Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study).

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. PATIENTS AND METHODS: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. RESULTS: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). CONCLUSIONS: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Evidence for X(3872)→J/ψπ

We report the first evidence for X(3872) production in two-photon interactions by tagging either the electron or the positron in the final state, exploring the highly virtual photon region. The search is performed in e^{+}e^{-}→e^{+}e^{-}J/ψπ^{+}π^{-}, using 825 fb^{-1} of data collected by the Belle detector operated at the KEKB e^{+}e^{-} collider. We observe three X(3872) candidates, where the expected background is 0.11±0.10 events, with a significance of 3.2σ. We obtain an estimated value for Γ[over ˜]_{γγ}B(X(3872)→J/ψπ^{+}π^{-}) assuming the Q^{2} dependence predicted by a cc[over ¯] meson model, where -Q^{2} is the invariant mass squared of the virtual photon. No X(3915)→J/ψπ^{+}π^{-} candidates are found.

Anti-PD1 checkpoint inhibitor therapy in acral melanoma: a multicenter study of 193 Japanese patients.

BACKGROUND: Acral melanoma (AM) is an epidemiologically and molecularly distinct entity that is underrepresented in clinical trials on immunotherapy in melanoma. We aimed to analyze the efficacy of anti-programmed cell death 1 (anti-PD-1) antibodies in advanced AM. PATIENTS AND METHODS: We retrospectively evaluated unresectable stage III or stage IV AM patients treated with an anti-PD-1 antibody in any line at 21 Japanese institutions between 2014 and 2018. The clinicobiologic characteristics, objective response rate (ORR, RECIST), survival estimated using Kaplan-Meier analysis, and toxicity (Common Terminology Criteria for Adverse Events 4.0.) were analyzed to estimate the efficacy of the anti-PD-1 antibodies. RESULTS: In total, 193 patients (nail apparatus, 70; palm and sole, 123) were included in the study. Anti-PD-1 antibody was used as first-line therapy in 143 patients (74.1%). Baseline lactate dehydrogenase (LDH) was within the normal concentration in 102 patients (52.8%). The ORR of all patients was 16.6% (complete response, 3.1%; partial response, 13.5%), and the median overall survival (OS) was 18.1 months. Normal LDH concentrations showed a significantly stronger association with better OS than abnormal concentrations (median OS 24.9 versus 10.7 months; P < 0.001). Although baseline characteristics were similar between the nail apparatus and the palm and sole groups, ORR was significantly lower in the nail apparatus group [6/70 patients (8.6%) versus 26/123 patients (21.1%); P = 0.026]. Moreover, the median OS in this group was significantly poorer (12.8 versus 22.3 months; P = 0.03). CONCLUSIONS: Anti-PD-1 antibodies have limited efficacy in AM patients. Notably, patients with nail apparatus melanoma had poorer response and survival, making nail apparatus melanoma a strong candidate for further research on the efficacy of novel combination therapies with immune checkpoint inhibitors.

2-mm surgical margins are adequate for most basal cell carcinomas in Japanese: a retrospective multicentre study on 1000 basal cell carcinomas.

BACKGROUND: Surgery is the gold standard for basal cell carcinomas (BCC). Current recommended surgical margins for BCCs are determined from studies in Caucasian populations. However, the appropriate surgical margins for BCCs in non-white races are unclear. OBJECTIVES: To investigate the accuracy of preoperative determination of clinical tumour borders and appropriate surgical margins in Japanese patients with BCC. METHODS: The maximum calculated differences in distance between the preoperatively determined surgical margins and the actual histologic tumour side margins were considered as 'accuracy gaps' of clinical tumour borders. Estimated side margin positivity rates (ESMPRs) with narrower (2 and 3 mm) surgical margins were calculated on the basis of the accuracy gaps. RESULTS: Overall, 1000 surgically excised BCCs from 980 Japanese patients were included. The most frequent histologic subtype was nodular BCC (67%). The median accuracy gap was 0.3 mm [interquartile range (IQR): -0.5 to +1 mm]. The ESMPRs with 2- and 3-mm surgical margins were 3.8% and 1.4%, respectively. Only the ESMPRs between the well-defined (n = 921) and poorly defined clinical tumour border groups (n = 79) showed statistical difference [2-mm margin: 3.1% vs. 11.7%, OR: 3.89, 95% confidential interval (CI): 1.41-10.71, P <0.01; 3-mm margin: 0.97% vs. 6.3%, OR: 6.58, 95% CI: 1.67-25.99, P <0.01]. No significant differences in ESMPRs were noted in other subgroups including risk classifications. CONCLUSIONS: The determined clinical tumour border accuracy gaps in this Japanese cohort were negligible. Dermatologic surgeons may use narrower surgical margins with acceptable margin positivity rates. The clarity of clinical tumour borders could be an appropriate guide for selection of different surgical margins in the Japanese cohort.

Recurrent Aphthous Stomatitis Caused by Cytomegalovirus, Herpes Simplex Virus, and Candida Species in a Kidney Transplant Recipient: A Case Report.

Recipients of organ transplants are immunosuppressed and at high risk of oral infection. Oral diseases are often neglected compared with infections of other organs that typically confer higher morbidity. However, severe local symptoms hinder oral intake, decrease quality of life, and are sometimes lethal. Here we describe a case of a 57-year-old woman who developed recurrent aphthous stomatitis after kidney transplantation; the cause of the infection was complex and included cytomegalovirus, herpes simplex virus, and Candida species. Since misdiagnosis of oral diseases impairs patient quality of life and increases morbidity, clinicians should be aware of possible etiologies of oral infections in renal transplant recipients.

Acral lentiginous melanoma: a skin cancer with unfavourable prognostic features. A study of the German central malignant melanoma registry (CMMR) in 2050 patients.

BACKGROUND: Acral lentiginous melanoma (ALM) is one of the four major subtypes in cutaneous melanoma (CM). Although ALM has a poorer prognosis than other CM subtypes, the prognostic factors associated with ALM have only been verified in small-sized cohorts because of the low incidence of ALM worldwide. OBJECTIVES: To investigate the clinical characteristics of ALM and to evaluate their prognostic values based on a large dataset from the Central Malignant Melanoma Registry (CMMR) of the German Dermatologic Society. METHODS: The Kaplan-Meier method was used to estimate the potential influence of clinical and histological parameters on ALM disease-specific survival (DSS) curves, which were compared using the log-rank test. A Cox proportional hazards model was used to identify independent prognostic factors for DSS. RESULTS: In total, 2050 patients with ALM were identified from 58 949 patients with CM recorded by the CMMR with follow-up data. In multivariate analyses, age (P = 0·006), ulceration (P = 0·013), tumour thickness (P < 0·001) and tumour spread (P < 0·001) turned out to be significant prognostic factors for DSS in ALM whereas sex, nevus association and level of invasion were not independent factors. CONCLUSIONS: ALM has the same prognostic factors as other subtypes of melanoma. Unfavourable prognosis probably derives from the delay in diagnosis in comparison with other melanoma subtypes.

Exploration of immobilization conditions of cellulosic lyotropic liquid crystals in monomeric solvents by in situ polymerization and achievement of dual mechanochromism at room temperature.

We investigated conditions to prepare cellulosic cholesteric liquid crystalline (ChLC) films in order to accomplish dual mechanochromism, i.e., colour control and circular dichroic inversion upon mechanical stimulus, at room temperature. Flexible propionylated hydroxypropyl cellulose (PHPC) was prepared by a simple reaction and found to be capable of forming lyotropic ChLC in various monomeric solvents. The ChLC solutions were subjected to in situ polymerization to obtain PHPC/synthetic polymer composite films incorporating the ChLC structure. However, the immobilization behaviour depended on the type of original monomers. Differential scanning calorimetry and solid-state NMR measurement revealed that the ChLC structure was more highly fixed when the compatibility between PHPC and the coexisting polymers was lower. Eventually, thus obtained ChLC composite films exhibited dual mechanochromism under ambient temperature.

LANGUAGE DEVELOPMENT. The developmental dynamics of marmoset monkey vocal production.

Human vocal development occurs through two parallel interactive processes that transform infant cries into more mature vocalizations, such as cooing sounds and babbling. First, natural categories of sounds change as the vocal apparatus matures. Second, parental vocal feedback sensitizes infants to certain features of those sounds, and the sounds are modified accordingly. Paradoxically, our closest living ancestors, nonhuman primates, are thought to undergo few or no production-related acoustic changes during development, and any such changes are thought to be impervious to social feedback. Using early and dense sampling, quantitative tracking of acoustic changes, and biomechanical modeling, we showed that vocalizations in infant marmoset monkeys undergo dramatic changes that cannot be solely attributed to simple consequences of growth. Using parental interaction experiments, we found that contingent parental feedback influences the rate of vocal development. These findings overturn decades-old ideas about primate vocalizations and show that marmoset monkeys are a compelling model system for early vocal development in humans.

Bone morphogenetic protein-2 and type IV collagen expression in psammoma body forming ovarian cancer.

Psammoma bodies (PBs), characterized as calco-spherules with concentric laminations, are common in serous tumors of the ovary. However, there is no agreements as to how the PBs are formed. Bone morphogenetic protein-2 (BMP-2) has recently been proposed to be involved in the calcification of tumor cells and recent electron microscopic studies demonstrated the presence of type IV collagen in PBs. Based on this evidence, we postulated a possibe role for BMP-2 and type IV collagen in the formation of PBs in ovarian cancer. We examined the expression of BMP-2 and typle IV collagen by immunohistochemistry and reverse transcription PCR (RT-PCR) in PBs-forming (NK-211) and -non-forming (SHIN-3, KF-1, A2780, KK-92, KOC-2S, SKOV-3, OMC-3, MN-1, EC, and KEN-3) ovarian cancer cell lines in vitro and in surgical specimens of serous adenocarcinoma (SA) with/without PBs and mucinous adenocarcinoma (MA) of the ovary. Cellular growth of cell lines was also evaluated by their doubling time in vitro. Transcripts for BMP-2 mRNA were detected by RT-PCR in all cell lines. By immunohistochemistry, BMP-2 protein expression was positive in 45% (5 out of 11) of cell lines. 36.4% (4 out of 11) were positive for type IV collagen. PBs-forming NK-211 was intensively positive for both BMP-2 and type IV collagen. In addition, NK-211 demonstrated extremely slow growth with a doubling time of 450 hours. In surgical specimens, BMP-2 vs. type IV collagen positivities in tumor cells were 100% (20 out of 20) vs. 40% (8 out of 20) in SA with PBs, 61.1% (11 out of 18) vs. 0% (0 out of 18) in SA without PBs and 75% (9 out of 12) vs. 0% (0 out of 12) in MA. In PBs themselves, 100% (20 out of 20) positivity for BMP-2 and 80% (16 out of 20) for type IV collagen was shown. These results raise the possibility that BMP-2 and type IV collagen-producing slow growing tumor cells form PBs in ovarian cancer.

Pharyngo-esophageal diverticulum arising from Laimer's triangle.

Among pharyngo-esophageal diverticula the most frequent type is Zenker's diverticulum, which originates above the cricopharyngeal muscle and below the thyropharyngeal muscle. Laimer's diverticulum, located below the cricopharyngeal muscle, is a much rarer type. We report a case of a 54-year-old woman with a 3-year history of pharyngeal discomfort that was diagnosed as Laimer's diverticulum. To the best of our knowledge, this is only the third such reported case.

Disappearance of the negative charge in giant DNA with a folding transition.

In the present study we measure the electrophoretic mobility of giant T4 DNA (166 kbp) by electrophoretic light scattering for the elongated and folded compact states at different spermidine (trivalent cation) concentrations in 50 mM sodium maleate buffer (pH 6.0). It is found that the electrophoretic mobility of elongated DNA in the absence of the multivalent cation is seven times greater than that of fully folded compact DNA, where, with the increase of the concentration of spermidine, an abrupt transition is generated after a gradual decrease of the mobility. An analysis of the electrophoretic mobility suggests that the folded compact DNA chains almost completely lose their negative charges, by taking into account the difference of friction mechanism between an elongated and folded compact state. From the single chain observation by use of fluorescence microscopy, it is found that a phase-segregated structure is generated at intermediate concentrations of spermidine. The gradual decrease of the electrophoretic mobility in the transition region is, thus, attributed to the formation of the segregated state, exhibiting partial electroneutralization in the folded part. Disappearance of the negative charges in the completely folded compact DNAs is discussed in relation to the mechanism of transition, in terms of a first-order phase transition.

Morphological study on rupture of posterior capsule in RLC mouse lens.

PURPOSE: To clarify the causative factor underlying rupture of the posterior capsule of the RLC mouse lens as a recessive trait around the 50th postnatal day. METHODS: The lenses of the RLC mouse were removed in the period from birth to 50th postnatal day. Some specimens were observed by light microscopy and transmission and scanning electron microscopy. Others were examined as flat preparations of the lens epithelium. RESULTS: There was an abnormal arrangement of lens fibers at the newborn stage, and lens fibers of the perinuclear zone ended almost vertical in relation to the posterior capsule. Consequently, the posterior suture was not formed in this mouse lens. On the 10th postnatal day, the ends of the lens fibers that terminated in the posterior capsule became swollen, and the posterior capsule at the posterior polar region became thin. On the 20th day, the area of swollen fibers was so large at the center of the posterior capsule that a vacuolated area was observed under the dissecting microscope. On the 30th day, the posterior cortical fibers in this area showed marked swelling, and the posterior capsule became extremely thin. On the 40th day, the anterior cortex became unusually thick, and the lens nucleus was dislocated towards the posterior capsule. On the 50th day, the posterior capsule ruptured. At this time the lens fibers from the perinuclear zone constituted the central area of rupture, and the cortical fibers from the equator formed the protruded area outside the lens. CONCLUSION: The findings revealed that the RLC mouse lens has an abnormal lens fiber arrangement from the early period of lens development, that the lens fibers from the perinuclear zone cause swelling without forming the posterior suture, and that the thin capsule is ruptured by pushing out of the nucleus by thickening of the anterior cortex.

Effects of various 5-HT3 receptor antagonists, granisetron, ondansetron, ramosetron and azasetron on serotonin (5-HT) release from the ferret isolated ileum.

The object of this study was to evaluate the involvement of 5-HT3 receptors in the regulation of 5-HT release from the small intestine using ferrets, an animal model of emesis. 2-Methyl-5-HT, a 5-HT3 receptor agonist, produced a concentration-dependent increase of 5-HT from the ferret ileum. This increase in 5-HT release was significantly inhibited by granisetron (10(-7) and 10(-6) M) or azasetron (10(-7) and 10(-6) M) in a concentration-dependent manner. Ondansetron (10(-7) M) and ramosetron (10(-6) M) also significantly inhibited the 2-methyl-5-HT-induced increase in 5-HT release. When the concentration of ondansetron was increased from 10(-7) M to 10(-6) M, inhibition of 5-HT release was reduced. Ramosetron, for which 5-HT3 receptor binding of the rat brain is remarkably stronger than for any other 5-HT3 receptor antagonists, inhibited the 5-HT release at only the highest concentration of 10(-6) M. Based on these observations that the mode of action on the 2-methyl-5-HT induced 5-HT release is different among 5-HT3 receptor antagonists, it is suggested that there is a possibility that the neuronal 5-HT3 receptors and the 5-HT3 receptors on the EC cells may represent two distinct subtypes.

Plasma levels of 5-HT and 5-HIAA increased after intestinal ischemia/reperfusion in rats.

Intestinal ischemia/reperfusion (I/R) causes serious systemic injury, mainly from a variety of bioactive substances released from the injured intestine. To assess the possible roles of serotonin (5-hydroxytryptamine, 5-HT), a bioactive amine mainly stored in the intestine, in I/R injury, we assayed the levels of tryptophan, 5-HT, and 5-hydroxyindole acetic acid (5-HIAA) in the blood and intestine in a rat I/R model. Plasma 5-HT increased significantly over time after reperfusion; the plateau level was obtained 4 h after reperfusion and was associated with an increase in 5-HIAA. Plasma tryptophan levels declined gradually after reperfusion. The ratio of 5-HIAA/5-HT was significantly higher in I/R rats than in control rats, suggesting that elevated 5-HT was quickly metabolized in the systemic circulation. In the intestine, 5-HT decreased dramatically, whereas tryptophan increased. This phenomenon was prominent in the severely damaged intestine. These findings suggest that the injured intestine released large amounts of 5-HT, whereas its synthesis in the injured intestine was suppressed. An increase in 5-HT in the circulation may be related to various circulatory disturbances observed in humans after intestinal ischemia.

Stenting of the extracranial carotid artery in a high-risk population.

SUMMARY: The results of nine patients with carotid stenosis in a high-risk surgical population that were treated by stent supported angioplasty are reported. There were eight males and one female between the ages of 53 to 74. A balloon expandable stent was deployed by a transfemoral approach. Technical success was achieved in all cases. There were no periprocedural complications. The mean % stenosis decreased from 84% to 5.2% after stenting. No arterial dissection was recorded and smooth contour of the vessel was demonstrated in all patients. We have observed long term patency for over 6 months in seven patients. Mean angiographic stenosis was 20% and 21% at 3 and 6 months, respectively (range, 5 to 32%). No further stenosis was recorded. Carotid stenting is an alternative strategy to carotid endoarterectomy (CEA) for high-risk patients, for whom the complications of CEA may exceed the potential benefits.

Tissue and serum c-erbB-2 and tissue EGFR in breast carcinoma: three years follow-up.

Amplification of erbB-1 and c-erbB-2 genes has been shown in human breast cancer. Expression of these protooncogenes results in production of epidermal growth factor receptor (EGFR) and c-erbB-2. Both are transmembrane receptors with tyrosine kinase activity. Recent data have indicated that the external domain of c-erbB-2 is shed into the culture supernatant of certain breast cancer cell lines and sera of breast cancer patients. A body of literature has shown that the overexpression of these receptors in malignant tissue and c-erbB-2 when shed into serum is associated with bad prognosis. In the present work, tissue EGFR and c-erbB-2 were determined in the membrane fractions of histopathologically verified malignant and normal tissues from the same breast of 94 patients. These values were also determined in 48 tissue specimens of benign mastopathies. Serum c-erbB-2 was quantified in breast cancer patients (n = 105), patients with benign breast disease (n = 48) and 30 apparently healthy women as controls. Patients were followed up by determination of serum c-erbB-2 for one year and clinically for three years to detect any distant metastasis or recurrence. The levels of tissue and serum c-erbB-2 and Estrogen receptors were significantly higher in the carcinomas and sera of breast cancer patients than benign breast diseases or normal controls. Follow-up, although short, of pre-operative serum c-erbB-2 showed a prognostic value (P = 0.007) better than that of tumor size (P = 0.04), EGFR (P = 0.18), nodal involvement (P = 0.25) and tissue c-erbB-2 (P = 0.85). The shedding of soluble fragments of c-erbB-2 into the serum seems to be a characteristic of the potentially malignant cell. The EGFR mean level, however, was significantly lower in malignant tissues than benign and normal ones. A new definition of EGFR status was developed. Accordingly, the recurrence of the disease was more frequent among patients with negative EGFR. The present work did not reveal any correlation between tissue, serum c-erbB-2 or EGFR on one hand and age, menopausal status, stage, histological type and grade of carcinomas and nodal involvement on the other hand. The present work showed an inverse correlation between estrogen receptor level and level of EGFR in malignant tissues.

Effects of the morning irradiation of light with different wavelengths on the behavior of core temperature and melatonin in humans.

Following the previous studies on the influence of light with different wavelengths on human biological rhythms during nighttime, present experiments were conducted to investigate the influence of morning light on the behavior of the core temperature and melatonin in humans. The experiments were carried out in four subjects with normal color vision. The subjects were exposed between 4:00 h to 9:00 h to red, green and blue light of 1,000 lux and 2,500 lux, and with an incandescent light of 50 lux as control. The main results were as follows: No differences in the behavior of core temperature and melatonin were found under the influences of red, green and blue light of 1,000 lux and the control light of 50 lux. On the other hand, a tendency to promote the increase of core temperature and the fall of melatonin secretion was found after exposure to green light of 2,500 lux, compared with control and red light. These results indicate that the behavior of core temperature and melatonin differs according to the wavelength of light, and that the phenomenon arises with morning as well as nocturnal irradiation. However, the intensity of light required to bring about the phenomenon seems to be different between morning and evening; an irradiation of 1,000 lux x 5h at night in the previous report, and one of 2,500 lux x 5h in the morning in the present experiments, were found to be necessary for green light to cause the effects.

Influence of circulating c-erbB-2 serum protein on response to adjuvant chemotherapy in node-positive breast cancer patients.

This retrospective case control study investigated the therametric value of the circulating c-erbB-2 gene product (Her-2, NEU) as (1) an eligibility criterion for high doses of chemotherapy and (2) response to standard adjuvant chemotherapy in node-positive breast cancer patients. Preoperative c-erbB-2 levels were measured in 211 locally advanced (> 3 nodes positive), pre- and perimenopausal breast cancer patients to determine if circulating levels of the gene product can assist in the determination of appropriate therapeutic options. 152 of 211 breast cancer patients received post-operatively a combination chemotherapy including the anthracycline analog mitoxantrone, while 59 patients were treated with conventional CMF therapy. Using 120 fmol/ml as a cut-off level, elevated c-erbB-2 values were found in 26 (12.3%) patients with locally advanced breast cancer. In univariate analysis significant survival differences were detected when c-erbB-2 'positive' patients were compared with c-erbB-2 'negative' patients. However, no significant survival differences were detected, when c-erbB-2 'positive' patients were compared according to regimen of adjuvant treatment. In multivariate analysis c-erbB-2 was an independent prognostic factor for predicting disease-free survival, but not for overall survival. High levels of c-erbB-2 were associated with low estrogen and progesterone receptor concentrations of the tumor cytosol. There was no correlation between elevated c-erbB-2 values and age, tumor size or degree of nodal involvement. c-erbB-2 was a better predictor of risk of recurrence than extent of nodal involvement or hormone receptor status.

Serial serum c-erbB-2 levels in patients with breast carcinoma.

BACKGROUND: Recently, the extracellular domain of the c-erbB-2 oncogene product (HER-2/neu) has been reported to be elevated in the serum of one-fourth of patients with metastatic breast carcinoma. The role of serum c-erbB-2 as a tumor marker, however, is still poorly defined. The purpose of this study was to evaluate the utility of serial serum c-erbB-2 levels as a tumor marker in patients with metastatic breast carcinoma. METHODS: c-erbB-2 levels in the sera of patients with breast carcinoma were determined by an enzyme immunoassay that detects the extracellular domain of c-erbB-2. Serum c-erbB-2 levels were evaluated prior to treatment as well as throughout the course of treatment with second-line hormonal therapy employing either megestrol acetate or fadrozole, an experimental aromatase inhibitor. RESULTS: Fifty-eight of 300 patients (19.3%) had elevated pretreatment serum c-erbB-2 levels. Of these 58 patients with elevated pretreatment c-erbB-2, 48 had more than 1 visit which enabled us to quantitate serial c-erbB-2 levels throughout the course of treatment. Of these 48 patients, 28 (58.3%) had serial c-erbB-2 values that correlated with the clinical course. CONCLUSIONS: Serial serum c-erbB-2 levels did not show a high overall correlation with the clinical course in this group of patients with metastatic breast carcinoma treated with second-line hormonal therapy.