Harald Puhalla

Activated Mammalian Target of Rapamycin Is an Adverse Prognostic Factor in Patients with Biliary Tract Adenocarcinoma

Purpose: The mammalian target of rapamycin (mTOR) is a protein kinase that plays a key role in cellular growth and homeostasis. Because its regulation is frequently altered in tumors, mTOR is currently under investigation as a potential target for anticancer therapy. The purpose of our study was to determine the prognostic value of activated mTOR (p-mTOR) in patients with biliary tract adenocarcinoma (BTA), in order to strengthen the rationale for targeted therapy of BTA using mTOR inhibitors. Experimental Design: We determined expression of p-mTOR in paraffin-embedded surgical specimens of BTA by immunohistochemistry with a monoclonal antibody to phosphorylated mTOR. Overall survival was analyzed with a Cox model adjusted for clinical and pathologic factors. Results: Immunostaining for p-mTOR was positive in 56 of 88 (64%) tumors. Activated mTOR was not associated with any of the clinical or pathologic variables of the patients but predicted overall survival of the patients. Overall survival was significantly shorter in patients with p-mTOR–positive tumors as compared with patients with p-mTOR–negative tumors (hazard ratio for death 2.57; 95% confidence interval, 1.35-4.89; P = 0.004). Multivariate Cox proportional hazards regression analyses identified p-mTOR to be an independent prognostic factor for death (adjusted hazard ratio for death, 2.44; 95% confidence interval, 1.24-4.80; P = 0.01). Conclusions: Patients with BTA and p-mTOR–positive tumors have a significantly shorter overall survival than patients with p-mTOR–negative tumors and may benefit from targeted therapy with mTOR inhibitors in the future.

Adequate preoperative staging rarely leads to a change of intraoperative strategy in patients undergoing surgery for colorectal cancer liver metastases

BACKGROUND Diagnostic tools used prior to hepatic surgery have significantly advanced during the last decade. We investigated the value of preoperative staging on detection of additional resectable hepatic lesions in metastatic colorectal cancer patients. METHODS One hundred ninety-four consecutive resections for colorectal liver metastases between January 2002 and December 2005 were prospectively analyzed. Data on imaging (multidetector computed tomography [MDCT] and magnetic resonance imaging [MRI]) were compared to intraoperative findings by intraoperative sonography and bimanual palpation together with histopathological examination. Univariate and multivariate analysis of factors influencing recurrence was performed. RESULTS In 16 (8.2%) resections, additional lesions were detected intraoperatively. In 11 cases (5.7%), these were small (<1 cm) and subcapsular. Detection of additional tumors was associated with shorter median recurrence free survival (5.4 vs. 13.4 months; P < .001) even though all lesions were resected and risk of recurrence was stratified by the Fong score. Patients treated with neoadjuvant chemotherapy did not generally have an increased risk of additional tumors; however, intraoperative detection of new lesions was associated with inferior outcome in this subgroup (median RFS 4.6 vs. 18.3 months in responders, P < .001). CONCLUSION Preoperative imaging with contrast-enhanced MDCT and MRI is efficient and very seldom leads to changes in intraoperative strategy. Patients exhibiting additional resectable hepatic lesions upon surgery have a high risk for early recurrence and should be monitored closely during follow-up.

Simultaneous blockade of the epidermal growth factor receptor/mammalian target of rapamycin pathway by epidermal growth factor receptor inhibitors and rapamycin results in reduced cell growth and survival in biliary tract cancer cells.

The prognosis of patients with biliary tract adenocarcinomas (BTA) is still poor due to lack of effective systemic treatment options. Knowledge of the molecular mechanisms involved in the pathogenesis of this disease is of importance for the development of new treatment strategies. We determined the expression of epidermal growth factor receptor (EGFR) and activated mammalian target of rapamycin (p-mTOR) in paraffin-embedded surgical specimens of BTA (n = 89) by immunohistochemistry. Overall survival was analyzed with Cox models adjusted for clinical and pathologic factors. Combined EGFR/p-mTOR expression was significantly associated with relapse-free survival [adjusted hazard ratio for relapse, 2.20; 95% confidence interval (95% CI), 1.45-3.33; P < 0.001] and overall survival (adjusted hazard ratio for death, 2.32; 95% CI, 1.50-3.58; P < 0.001) of the patients. The effect of the EGFR inhibitors erlotinib or cetuximab and the mTOR inhibitor rapamycin on growth and survival of five BTA cell lines was tested in short-term 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays and long-term colony formation assays. Simultaneous blockade of EGFR and mTOR in biliary tract cancer cell lines results in a synergistic inhibition of both phosphatidylinositol-3-kinase and mitogen-activated protein kinase pathways, leading to reduced cell growth and survival. These results suggest that combined targeted therapy with EGFR and mTOR inhibitors may potentially benefit patients with BTAs and should be further evaluated in clinical trials. [Mol Cancer Ther 2009;8(6):1547–56]

TP53 Mutational Status and Prediction of Benefit from Adjuvant 5-Fluorouracil in Stage III Colon Cancer Patients.

We investigated the hypothesis that the varying treatment efficacy of adjuvant 5-fluorouracil (5FU) in stage III colon cancer is linked to the TP53 mutational status. ABCSG-90 was a prospective randomized trial in which effect of adjuvant 5FU was studied in stage III colon cancer patients. Tumor material of 70% of these patients (389/572) was available for analysis of the biomarker TP53 using a TP53-gene-specific Sanger sequencing protocol. Median follow-up was 88 months. TP53 mutation frequency was 33%. A significant interaction between TP53 status, outcomes and nodal category was found (P = 0.0095). In the N1 category, TP53 wildtype patients had significantly better overall survival than TP53 mutated (81.0% vs. 62.0% overall survival at 5 years; HR = 2.131; 95% CI: 1.344–3.378; P = 0.0010). In the N2 category, the TP53 status did not affect survival (P = 0.4992). In TP53 wildtype patients, the prognostic significance of N category was significantly enhanced (P = 0.0002). In TP53 mutated patients, survival curves of N1 and N2 patients overlapped and nodal category was no longer prognostic. The biomarker TP53 independently predicted effect of adjuvant 5FU in N1 colon cancer patients. TP53 was not predictive in N2 patients, in whom 5FU is known to have no effect.

Changes in liver surgery for colorectal cancer liver metastases under neoadjuvant treatment strategies

SummaryBACKGROUND: Liver resection remains the best treatment option for patients with colorectal cancer liver metastases. Major effort on the part of interdisciplinary groups has achieved an impressive gain of possible curative treatment possibilities. METHODS: Recent literature and personal data addressing modern liver surgery and chemotherapeutic treatment protocols are highlighted. RESULTS: Liver surgery has become safe due to technical improvement and the development of specialized centers. Treatment modalities for curative liver resection have expanded and realize better long-term results. Oncosurgical concepts have substantial impact on the prolongation of life expectancy of patients with metastatic colorectal cancer. CONCLUSION: Multimodal treatment strategies designed by different specialists in the management of advanced colorectal cancer have substantially increased the overall survival of these patients.ZusammenfassungGRUNDLAGEN: Die Leberresektion stellt die beste Therapieoption für Patienten mit kolorektalen Lebermetastasen dar. Durch intensive Zusammenarbeit von interdisziplinären Teams konnten die Möglichkeiten der potentiell kurativen Therapie deutlich erweitert werden. METHODIK: Es wird eine Übersicht über rezente Literatur und persönliche Daten, die sich mit moderner Leberchirurgie und neoadjuvanten chemotherapeutischen Protokollen beschäftigen, präsentiert. ERGEBNISSE: Die Leberchirurgie wurde sowohl durch technische Verbesserungen als auch durch die Zentralisierung der Anwendung zu einem sicheren Therapieverfahren. Die therapeutischen Möglichkeiten der kurativen Resektion konnten erweitert werden und mit ihnen die Langzeitprognose. Wesentlichen Beitrag zu dieser Lebensverlängerung stellen onkochirurgische Therapiekonzepte dar. SCHLUSSFOLGERUNGEN: Multimodale Therapiekonzepte, die von unterschiedlichsten Spezialisten in der Therapie des fortgeschrittenen kolorektalen Karzinoms erstellt wurden, haben zu einer beeindruckenden Verlängerung der Lebenserwartung dieser Patienten geführt.

The EGF 61A/G polymorphism – a predictive marker for recurrence of liver metastases from colorectal cancer

ZusammenfassungHINTERGRUND: Der epidermale Wachstumsfaktor (EGF) spielt eine bedeutende Rolle in der Tumorentstehung. Variationen in der DNA Sequenz des EGF Gens, können zu einer Erhöhung der EGF Aktivität führen, von der man annimmt, dass sie das Tumorwachstum beeinflusst. Die aktuelle Studie untersucht den Einfluss des EGF 61A/G Polymorphismus auf das Wiederauftreten von Lebermetastasen beim kolorektalen Karzinom nach Operation. METHODE: Der EGF 61A/G Polymorphismus wurde retrospektiv in 268 fortlaufenden Patienten beiderlei Geschlechts bestimmt: 175 (65%) männliche und 93 (35%) weibliche Patienten, welche chirurgisch kurativ mit (R0) bei Lebermetastasen im Rahmen eines kolorektalen Karzinoms behandelt wurden. ERGEBNISSE: Von den 268 Patienten, hatten 81 (30%) die häufigste (Wildtyp) Variante EGF 61 A/A, 137 (51%) waren heterozygot EGF 61 A/G und 50 (19%) waren homozygot EGF 61 G/G. Adjustiert nach Alter, Geschlecht, UICC Staging und Tumorlokalisation konnten wir ein 1.6 fach höheres Risiko für das Wiederauftreten von Lebermetastasen (HR: 1,6; 95% CI: 1,0–2,5 p = 0,06) bei EGF 61 G/G Homozygoten verglichen mit Trägern des EGF 61 A Allels feststellen. Dieser Effekt war in jungen Patienten (≤ 65 Jahren), welche ein 2.0-fach höheres Risiko für das neuerliche Auftreten von Lebermetastasen hatten (HR: 2,0; 95% CI: 1,1–3,5 p = 0,021), stärker. Bei Patienten über 65 Jahren konnte kein Effekt nachgewiesen werden. Interessanter Weise konnten wir feststellen, dass männliche Patienten mit EGF G/G ein 1,6 fach höheres Risiko für das Wiederauftreten von Metastasen hatten (HR: 1,6; 95% CI: 1,0–2,5 p = 0,07). Eine signifikante Korrelation (p = 0,033) zwischen der Dukes Klassifikation und homozygot EGF 61 G/G konnte ebenfalls festgestellt werden. KONKLUSION: Mit unseren Ergebnissen konnten wir zeigen, auch unter Berücksichtigung unserer kleinen Patientenpopulation, dass Träger des EGF 61G/G Genotyps ein höheres Risiko für neuerliche Lebermetastasen haben – eine Vermutung, die allerdings durch weitere Studien bestätigt werden muss.SummaryBACKGROUND: Epidermal growth factor (EGF) plays an important role in tumorigenesis. Variations in the DNA sequence of the gene EGF can lead to alterations in EGF activity, which is suspected to influence tumor progression. This retrospective study aimed to investigate the influence of EGF 61A/G polymorphism on the recurrence of liver metastases after hepatic surgery in patients with colorectal cancer. METHODS: EGF 61A/G polymorphism was determined in 268 consecutive patients (175 [65%] men and 93 [35%] women, mean age 62 ± 10.3 years) who had liver metastases at primary diagnosis and were treated by surgery with curative intent (R0) for liver metastases from colorectal cancer. RESULTS: Overall, 81 of 268 (30%) patients exhibited wild-type EGF 61 A/A, 137 (51%) were heterozygous EGF 61 A/G and 50 (19%) were homozygous EGF 61 G/G. After adjusting for age, sex, UICC stage and tumor location, we observed a trend-wise 1.6-fold increased risk for hepatic recurrence (HR 1.6; 95% CI 1.0–2.5, P = 0.06) in individuals with the G/G genotype compared with carriers of the A-allele. The effect was much more pronounced in younger patients (≤ 65 years), who showed a 2.0-fold increased risk of hepatic recurrence (HR 2.0; 95% CI 1.1–3.5, P = 0.021). No effect was observed in older patients (≥ 65 years). Interestingly, male patients with EGF G/G had a 1.6-fold higher risk of recurrence (HR 1.6; 95% CI 1.0–2.5, P = 0.07). A significant correlation (P = 0.033) was detected between Dukes classification and the homozygous 61 G/G genotype. CONCLUSION: Despite the limitations of our study, the retrospective results indicate that carriers of the EGF polymorphism might be at higher risk of developing liver recurrences. If confirmed in subsequent studies, genotyping for the EGF A/G variant might help in identification of patients at high risk of recurrence of liver metastases.

Cystic neoplasms of the pancreas: conservative or operative treatment?

ZusammenfassungGRUNDLAGEN: Die modernen bildgebenden Verfahren haben zu einem Anstieg der Inzidenz der primär zystischen Pankreastumore geführt. Früher war die chirurgische Behandlung obligat. Nach Art und Größe des Tumors kann jedoch auch ein konservativer Ansatz befürwortet werden. METHODIK: Literaturübersicht und Darstellung eigener Erfahrungen. ERGEBNISSE: Von 43 zystischen Neoplasmen wurden 11 (33 %) zufällig entdeckt, 22 (77 %) Patienten hatten Symptome zum Zeitpunkt der Diagnose. 33 (78 %) Patienten wurden operativ, 10 (22 %) Patienten jedoch konservativ behandelt. Bei neun (27 %) Patienten wurde Malignität festgestellt. Sieben (78 %) mit malignen und 15 (63 %) mit benignen Pankreastumor hatten Symptome. Die mediane Zystengröße lag bei 3,5 cm (1,5–12). SCHLUSSFOLGERUNGEN: Die Therapie kann, nach Größe und Charakter der Pankreaszyste, adaptiert werden. Die chirurgische Behandlung allein ist nicht mehr die einzige Behandlungsmöglichkeit der primär zystischen Pankreastumore.SummaryBACKGROUND: Owing to modern imaging techniques, the incidence of primary cystic neoplasms of the pancreas is increasing. During the past decades all pancreatic cysts were treated operatively. Depending on type and size a more conservative approach can be advocated. METHOD: Review of the literature and presentation of institutional experience. RESULTS: From 43 patients, 11 (33%) were discovered incidentally and 22 (77%) had symptoms at the time of diagnosis. 33 (78%) underwent operative treatment, whereas 10 (22%) were treated conservatively. Malignancy was found in nine (27%) operated patients. Seven patients (78%) with malignant cystic neoplasm and 15 patients (63%) with a benign cystic neoplasm had symptoms. Median cyst size was 3.5 cm (1.5–12). There was one case of malignancy within cystic lesion smaller than 3 cm. CONCLUSIONS: Therapy can be tailored depending on size and character of the pancreatic cyst. Surgical treatment alone is no longer pivotal.