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Normalization of the Tumor Marker CA-125 after Oophorectomy in a Patient with Paraneoplastic Cerebellar Degeneration without Detectable Cancer
GYNECOLOGIC ONCOLOGY ARTICLE NO.
65, 173–176 (1997)
GO974618
CASE REPORT Normalization of the Tumor Marker CA-125 after Oophorectomy in a Patient with Paraneoplastic Cerebellar Degeneration without Detectable Cancer WARREN P. MASON, M.D.,* JOSEP DALMAU, M.D., PH.D.,* JOHN P. CURTIN, M.D.,†
AND
JEROME B. POSNER, M.D.*,1
Departments of *Neurology and †Gynecology, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, New York 10021 Received July 10, 1996
CA-125 are detected, the association becomes more certain. Patients with well-characterized paraneoplastic autoantibodies and neurologic syndromes may have no evidence of cancer despite exhaustive investigations [4]. Presumably some of these patients have cancer which either is too small to detect or undergoes spontaneous regression [6]. We report a patient with an antineuronal antibody-positive PCD and an elevated CA-125 level, who, following surgery that failed to uncover tumor, stabilized neurologically with regression of CA-125 levels.
A 61-year-old woman developed severe subacute cerebellar degeneration in association with a neuronal antinuclear autoantibody. Neurologic investigations were remarkable only for mild CSF leukocytosis. Despite no radiographic evidence of cancer, a salpingo-oophorectomy was performed on the basis of an increased gynecologic cancer marker (CA-125) and the neurologic symptoms that were strongly suggestive of paraneoplastic cerebellar degeneration. Although no tumor was detected in the surgical specimen, CA-125 levels normalized after surgery. The patient remains stable 12 months after surgery with a severe cerebellar syndrome, no evidence of cancer, and persistent circulating antineuronal autoantibodies. An elevated tumor marker in a patient with a presumed paraneoplastic neurologic disorder should suffice as evidence of an occult neoplasm, and guide definitive treatment. q 1997 Academic Press
CASE REPORT
INTRODUCTION
Paraneoplastic cerebellar degeneration (PCD) is usually associated with tumors of bronchial, gynecologic, and lymphatic origin. Symptoms of cerebellar dysfunction usually develop before the cancer is identified, and the tumor, when detected, is often small and localized [1]. Patients with PCD may develop antibodies against neuronal proteins expressed by the tumor [2]. The best characterized of these autoantibodies are the anti-Yo and anti-Hu antibodies, which are highly specific for gynecologic tumors and small cell lung cancer, respectively [3, 4]. However, some patients with cerebellar dysfunction and cancer may have atypical antineuronal antibodies, which, while not yet characterized as markers of a paraneoplastic disorder, may help to identify the neurologic syndrome as paraneoplastic [5]. In addition, if abnormal serum concentrations of tumor markers such as 1
To whom reprint requests should be addressed. Fax: (212) 717-3296.
A 61-year-old woman awoke one morning with diplopia. Ataxia of limbs and gait began a few days later and within 2 weeks she required assistance with walking. She was admitted to a local hospital where examination disclosed evidence of a pure cerebellar disorder characterized by downbeat nystagmus, severe dysarthria, occasional dysphagia for liquids, head tremor, truncal ataxia, and incoordination of limbs. The patient had a left oophorectomy at age 23 for a dermoid cyst and had a history of hypothyroidism corrected with replacement thyroxine. She had stopped smoking 20 years ago. A lumbar puncture revealed an elevated CSF white cell count of 17 cells/mm3, but was otherwise normal. Serum and CSF VDRL and Lyme antibody titers were negative. Other neurologic investigations including MRI of the head, EEG, and brain stem auditory evoked potentials were normal. A rheumatologic evaluation including ANA, rheumatoid factor, serum cryoglobulins, and sedimentation rate were unremarkable. Thyroid function tests were normal. An investigation for cancer, including mammogram, and CT scans of chest, abdomen, and pelvis revealed no evidence of tumor. A pelvic sonogram disclosed a thickened endome-
173
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0090-8258/97 $25.00 Copyright q 1997 by Academic Press All rights of reproduction in any form reserved.
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FIG. 1. Photomicrograph of a frozen section of normal human cerebellum incubated with the patient’s IgG labeled with biotin (dilution 1:40), without counterstaining. There is intense nuclear reactivity with Purkinje cells and scattered neurons of the molecular and granular layers of the cerebellum. The two arrows indicate a Purkinje cell (original magnification 1250). Consecutive tissue sections reacted with biotinylated IgG from a normal individual (dilution 1:40) produced no immunostaining (data not shown).
trium but no tumor. Serum CEA was less than 0.05 ng/mL (normal, õ5) and CA-19-9 was 25 U/mL (normal, õ35). Serum CA-125 was not obtained. Three months later, she was admitted to Memorial Sloan– Kettering Cancer Center for investigation of occult malignancy. Her neurologic condition had worsened, and she was unable to walk. She complained of poor appetite, and had lost approximately 25 pounds. The neurologic examination demonstrated a severe pancerebellar syndrome and generalized hyperreflexia with bilateral extensor plantar responses. Formal psychometric evaluation suggested depression, but no cognitive impairment. A repeat lumbar puncture was normal without leukocytosis or malignant cells. No evidence of intrathecal IgG synthesis (CSF IgG õ2.90 mg/dL) or oligoclonal bands was detected. The presence of antineuronal antibodies in the patient’s serum was examined using immunohistochemical and Western blot techniques, as previously reported [3–5]. Immunohistochemistry using sections of human cerebellum and cerebral cortex revealed the presence of a novel autoantibody that reacted at dilution of 1:4000 with nuclei of neurons in cerebral and cerebellar cortex (Fig. 1). Reactivity was not
AID
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/
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03-07-97 00:29:57
observed in sections of normal kidney, spleen, and ovary, and nine ovarian carcinomas of various histologies. Immunoblots of human cortical neurons and Purkinje cells were negative. An investigation for occult cancer yielded an elevated serum CA-125 level of 131 U/mL (normal, õ35). Repeat CT scans of abdomen and pelvis were unchanged. On the basis of an abnormal CA-125 level, the patient underwent fractional dilatation with cervical and endometrial curettage and laparoscopic salpingo-oophorectomy. Findings at surgery were normal. Pathologic examination of surgical specimens including, endometrium, right ovary, both fallopian tubes, and pelvic washings failed to disclose a tumor or other pathology. CA-125 declined to normal levels within 1 month after surgery; antineuronal antibody titers did not change in four serial specimens obtained periodically over 12 months (Fig. 2). After surgery, the patient was treated with 10 courses of plasma exchange over 2 weeks, and 1 course of intravenous g-globulin (IVIgG), 1 g/kg in two divided doses, without improvement of neurologic symptoms. Fourteen months after neurologic presentation, the patient remains without clinical or radiographic evidence of cancer. The patient is
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CASE REPORT
FIG. 2. Serial CA-125 levels (black circles) and antineuronal antibody titers (open circles) before and after oophorectomy. Hatched line represents upper normal limit of serum CA-125.
stable neurologically, but is unable to care for herself. Attempts to alleviate disabling nystagmus with baclofen, clonazepam, and gabapentin have been unrewarding. DISCUSSION
The clinical picture of our patient is typical of PCD, a syndrome that is associated with downbeat nystagmus and long tract signs such as hyperreflexia and extensor plantar responses [1–3]. The diagnosis of PCD is relatively straightforward when the syndrome develops in a patient with known cancer, or when an underlying tumor is demonstrated
AID
Gyn 4618
/
6d1a$$$$82
03-07-97 00:29:57
shortly thereafter. While the identification of specific antineuronal autoantibodies such as anti-Hu, anti-Yo or anti-Ri autoantibodies can help to establish the paraneoplastic origin of the disorder and focus the investigation for an underlying tumor, the detection of an occult neoplasm is never assured [1]. In some patients the tumor may remain elusive despite exhaustive investigations [3, 4, 6]. In our patient, the neurologic symptoms were associated with an elevated tumor marker CA-125 which normalized following removal of apparently normal female internal pelvic organs. Although valuable as a cancer marker, CA-125 can occasionally be elevated in nonmalignant disorders, such
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MASON ET AL.
as endometriosis [7, 8]. However, levels in excess of 65 U/ mL are usually associated with malignant tumors, and are seen in less than 2.1% of patients with benign disorders, and less than 0.2% of normal individuals [9]. In our patient, CA125 levels prior to surgery were nearly four times the upper normal limit, a finding which is highly suggestive of an underlying malignancy [9]. Although a variety of nongynecologic neoplasms can produce CA-125 elevations in the range seen in this patient [8], the rapid normalization of CA125 levels following surgery suggests that the source of the elevated tumor antigen was an occult ovarian neoplasm that was removed with the pelvic organs. Furthermore, benign gynecologic disorders, such as endometriosis, although unlikely in a postmenopausal woman, would have been detected during pathological examination of the surgical specimen. Serial CA-125 levels are routinely used to assess response to treatment and to screen for disease recurrence [10]. The durability of serum CA-125 normalization for more than 1 year indicates a complete surgical cure [11]. Unless one identifies an antineuronal antibody already characterized as a marker of paraneoplastic disorders, such as anti-Hu, anti-Yo, or anti-Ri, the identification of a ‘‘new or atypical’’ antineuronal antibody in a single patient, as the current case, is not sufficient to confirm the diagnosis of paraneoplasia [12]. However, when clinical estimates that suggest that about 50% of patients who develop signs of subacute cerebellar degeneration have cancer as the underlying cause [1, 13] are combined with the exclusion of other etiologies (i.e., viral infection, prion disease) and the detection of ‘‘cancer levels’’ of the tumor marker CA-125, the diagnosis of cancer is highly likely. The detection of an atypical antibody indicates the presence of an immunological disorder against the nervous system, but does not prove that the cerebellar disorder is immune mediated. Furthermore, the persistence of an autoantibody in our patient’s serum without decline of titer is not unusual in paraneoplastic disorders. We have previously reported a patient without cancer who continues to have very high titer of anti-Hu antibody 7 years after developing sensory neuronopathy [14]. The neurologic deficits in patients with paraneoplastic neurologic disorders are usually irreversible and resistant to therapy [12]. Our patient remains devastated by a severe cerebellar syndrome which did not respond to plasma ex-
AID
Gyn 4618
/
6d1a$$$$82
03-07-97 00:29:57
change, IVIgG, and pharmacotherapy. However, the recognition of subacute cerebellar degeneration as a paraneoplastic phenomenon, and the subsequent detection of an abnormal CA-125 provided, with high probability, the curative resection of an occult ovarian malignancy. REFERENCES 1. Posner JB: Paraneoplastic cerebellar degeneration. Can J Neurol Sci 20:S117–S122, 1993 2. Greenlee JE, Brashear HR: Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degeneration and ovarian cancer. Ann Neurol 14:609–613, 1983 3. Peterson K, Rosenblum MK, Kotanides H, Posner JB: Paraneoplastic cerebellar degeneration: A clinical analysis of 55 anti-Yo antibodypositive patients. Neurology 42:1931–1937, 1992 4. Dalmau J, Graus F, Rosenblum MK, Posner JB: Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy: A clinical study of 71 patients. Medicine 71:59–72, 1992 5. Anderson NE, Budde-Steffen C, Wiley RG, et al: A variant of the anti-Purkinje cell antibody in a patient with paraneoplastic cerebellar degeneration. Neurology 38:1018–1026, 1988 6. Darnell RB, DeAngelis LM: Regression of small cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 341:21–22, 1993 7. Kammerer-Doak DN, Magrina JF, Nemiro JS, Lidner TK: Benign gynecologic conditions associated with a CA-125 level ú1,000 U/ml. J Reprod Med 41:179–182, 1996 8. Apel RL, Fernandes BJ: Malignant lymphoma presenting with an elevated serum CA-125 level. Arch Pathol Lab Med 119:373–376, 1995 9. Bast RC, Klug TL, John ES, et al: A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883–887, 1983 10. Canney PA, Moore M, Wilkinson PM, James RD: Ovarian cancer antigen CA125: A prospective clinical assessment of its role as a tumour marker. Br J Cancer 50:765–769, 1984 11. Rustin GJS, Nelstrop AE, McClean P, et al: Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 14:1545–1551, 1996 12. Posner JB, Dalmau J: Neurological paraneoplastic syndromes: A review of diagnosis and prospects for therapy. J Clin Neurosci 3:8–15, 1996 13. Henson RA, Urich H: Cortical Cerebellar Degeneration, in Henson RA, Urich H (eds): Cancer and the Nervous System. Oxford, Blackwell Sci, 1982, pp 314–345 14. Twijnstra A, Verschuuren J, Byrne TN, De Baets M, Posner JB, Dalmau J: Prolonged or remitting anti-Hu associated paraneoplastic sensory neuronopathy (PSN) and encephalomyelitis (PEM). Neurology 45(Suppl 4):A321, 1995
goa
AP: GYN
65, 173–176 (1997)
GO974618
CASE REPORT Normalization of the Tumor Marker CA-125 after Oophorectomy in a Patient with Paraneoplastic Cerebellar Degeneration without Detectable Cancer WARREN P. MASON, M.D.,* JOSEP DALMAU, M.D., PH.D.,* JOHN P. CURTIN, M.D.,†
AND
JEROME B. POSNER, M.D.*,1
Departments of *Neurology and †Gynecology, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, New York 10021 Received July 10, 1996
CA-125 are detected, the association becomes more certain. Patients with well-characterized paraneoplastic autoantibodies and neurologic syndromes may have no evidence of cancer despite exhaustive investigations [4]. Presumably some of these patients have cancer which either is too small to detect or undergoes spontaneous regression [6]. We report a patient with an antineuronal antibody-positive PCD and an elevated CA-125 level, who, following surgery that failed to uncover tumor, stabilized neurologically with regression of CA-125 levels.
A 61-year-old woman developed severe subacute cerebellar degeneration in association with a neuronal antinuclear autoantibody. Neurologic investigations were remarkable only for mild CSF leukocytosis. Despite no radiographic evidence of cancer, a salpingo-oophorectomy was performed on the basis of an increased gynecologic cancer marker (CA-125) and the neurologic symptoms that were strongly suggestive of paraneoplastic cerebellar degeneration. Although no tumor was detected in the surgical specimen, CA-125 levels normalized after surgery. The patient remains stable 12 months after surgery with a severe cerebellar syndrome, no evidence of cancer, and persistent circulating antineuronal autoantibodies. An elevated tumor marker in a patient with a presumed paraneoplastic neurologic disorder should suffice as evidence of an occult neoplasm, and guide definitive treatment. q 1997 Academic Press
CASE REPORT
INTRODUCTION
Paraneoplastic cerebellar degeneration (PCD) is usually associated with tumors of bronchial, gynecologic, and lymphatic origin. Symptoms of cerebellar dysfunction usually develop before the cancer is identified, and the tumor, when detected, is often small and localized [1]. Patients with PCD may develop antibodies against neuronal proteins expressed by the tumor [2]. The best characterized of these autoantibodies are the anti-Yo and anti-Hu antibodies, which are highly specific for gynecologic tumors and small cell lung cancer, respectively [3, 4]. However, some patients with cerebellar dysfunction and cancer may have atypical antineuronal antibodies, which, while not yet characterized as markers of a paraneoplastic disorder, may help to identify the neurologic syndrome as paraneoplastic [5]. In addition, if abnormal serum concentrations of tumor markers such as 1
To whom reprint requests should be addressed. Fax: (212) 717-3296.
A 61-year-old woman awoke one morning with diplopia. Ataxia of limbs and gait began a few days later and within 2 weeks she required assistance with walking. She was admitted to a local hospital where examination disclosed evidence of a pure cerebellar disorder characterized by downbeat nystagmus, severe dysarthria, occasional dysphagia for liquids, head tremor, truncal ataxia, and incoordination of limbs. The patient had a left oophorectomy at age 23 for a dermoid cyst and had a history of hypothyroidism corrected with replacement thyroxine. She had stopped smoking 20 years ago. A lumbar puncture revealed an elevated CSF white cell count of 17 cells/mm3, but was otherwise normal. Serum and CSF VDRL and Lyme antibody titers were negative. Other neurologic investigations including MRI of the head, EEG, and brain stem auditory evoked potentials were normal. A rheumatologic evaluation including ANA, rheumatoid factor, serum cryoglobulins, and sedimentation rate were unremarkable. Thyroid function tests were normal. An investigation for cancer, including mammogram, and CT scans of chest, abdomen, and pelvis revealed no evidence of tumor. A pelvic sonogram disclosed a thickened endome-
173
AID
Gyn 4618
/
6d1a$$$$81
03-07-97 00:29:57
0090-8258/97 $25.00 Copyright q 1997 by Academic Press All rights of reproduction in any form reserved.
goa
AP: GYN
174
MASON ET AL.
FIG. 1. Photomicrograph of a frozen section of normal human cerebellum incubated with the patient’s IgG labeled with biotin (dilution 1:40), without counterstaining. There is intense nuclear reactivity with Purkinje cells and scattered neurons of the molecular and granular layers of the cerebellum. The two arrows indicate a Purkinje cell (original magnification 1250). Consecutive tissue sections reacted with biotinylated IgG from a normal individual (dilution 1:40) produced no immunostaining (data not shown).
trium but no tumor. Serum CEA was less than 0.05 ng/mL (normal, õ5) and CA-19-9 was 25 U/mL (normal, õ35). Serum CA-125 was not obtained. Three months later, she was admitted to Memorial Sloan– Kettering Cancer Center for investigation of occult malignancy. Her neurologic condition had worsened, and she was unable to walk. She complained of poor appetite, and had lost approximately 25 pounds. The neurologic examination demonstrated a severe pancerebellar syndrome and generalized hyperreflexia with bilateral extensor plantar responses. Formal psychometric evaluation suggested depression, but no cognitive impairment. A repeat lumbar puncture was normal without leukocytosis or malignant cells. No evidence of intrathecal IgG synthesis (CSF IgG õ2.90 mg/dL) or oligoclonal bands was detected. The presence of antineuronal antibodies in the patient’s serum was examined using immunohistochemical and Western blot techniques, as previously reported [3–5]. Immunohistochemistry using sections of human cerebellum and cerebral cortex revealed the presence of a novel autoantibody that reacted at dilution of 1:4000 with nuclei of neurons in cerebral and cerebellar cortex (Fig. 1). Reactivity was not
AID
Gyn 4618
/
6d1a$$$$82
03-07-97 00:29:57
observed in sections of normal kidney, spleen, and ovary, and nine ovarian carcinomas of various histologies. Immunoblots of human cortical neurons and Purkinje cells were negative. An investigation for occult cancer yielded an elevated serum CA-125 level of 131 U/mL (normal, õ35). Repeat CT scans of abdomen and pelvis were unchanged. On the basis of an abnormal CA-125 level, the patient underwent fractional dilatation with cervical and endometrial curettage and laparoscopic salpingo-oophorectomy. Findings at surgery were normal. Pathologic examination of surgical specimens including, endometrium, right ovary, both fallopian tubes, and pelvic washings failed to disclose a tumor or other pathology. CA-125 declined to normal levels within 1 month after surgery; antineuronal antibody titers did not change in four serial specimens obtained periodically over 12 months (Fig. 2). After surgery, the patient was treated with 10 courses of plasma exchange over 2 weeks, and 1 course of intravenous g-globulin (IVIgG), 1 g/kg in two divided doses, without improvement of neurologic symptoms. Fourteen months after neurologic presentation, the patient remains without clinical or radiographic evidence of cancer. The patient is
goa
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175
CASE REPORT
FIG. 2. Serial CA-125 levels (black circles) and antineuronal antibody titers (open circles) before and after oophorectomy. Hatched line represents upper normal limit of serum CA-125.
stable neurologically, but is unable to care for herself. Attempts to alleviate disabling nystagmus with baclofen, clonazepam, and gabapentin have been unrewarding. DISCUSSION
The clinical picture of our patient is typical of PCD, a syndrome that is associated with downbeat nystagmus and long tract signs such as hyperreflexia and extensor plantar responses [1–3]. The diagnosis of PCD is relatively straightforward when the syndrome develops in a patient with known cancer, or when an underlying tumor is demonstrated
AID
Gyn 4618
/
6d1a$$$$82
03-07-97 00:29:57
shortly thereafter. While the identification of specific antineuronal autoantibodies such as anti-Hu, anti-Yo or anti-Ri autoantibodies can help to establish the paraneoplastic origin of the disorder and focus the investigation for an underlying tumor, the detection of an occult neoplasm is never assured [1]. In some patients the tumor may remain elusive despite exhaustive investigations [3, 4, 6]. In our patient, the neurologic symptoms were associated with an elevated tumor marker CA-125 which normalized following removal of apparently normal female internal pelvic organs. Although valuable as a cancer marker, CA-125 can occasionally be elevated in nonmalignant disorders, such
goa
AP: GYN
176
MASON ET AL.
as endometriosis [7, 8]. However, levels in excess of 65 U/ mL are usually associated with malignant tumors, and are seen in less than 2.1% of patients with benign disorders, and less than 0.2% of normal individuals [9]. In our patient, CA125 levels prior to surgery were nearly four times the upper normal limit, a finding which is highly suggestive of an underlying malignancy [9]. Although a variety of nongynecologic neoplasms can produce CA-125 elevations in the range seen in this patient [8], the rapid normalization of CA125 levels following surgery suggests that the source of the elevated tumor antigen was an occult ovarian neoplasm that was removed with the pelvic organs. Furthermore, benign gynecologic disorders, such as endometriosis, although unlikely in a postmenopausal woman, would have been detected during pathological examination of the surgical specimen. Serial CA-125 levels are routinely used to assess response to treatment and to screen for disease recurrence [10]. The durability of serum CA-125 normalization for more than 1 year indicates a complete surgical cure [11]. Unless one identifies an antineuronal antibody already characterized as a marker of paraneoplastic disorders, such as anti-Hu, anti-Yo, or anti-Ri, the identification of a ‘‘new or atypical’’ antineuronal antibody in a single patient, as the current case, is not sufficient to confirm the diagnosis of paraneoplasia [12]. However, when clinical estimates that suggest that about 50% of patients who develop signs of subacute cerebellar degeneration have cancer as the underlying cause [1, 13] are combined with the exclusion of other etiologies (i.e., viral infection, prion disease) and the detection of ‘‘cancer levels’’ of the tumor marker CA-125, the diagnosis of cancer is highly likely. The detection of an atypical antibody indicates the presence of an immunological disorder against the nervous system, but does not prove that the cerebellar disorder is immune mediated. Furthermore, the persistence of an autoantibody in our patient’s serum without decline of titer is not unusual in paraneoplastic disorders. We have previously reported a patient without cancer who continues to have very high titer of anti-Hu antibody 7 years after developing sensory neuronopathy [14]. The neurologic deficits in patients with paraneoplastic neurologic disorders are usually irreversible and resistant to therapy [12]. Our patient remains devastated by a severe cerebellar syndrome which did not respond to plasma ex-
AID
Gyn 4618
/
6d1a$$$$82
03-07-97 00:29:57
change, IVIgG, and pharmacotherapy. However, the recognition of subacute cerebellar degeneration as a paraneoplastic phenomenon, and the subsequent detection of an abnormal CA-125 provided, with high probability, the curative resection of an occult ovarian malignancy. REFERENCES 1. Posner JB: Paraneoplastic cerebellar degeneration. Can J Neurol Sci 20:S117–S122, 1993 2. Greenlee JE, Brashear HR: Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degeneration and ovarian cancer. Ann Neurol 14:609–613, 1983 3. Peterson K, Rosenblum MK, Kotanides H, Posner JB: Paraneoplastic cerebellar degeneration: A clinical analysis of 55 anti-Yo antibodypositive patients. Neurology 42:1931–1937, 1992 4. Dalmau J, Graus F, Rosenblum MK, Posner JB: Anti-Hu-associated paraneoplastic encephalomyelitis/sensory neuronopathy: A clinical study of 71 patients. Medicine 71:59–72, 1992 5. Anderson NE, Budde-Steffen C, Wiley RG, et al: A variant of the anti-Purkinje cell antibody in a patient with paraneoplastic cerebellar degeneration. Neurology 38:1018–1026, 1988 6. Darnell RB, DeAngelis LM: Regression of small cell lung carcinoma in patients with paraneoplastic neuronal antibodies. Lancet 341:21–22, 1993 7. Kammerer-Doak DN, Magrina JF, Nemiro JS, Lidner TK: Benign gynecologic conditions associated with a CA-125 level ú1,000 U/ml. J Reprod Med 41:179–182, 1996 8. Apel RL, Fernandes BJ: Malignant lymphoma presenting with an elevated serum CA-125 level. Arch Pathol Lab Med 119:373–376, 1995 9. Bast RC, Klug TL, John ES, et al: A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883–887, 1983 10. Canney PA, Moore M, Wilkinson PM, James RD: Ovarian cancer antigen CA125: A prospective clinical assessment of its role as a tumour marker. Br J Cancer 50:765–769, 1984 11. Rustin GJS, Nelstrop AE, McClean P, et al: Defining response of ovarian carcinoma to initial chemotherapy according to serum CA 125. J Clin Oncol 14:1545–1551, 1996 12. Posner JB, Dalmau J: Neurological paraneoplastic syndromes: A review of diagnosis and prospects for therapy. J Clin Neurosci 3:8–15, 1996 13. Henson RA, Urich H: Cortical Cerebellar Degeneration, in Henson RA, Urich H (eds): Cancer and the Nervous System. Oxford, Blackwell Sci, 1982, pp 314–345 14. Twijnstra A, Verschuuren J, Byrne TN, De Baets M, Posner JB, Dalmau J: Prolonged or remitting anti-Hu associated paraneoplastic sensory neuronopathy (PSN) and encephalomyelitis (PEM). Neurology 45(Suppl 4):A321, 1995
goa
AP: GYN