurrence of thyroid carcinoma, APC gene mutation could play a minor role as compared to colonic adenomas, hepatoblastomas or desmoids, in which biallelic inactivation of the APC gene has frequently been found. On the contrary, environmental factors, namely radiation (3), but also sex related factors, could play an important cooperative role. even if the exact mechanism of this cooperation has not yet been elucidated. [1] Palmirotta et al. Hum. Mul. 1995; 10:1979-1981; [2] Caspari R. et al. Hum, Mol. Genet. 1995; 4:337-340; [3] Cetta F. J. Clin. Endocrinol. Metab. 82:2015-2017; 1997. • L0093 QUALITY OF LIFE IN PATIENTS WITH CHRONIC HEPATITIS C (HCV) DURING HIGH DOSE INDUCTION INTERFERON (IFN) TREATMENT. JW Cha, TJ Layden*, NP Lam. Depts of Pharmacy Practice and Medicine*, University of Illinois, Chicago, IL. We reported in recent studies (Gastroenterology 1997;112(4):A1312) that daily, high doses of IFN (5-15 mlU) for 2 weeks (wks) led to a significant decrease in HCV levels at the end of the induction treatment (tx). A concern, however, is the effect of high doses of IFN on the health related quality of life (HRQOL) of these patients (pts) and how well pts can tolerate such doses during tx. Aim: The purpose of this study was to evaluate the effect of various daily, high doses of IFN on the HRQOL of HCV pts at the end of a 2-wk induction tx, and to assess the tolerability to such dosing regimens. Methods: Twenty-one pts with HCV who were enrolled in a viral kinetic study participated. The different daily dosing regimens of IFN were 5 mlU, 10 mlU, and 15 mlU. To assess the HRQOL, the SF-36 HRQOL survey was administered to these pts before and at the end of the induction tx. The SF-36 reports a score for the physical component summary (PCS) and the mental component summary (MCS). A score of 50 is considered as the US population mean for each summary. The PCS consists of scales to measure bodily pain (BP), general health (GH), physical functioning (PF) and role limitations due to physical problems (RP). The MCS consists of scales to measure mental health (MH), role limitations due to emotional problems (RE), social functioning (SF), and vitality (VT). All scales range between 0 and 100. The higher the scores, the better the HRQOL. The changes (A) in the PCS and MCS, and individual scale were assessed for all pts and compared between the various dosing regimens. Results: Compared to the US population mean, the mean PCS (45.8 -+ 12.2) and MCS (48.2 _ 10.1) were slightly lower in pts with HCV. High daily doses (5-15 mIU) of IFN have most impact on the pts' perception of role limitations due to physical (ARP=-44.1-+ 53.6) or emotional problems (ARE=-31.8 -+44.1), and least impact on physical functioning (APF=-2.9 +- 36.5) and mental health (AMH=-7.1-4- 17.9). Overall, IFN reduced the score of MCS (-8.1 -+ 9.7) more than PCS (-4.9 +_.10.2). The mean PCS score reduction was not significantly different between the 3 doses of IFN. The mean MCS score reduction was most significant with 10 mlU as compared to 5 or 15 mlU. However, none of the pts withdrew because of side effects (SE). Only 2 pts who received 10 mlU and 1 pt who received 15 mlU required dosage adjustment due to SE. In Summary: Daily, high doses of IFN for 2 wks reduced HRQOL of pts, with more impact on mental components as opposed to physical components, and there was no dose-dependent effect on the reductions of HRQOL of pts. Overall, the induction treatment with IFN was well-tolerated. This research was funded by Schering Plough, Kenilworth, NJ.