S.A. Im

High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer.

The purpose of this study was to investigate the prognostic value of tumour-associated macrophages with a focus on micro-anatomical localisation and determine whether molecular changes of the epidermal growth factor receptor (EGFR) are related to macrophage infiltration in resected non-small cell lung cancer (NSCLC). One hundred and forty-four patients were included in this study. Immunohistochemistry was used to identify CD68+ macrophages in the tumour islet and surrounding stroma. Epidermal growth factor receptor mutations were studied by direct sequencing. The EGFR gene copy number and protein expression were analysed by fluorescence in situ hybridisation and immunohistochemistry. Patients with a high tumour islet macrophage density survived longer than did the patient with a low tumour islet macrophage density (5-year overall survival rate was 63.9 vs 38.9%, P=0.0002). A multivariate Cox proportional hazard analysis revealed that the tumour islet macrophage count was an independent prognostic factor for survival (hazard ratio 0.471, 95% confidence interval 0.300–0.740). However, EGFR mutations, gene copy number, and protein expression were not related to the macrophage infiltration. In conclusion, tumour islet macrophage infiltration was identified as a strong favourable independent prognostic marker for survival but not correlated with the molecular changes of the EGFR in patients with resected NSCLC.

Prognostic and predictive values of EGFR overexpression and EGFR copy number alteration in HER2-positive breast cancer

Background:Epidermal growth factor receptor (EGFR) is overexpressed in a subset of human epidermal growth factor receptor 2 (HER2)-positive breast cancers, and coexpression of HER2 and EGFR has been reported to be associated with poor clinical outcome. Moreover, interaction between HER2 and EGFR has been suggested to be a possible basis for trastuzumab resistance.Methods:We analysed the clinical significance of EGFR overexpression and EGFR gene copy number alterations in 242 HER2-positive primary breast cancers. In addition, we examined the correlations between EGFR overexpression, trastuzumab response and clinical outcome in 447 primary, and 112 metastatic HER2-positive breast cancer patients treated by trastuzumab.Results:Of the 242 primary cases, the level of EGFR overexpression was 2+ in 12.7% and 3+ in 11.8%. High EGFR gene copy number was detected in 10.3%. Epidermal growth factor receptor overexpression was associated with hormone receptor negativity and high Ki-67 proliferation index. In survival analyses, EGFR overexpression, but not high EGFR copy number, was associated with poor disease-free survival in all patients, and in the subgroup not receiving adjuvant trastuzumab. In 447 HER2-positive primary breast cancer patients treated with adjuvant trastuzumab, EGFR overexpression was also an independent poor prognostic factor. However, EGFR overexpression was not associated with trastuzumab response, progression-free survival or overall survival in the metastatic setting.Conclusions:Epidermal growth factor receptor overexpression, but not high EGFR copy number, is a poor prognostic factor in HER2-positive primary breast cancer. Epidermal growth factor receptor overexpression is a predictive factor for trastuzumab response in HER2-positive primary breast cancer, but not in metastatic breast cancer.

A phase II study of epirubicin, cisplatin and capecitabine combination chemotherapy in patients with metastatic or advanced gastric cancer

Objectives: The purpose of this study was to evaluate the antitumor activity and safety of an epirubicin, cisplatin, and capecitabine (ECX) combination in patients with metastatic or advanced gastric cancer. Patients and Methods: Patients with metastatic or advanced measurable gastric adenocarcinoma received ECX combination chemotherapy. Epirubicin 50 mg/m2 and cisplatin 60 mg/m2 were administered on day 1 by intravenous injection. Capecitabine 1,000 mg/m2 twice daily was administered orally on day 1–14. The cycle was repeated every 3 weeks. Results: Fifty-four patients were enrolled in this study. Fifty patients were assessable for responses and 53 for toxicity. A total of 250 cycles were administered. The overall best response rate by intent-to-treat analysis was 59% including 52% partial responses and 7% complete responses. Median response duration and time to progression was 5.8 and 6 months, respectively. Median survival for all patients was 9.6 months (95% CI, 8.7–10.5 months). The most common grade 3/4 hematological adverse event was neutropenia in 31% (76 cycles) including febrile neutropenia in 4.8% (11 cycles). Non-hematological toxicity was generally mild and reversible. Grade 3/4 nausea, vomiting and stomatitis occurred in 8, 9, and 8% of the patients, respectively. Hand-foot skin reactions developed in 51% of patients, but most were self-limited. Grade 3 occurred in only 4%. One patient died of neutropenic sepsis. Conclusions: ECX combination regimen showed high anti-tumor activity with a tolerable toxicity pattern as a front-line chemotherapy for patients with metastatic or advanced gastric cancer.

Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy

Background:There have been controversies in prognostic impact of mucinous histology on colorectal cancer, and its implication in patients treated with adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is unclear.Methods:Stage II and III colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Patients were grouped according to the mucinous content: >50%, mucinous adenocarcinoma (MAC); <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA). Clinicopathological features and disease-free survival (DFS) were compared.Results:Among a total of 521 patients, 27 patients (5.2%) had MAC, 41 patients (7.9%) had AIM, and 453 patients (86.9%) had NMA. Mucinous adenocarcinoma and AIM had higher frequency of proximal location and microsatellite instability, but lower frequency of angiolymphatic invasion. Disease-free survival was significantly worse in the MAC compared with NMA (3-year DFS 57% and 86%, respectively; P<0.001) and AIM (3-year DFS 87%, P=0.01 vs MAC). Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted hazard ratio 7.96, 95% confidence interval 3.76–16.8).Conclusion:Adenocarcinoma with intermediated mucinous component and MAC have distinct clinicopathological features compared with NMA. Mucinous adenocarcinoma has an adverse prognostic impact on stage II or III colorectal cancer treated with adjuvant FOLFOX.

The beneficial effect of palliative resection in metastatic colorectal cancer

Background:We aimed to determine the role of palliative resection in metastatic colorectal cancer (mCRC) and ascertain which patient populations would benefit most from this treatment.Methods:A total of 1015 patients diagnosed with mCRC at Seoul National University Hospital between 2000 and 2009 were retrospectively studied.Results:Of the 1015 patients, 168 patients with only liver and/or lung metastasis received curative resection. The remaining 847 patients were treated with palliative chemotherapy and/or palliative resection combined with best supportive care. Palliative resection was performed in 527 (62.2%) cases (complete resection with negative margin (R0) in 93, R1/2 in 434). Resected patients had a more prolonged median overall survival (OS) than unresected patients (21.3 vs 14.1 months; P<0.001). In multivariate analysis, R0 resection was found to be associated with a superior OS compared with R1/2 resection (51.3 vs 19.1 months; P<0.001) and no resection (51.3 vs 14.1 months; P<0.001). When we performed propensity score matching, palliative resection was found to be related to prolonged OS (hazard ratio=0.72, 95% confidence interval=0.59–0.89; P=0.003).Conclusion:Palliative resection without residual disease and chemotherapy confers a longer-term survival outcome than palliative chemotherapy alone in mCRC patient subset.

Postoperative chemoradiotherapy for gallbladder cancer

PurposeThe goal of this work was to analyze the outcome of adjuvant chemoradiotherapy for patients with gallbladder cancer who underwent surgical resection and to identify the prognostic factors for these patients.Patients and methodsBetween August 1989 and November 2006, 47 patients with gallbladder cancer underwent surgical resection followed by adjuvant radiotherapy. There were 21 males and 26 females, and median age was 60 years (range 44–75xa0years). Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes up to 40–50xa0Gy at 2xa0Gy/fraction; 41xa0patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 48xa0months for survivors.ResultsThere were 2xa0isolated locoregional recurrences, 14xa0isolated distant metastases, and 7xa0combined locoregional and distant relapses. The 5-year overall survival rate was 43.7%. According to the extent of resection, the 5-year overall survival rates were 52.8%, 20.0%, and 0% in R0-, R1-, and R2-resected patients, respectively (pu2009=u20090.0038). On multivariate analysis incorporating extent of resection, T stage, N stage, performance of lymph node dissection, and histologic differentiation, extent of resection was the only prognostic factor associated with overall survival (pu2009=u20090.0075). Among the 37xa0patients with R0 resection, there was no difference of 5-year overall survival rates in patients with N0, N1, and Nx diseases (46.2%, 60.0%, and 44.4%, respectively, pu2009=u20090.6246). As for significant treatment-related morbidity, there was only 1xa0patient with grade 4 gastric ulcer.ConclusionAdjuvant chemoradiotherapy after R0 resection can achieve a good long-term survival rate in gallbladder cancer patients, even in those with lymph node metastases, and may play a role for patients who underwent R0 resection of primary tumor without lymph node dissection.ZusammenfassungZielAnalyse der Ergebnisse adjuvanter Radiochemotherapie bei Patienten mit Gallenblasenkarzinom und Ermittlung prognostischer Faktoren.Patienten und MethodenZwischen August 1989 und November 2006 wurden 47xa0Patienten mit einem Gallenblasenkarzinom einem chirurgischen Eingriff sowie einer darauf folgenden Strahlentherapie unterzogen. Das Patientenkollektiv bestand aus 21xa0Männer und 26xa0Frauen mit einem durchschnittlichen Alter von 60xa0Jahren (Bereich 44–75xa0Jahre). Die postoperative Strahlentherapie umfasste das Tumorbett und die regionalen Lymphknoten mit bis zu 40–50xa0Gy in 2-Gy-Fraktionen. 41xa0Patienten erhielten außerdem 5-Fluorouracil i.v. als Radiosensitizer. Die mittlere Follow-up-Dauer der überlebenden Patienten betrug 48xa0Monate.ErgebnisseEs gab 2 isolierte lokoregionäre Rezidive, 14 isolierte Fernmetastasen und 7 kombiniert lokoregionäre und Fernrezidive (Tab. 2). Die 5-Jahres-Überlebensrate betrug 43,7%. Bezogen auf den Resektionsstatus lag die 5-Jahres-Überlebensrate bei 52,8%, 20,0%, und 0% für R0- bzw. R1- und R2-resezierte Patienten (pu2009=u20090,0038; Tab. 3, Fig. 1). Das Resektionsausmaß war in der multivariaten Analyse der einzige prognostische Faktor für das Gesamtüberleben (pu2009=u20090,0075). Unter den 37xa0Patienten mit R0-Resektion gab es keine Unterschiede bei der 5-Jahres-Überlebensrate bezogen auf die Stadien N0, N1 und Nx (46,2%, 60,0% bzw. 44,4%; pu2009=u20090,6246; Tab. 4, Fig. 3). Was die signifikante Toxizität betraf, gab es nur bei einem Patienten ein Grad-4-Magengeschwür.SchlussfolgerungDie adjuvante Radiochemotherapie nach einer R0-Resektion kann bei Gallenblasenkrebspatienten, auch bei jenen mit Lymphknotenmetastasen, eine gute Langzeitüberlebensrate erzielen und für Patienten nach R0-Resektion des Primärtumors ohne Lymphknotendissektion relevant sein.

Cancer patients' awareness of clinical trials, perceptions on the benefit and willingness to participate: Korean perspectives

To understand patients perceptions of clinical trials (CTs) is the principal step in the enrolment of patients to CTs. However, these perceptions in eastern countries are very rare. From 12 February 2007 to 13 April 2007, we consecutively distributed the questionnaire to 842 cancer patients who initiated a first cycle of chemotherapy regardless of each treatment step in the Seoul National University Hospital. Younger age, higher educational degree, higher economic status, and possession of private cancer insurance were related with significantly higher awareness of CTs (P=0.001, P=0.006, P=0.002, and P=0.009, respectively). However, unlike awareness, perceptions on benefits of CTs were not changed according to age, educational degree, and economic status (P=0.709, P=0.920, and P=0.847, respectively). Willingness was also not changed according to age, educational degree, economic status, and private cancer insurance (P=0.381, P=0.775, P=0.887, and P=0.392, respectively). Instead, males and heavily treated patients had more positive perceptions on benefits (P=0.002 and P=0.001, respectively) and more willingness to participate in CTs (OR=1.17, 1.14–2.75: OR=1.59, 1.01–2.51, respectively). In summary, cancer patients awareness of CTs, perceptions on the benefit in CTs, and willingness to participate are differently influenced by diverse medical and social conditions. This information would be very helpful for investigators to properly conduct CTs in eastern cancer patients.

Long-term effect of aromatase inhibitors on bone microarchitecture and macroarchitecture in non-osteoporotic postmenopausal women with breast cancer.

SummaryIn non-osteoporotic postmenopausal women with breast cancer, aromatase inhibitors (AIs) negatively affected bone mineral density (BMD), lumbar spine trabecular bone score (TBS) as a bone microarchitecture index, and hip geometry as a bone macroarchitecture index.IntroductionAIs increase the risk of fracture in patients with breast cancer. Therefore, we aimed to evaluate the long-term skeletal effects of AIs in postmenopausal women with primary breast cancer.MethodsWe performed a retrospective longitudinal observational study in non-osteoporotic patients with breast cancer who were treated with AIs for ≥3xa0years (T-score >−2.5). Patients with previous anti-osteoporosis treatment or those who were given bisphosphonate during AI treatment were excluded from the analysis. We serially assessed BMD, lumbar spine TBS, and hip geometry using dual-energy X-ray absorptiometry.ResultsBMD significantly decreased from baseline to 5xa0years at the lumbar spine (−6.15%), femur neck (−7.12%), and total hip (−6.35%). Lumbar spine TBS also significantly decreased from baseline to 5xa0years (−2.12%); this change remained significant after adjusting for lumbar spine BMD. The annual loss of lumbar spine BMD and TBS slowed after 3 and 1xa0year of treatment, respectively, although there was a relatively constant loss of BMD at the femur neck and total hip for up to 4xa0years. The cross-sectional area, cross-sectional moment of inertia, minimal neck width, femur strength index, and section modulus significantly decreased, although the buckling ratio increased over the treatment period (all Pxa0<xa00.001); these changes were independent of total hip BMD.ConclusionsLong-term adjuvant AI treatment negatively influenced bone quality in addition to BMD in patients with breast cancer. This study suggests that early monitoring and management are needed in non-osteoporotic patients with breast cancer who are starting AIs.

Primary Systemic Anaplastic Large Cell Lymphoma in a Single Korean Institution: Clinical Characteristics and Treatment Outcome

Despite advances in the characterization of anaplastic large cell lymphoma (ALCL), little data is available on Asian patients. We report here upon single Korean institutions experience regarding the clinical characteristics and outcomes of ALCL. We performed a retrospective study of 32 adults with ALCL. Most of the patients received anthracycline-based chemotherapy. Ann Arbor stage III-IV, B symptoms, high-intermediate/high International Prognostic Index (IPI), and extranodal disease at diagnosis were present in 56%, 44%, 41%, and 63%, respectively. Compared with Western studies, the male/female ratio (4.3) was markedly higher and skin (9%) and bone involvement (9%) were less frequent. The staining results for anaplastic lymphoma kinase were positive in 6 (33%) of 18 cases available. The complete response (CR) rate was 62% (95% CI, 44-80%). With a median follow-up of 51.0 months, 5 yr overall survival was 40±11%. The 3 yr relapse-free survival for the 18 patients who achieved CR was 74±12%. Age, performance status, lactate dehydrogenase, extranodal disease sites number, and IPI were correlated with treatment response and survival. Our data suggest that Korean ALCL patients appear to have a higher male/female ratio, less frequent skin/bone involvement, and lower CR rate compared with those of Western studies.

Postoperative chemoradiotherapy following pancreaticoduodenectomy

PurposeThe purpose of this research was to analyze the relationship between dose–volumetric parameters and the development of diabetes mellitus (DM) in patients treated with chemoradiotherapy (CRT) following curative resection for upper gastrointestinal (GI) cancers.Patients and methodsMedical records of patients who underwent postoperative CRT following curative resection, either pancreaticoduodenectomy (PD) or pylorus preserving pancreaticoduodenectomy (PPPD) for upper GI cancers including pancreas, biliary, ampullary, and duodenal cancers, between January 2006 and December 2008 were retrospectively reviewed. A total of 42xa0patients who were regularly followed for at least 2xa0years were included for analysis. Dose–volumetric parameters such as remnant pancreatic volume, mean dose, maximum dose (Dmax), and percentage of volume receiving specific dose or more were obtained from pre- and postoperative CT scan images and treatment plan.ResultsDmax and V50 (percentage of volume receiving at least 50xa0Gy) were statistically significant factors for the development of DM (pu2009=u20090.013, pu2009=u20090.031, respectively). The sensitivity and specificity of Dmax was 0.875 and 0.559, with cut-off value of 51.1xa0Gy, respectively. V50 had sensitivity of 0.875 and specificity of 0.618 for cut-off value of 16u2009%. No patient-related factor other than pretreatment cerebrovascular events was associated with the development of DM. On multivariate analysis, V50 was the only factor with statistical significance (pu2009=u20090.028), whereas Dmax showed borderline significance (pu2009=u20090.079).ConclusionV50 was the only independent factor associated with the development of diabetes and may function as guideline to predict the development of DM in patients receiving CRT following curative resection.ZusammenfassungZielUntersuchung der Beziehung zwischen Dosis-Volumen-Parametern und der Entstehung von Diabetes mellitus (DM) bei Patienten, die nach kurativer Resektion wegen oberer gastrointestinaler (GI) Krebserkrankungen mit Chemoradiotherapie (CRT) behandelt wurden.Patienten und MethodenDie Krankenakten von Patienten, die sich zwischen Januar 2006 und Dezember 2008 einer CRT gefolgt von einer kurativen Resektion, entweder einer Duodenopankreatektomie (PD) oder einer pyloruserhaltenden Duodenopankreatektomie (PPPD), wegen Krebserkrankungen im oberen Verdauungstrakt, einschließlich Bauchspeicheldrüsen-, biliärem, Ampullen- und Duodenal-Karzinomen, unterzogen haben, wurden retrospektiv begutachtet. An dieser Untersuchung nahmen 42xa0Patienten teil, die regelmäßig über mindestens 2xa0Jahre nachuntersucht wurden. Dosis-Volumen-Parameter, wie restliches Pankreasvolumen, mittlere Dosis, Maximaldosis (Dmax) und Prozentsatz des Volumens, das eine spezifische Dosis erhält, wurden aus prä- und postoperativen CT-Bildern und dem Behandlungsplan gewonnen.ErgebnisseDmax und V50 (prozentualer Anteil, der mindestens 50xa0Gy erhält) waren statistisch signifikante Faktoren für die Entstehung von DM (pu2009=u20090,013 bzw. pu2009=u20090,031). Die Sensitivität und Spezifizität von Dmax lag bei 0,875 bzw. bei 0,559 mit einem Cutoff von 51,1xa0Gy. V50 hatte eine Sensitivität von 0,875 und eine Spezifizität von 0,618 für den Cutoff von 16u2009%. Kein anderer patientenbezogener Faktor als die vor der Behandlung auftretenden zerebrovaskulären Ereignisse wurde mit der Entstehung von DM assoziiert. In der multivariaten Analyse war V50 der einzige Faktor mit statistischer Signifikanz (pu2009=u20090,028), während Dmax grenzwertig signifikant war (pu2009=u20090,079).SchlussfolgerungV50 war der einzige unabhängige Faktor, der mit der Entwicklung von DM assoziiert war und als Richtschnur angesehen werden kann, mit deren Hilfe das Entstehen von DM bei Patienten, die nach kurativer Resektion mit CRT behandelt wurden, vorhergesagt werden kann.