Choice of first line systemic treatment in pancreatic cancer among national experts.

BACKGROUND: Treatment options for patients with metastatic pancreatic cancer depend on various factors, including performance status, tumor burden and patient preferences. Metastatic pancreatic cancer is incurable and many systemic treatment options have been investigated over the past decades. This analysis of patterns of practice was performed to identify decision criteria and their impact on the choice of first-line management of metastatic pancreatic cancer. MATERIALS AND METHODS: Members of the Swiss Group for Clinical Cancer Research (SAKK) Gastrointestinal Cancer Group were contacted and agreed to participate in this analysis. Decision trees for the first line treatment of metastatic pancreatic cancer from 9 centers in Switzerland were collected and analyzed based on the objective consensus methodology to identify consensus and discrepancies in clinical decision-making. RESULTS: The final treatment algorithms included 3 decision criteria (comorbidities, performance status and age) and 5 treatment options: FOLFIRINOX, FOLFOX, gemcitabine + nab-paclitaxel, gemcitabine mono and best supportive care. CONCLUSION: We identified multiple decision criteria relevant to all participating centers. We found consensus for the treatment of young (age below 65) patients with good performance status with FOLFIRINOX. For patients with increasing age and reducing performance status there was a decreasing trend to use gemcitabine + nab-paclitaxel. Gemcitabine monotherapy was typically offered to patients in the presence of comorbidities. For patients with ECOG 3-4, most of the experts recommended BSC.

Neoadjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08).

Background: This open-label, phase III trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma. Patients and methods: Patients were randomly assigned (1 : 1) to two cycles of chemotherapy (docetaxel 75 mg/m2, cisplatin 75 mg/m2) followed by chemoradiation (45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m2 weekly and adjuvant cetuximab 500 mg/m2 fortnightly for 3 months. The primary end point was progression-free survival (PFS). Results: In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years [95% confidence interval (CI), 2.0 to not reached] with cetuximab and 2.0 years (95% CI, 1.5-2.8) with control [hazard ratio (HR), 0.79; 95% CI, 0.58-1.07; P = 0.13]. Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2-4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52-1.01; P = 0.055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31-0.90; P = 0.017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64-1.59, P = 0.97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings. Conclusion: Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma. Clinical trial information: NCT01107639.

Sorafenib with or without everolimus in patients with advanced hepatocellular carcinoma (HCC): a randomized multicenter, multinational phase II trial (SAKK 77/08 and SASL 29).

BACKGROUND: Sorafenib (S), a multitargeted tyrosine kinase inhibitor, is the standard of care for first-line systemic treatment of advanced hepatocellular carcinoma (HCC). Everolimus (E) is a potent inhibitor of mTOR, a pathway frequently activated in HCC. Preclinical data suggest that the combination S + E has additive effects compared with single-agent S. PATIENTS AND METHODS: Patients with unresectable or metastatic HCC and Child-Pugh ≤7 liver dysfunction were randomized to receive daily S 800 mg alone or with E 5 mg until progression or unacceptable toxicity. The primary end point was progression-free survival at 12 weeks (PFS12). The secondary end points included response rate, PFS, time to progression (TTP), overall survival (OS), duration of disease stabilization (DDS), safety, and quality-of-life (QoL) assessments. RESULTS: A total of 106 patients were randomized: 46 patients received S and 60 patients received S + E. Ninety-three patients were assessable for the primary end point and 105 patients for the safety analysis. The PFS12 rate was 70% [95% confidence interval (CI) 54-83] and 68% (95% CI 53-81) in patients randomized to S and S + E, respectively. The RECIST (mRECIST) response rate was 0% (23%) in the S arm and 10% (35%) in the S + E arm. Median PFS (6.6 versus 5.7 months), TTP (7.6 versus 6.3 months), DDS (6.7 versus 6.7 months), and OS (10 versus 12 months) were similar in the S and S + E arms, respectively. Grade 3/4 adverse events occurred in 72% and 86% of patients in arm S and arm S + E, respectively. Patients had similar QoL scores over time, except for a greater worsening in physical well-being and mood in the arm S + E. CONCLUSIONS: No evidence was found that S + E improves the efficacy compared with S alone. Combining 5 mg E with full-dose S is feasible, but more toxic than S alone. Further testing of this drug combination in molecularly unselected HCCs appears unwarranted. CLINICALTRIALSGOV: NCT01005199.

[Gastrointestinal stromal tumours (GIST)--development in pathology, surgery and medical therapy. Developed during the 10th German GIST-meeting, Göttingen]. / Gastrointestinale Stromatumoren (GIST)--Neues zu Pathologie, Chirurgie und medikamentöser Therapie. Erarbeitet im Rahmen des 10. Deutschen GIST-Treffens, Göttingen.

The first description of ligand-independent activating mutations in the KIT gene, which encodes the tyrosine-kinase KIT, greatly improved our understanding of gastrointestinal stromal tumour (GIST) biology. The therapeutic success in GIST has made tyrosine kinase inhibitors a "paradigm of targeted therapy". Deciphering resistance mechanisms in GIST has had implications for many other kinase-driven cancers. To exchange current knowledge within the field of GIST, the German GIST Meeting has taken place for now 10 years, traditionally in Göttingen. Subjects discussed include clinical diagnostics, pathology, surgery, and medical therapy. The following presentation gives an overview of the last meeting held in December 2013, including distinctive features in GIST and current data on the different topics.

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hamatologie und Onkologie OSHO-53 phase II study.

BACKGROUND: We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. PATIENTS AND METHODS: From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. RESULTS: Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. CONCLUSIONS: Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.

[Anti-angiogenic therapies for metastatic colorectal, breast and lung cancer: benefits and risks]. / Traitements antiangiogéniques des cancers métastatiques du côlon et du rectum, du sein et du poumon: bénéfices et risques.

Anti-angiogenic therapies have recently enriched the therapeutic armentarium against the most common cancers. Among these, bevacizumab, a monoclonal antibody against vascular endothelial growth factor, is currently used most frequently. While the addition of bevacizumab to chemotherapy improves overall survival in first and second line treatment of metastatic colorectal cancer, its effect in metastatic breast cancer is limited to improvements in tumor response and progression-free-survival. In non-small-cell lung cancer, the positive results of a first American phase III study have not been confirmed by a second European study and are subject to controversies. A summary of the data concerning anti-angiogenic therapies in these three cancers is presented including safety information.

[Management of hepatocellular carcinoma]. / Prise en charge du carcinome hépatocettulaire en 2010.

Hepatocellular carcinoma (HCC) is one of the most frequent malignant tumors worldwide and its incidence has increased over the last years in most developed countries. The majority of HCCs occur in the context of liver cirrhosis. Therefore, patients with cirrhosis and those with hepatitis B virus infection should enter a surveillance program. Detection of a focal liver lesion by ultrasound should be followed by further investigations to confirm the diagnosis and to permit staging. A number of curative and palliative treatment options are available today. The choice of treatment will depend on the tumor stage, liver function and the presence of portal hypertension as well as the general condition of the patient. A multidisciplinary approach is mandatory to offer to each patient the best treatment.

Contributi scientifici in memoria di Antonio Fusco.

Come si leggerà nell'Introduzione della sezione propriamente scientifica del Volume, il presente testo nasce dalla volontà e, soprattutto, dall'esigenza culturale di omaggiare il fu Prof. Antonio Fusco. Un debito scientifico ed umano che trova il suo locus naturale in questa prima parte del testo stesso, cui farà poi seguito la parte propriamente scientifica. In siffatta parentesi dovuta per le ragioni appena menzionate, il lettore, l'amico o l'allievo dell'opera del Prof. Fusco potranno trovare un suo sintetico Curriculum Vitae, correlato da una specifica ed accurata prosa, svolta dal già Magnifico Rettore Carlo Cipolli; il quale, oltre che evidenziare, ricordando, i meriti del collega oramai scomparso, aggiunge alsuo scritto un elemento che sarebbe imprescindibile a non trasformare lo stesso in una mera sequenza di parole: l'amicizia e l'affetto per un amico che, oramai, non c'è più. A fine lettura, evidente risuonerà il fatto che la vita di ognuno, se mossa dalla passione per ciò per cui si è predisposti cognitivamente e psicologicamente, può essere ricca di riconoscimenti, riconoscenze e soddisfazioni che, lungi dal divenire un cuscino di allori su cui adagiarsi, per una mente creativa come quella del Prof. Fusco hanno funto solo da motivazioni ad agire instancabilmente guardando sempre al futuro. Il lavoro di una vita che, materialmente, è sancito da un supporto poco più di cm 25x15: una targa. Una materialità evidente che, con grande commozione e riconoscenza, è stata affissa il 25 ottobre 2019 sull'aula fronte l'Aula Magna del Campus "La Folcara", a testimonianza che quello spirito creativo in continua evoluzione non si ferma; non si arresta neppure con la fine biologica di chi lo ha "posseduto". Rimangono le opere ed il pensiero del Prof. Fusco e restano gli affetti. A tal proposito, il lettore troverà una breve e sentita sezione su Testimonianze; coloro i quali hanno avuto modo, nell'arco della vita accademica ed umana, personale, di Fusco di conoscerlo. Ecco, allora, che i ricordi saranno i veri protagonisti di questa parentesi. Dopo di ciò, prima dei contributi prettamente scientifici dei lavori, tenutisi in occasione del Convegno Internazionale Psicologia, Arte, Letteratura. Antiche e Nuove Tendenze, seguiranno i saluti delle autorità che in quei due giorni si sono succedute a rappresentare non solo l'istituzione affiliata, ma anche la relazione di stima e di affetto che le legava al compianto Professore. Si passerà, infine, al volume tradizionalmente inteso.

Lactic Acid Fermentation of Pomegranate Juice as a Tool to Improve Antioxidant Activity.

An increasing consumer demand for pomegranate has been globally observed, mainly thanks to the scientific evidence related to its functional and health-promoting features. Pomegranate fruits from twenty accessions identified in Southeastern Italy were characterized according to morphological and chemical features. Juices extracted from pomegranate fruits were fermented with selected Lactobacillus plantarum PU1 and the antioxidant activity investigated. Whey was added to juices to promote the microbial growth. Fermentation led to the increase of the radical scavenging activity (up to 40%) and significant inhibition of the linoleic acid peroxidation. The three fermented juices showing the highest antioxidant activity, and the corresponding unfermented controls, were further characterized. In detail, the cytotoxicity and the protective role toward artificially induced oxidative stress were determined on murine fibroblasts Balb 3T3 through the determination of the viability and the intracellular ROS (reactive oxygen species) scavenging activity (RSA). RSA reached values of ca. 70% in fermented juices, being ca. 40% higher than the unfermented and control samples. Phenols compounds of the pomegranate juices obtained from accessions "Bitonto Piscina," "Sanrà nero," and "Wonderful (reference cultivar) were analyzed through ultrahigh pressure liquid chromatography coupled with mass spectrometry, showing that a marked increase (up to 60%) of the ellagitannins derivatives occurred during fermentation. Sensory analysis showed suitability of the fermented juices to be used as beverage and food ingredient.

[Systemic treatment of metastatic colorectal cancer]. / Traitements systémiques du cancer colorectal métastatique.

Colorectal cancer is the 2nd cause of cancer related death in industrialised countries. 20% of all patients present with metastatic disease at diagnosis and need systemic treatment. Since the introduction of irinotecan and oxaliplatin as part of standard chemotherapy, and recently the new targeted agents bevacizumab, cetuximab and panitumumab, the overall survival for patients suffering from metastatic colorectal cancer (mCRC) has increased significantly and nearly reaches 2 years nowadays. Surgery or radiofrequency ablation has become central in the care of metastatic disease. This article resumes recent therapeutic advances in the field and emphasizes the multidisciplinary concertation between specialists to obtain the best outcome.

Real time PCR for the assessment of CD8+ T cellular immune response after prophylactic vaccinia vaccination.

BACKGROUND: The magnitude of specific CD8+ T cell reactivity responsible for vaccine-induced protection against smallpox infection has not yet been fully elucidated. Among other techniques, RT-PCR for the monitoring of cytokine release in effector T cells against tumor and viral antigens has demonstrated a novel promising method. OBJECTIVE: To determine the functional status of antigen specific CD8+ T cells in healthy participants before and 4 weeks after prophylactic vaccination (Lister strain) against smallpox using quantitative real-time PCR (qRT-PCR). STUDY DESIGN: Changes of interferon-gamma (IFNgamma) mRNA expression levels on short term ex vivo peptide antigen stimulation were measured. The corresponding specific CD8+ T cell reactivity was then displayed as CD8-normalized IFN-gamma levels (IFN-gamma/CD8 ratio). RESULTS: We found a 5-9 fold increase of CD8+ T cell reactivity in three out of four vaccinated individuals. The kinetics and strength determined in responders reveal a virus specific T cell effector repertoire pre-vaccination and a corresponding functional state after immunization comparable also to data obtained from tetramer- and ELISPOT analysis. CONCLUSIONS: Apart from protective vaccinia-specific neutralizing antibodies, the presence of antigen-specific CD8+ T-cells has been demonstrated after vaccinia vaccination. In concordance with others, results from this PCR-based study indicate that this smallpox vaccine induces strong vaccinia virus-specific CD8+ and IFN-gamma producing T cell responses.

Effects of late administration of tissue-type plasminogen activator on left ventricular remodeling and function after myocardial infarction.

To evaluate the effects of late thrombolysis on left ventricular volume and function in acute myocardial infarction, two-dimensional echocardiography and radionuclide angiography were performed before discharge and after 1 year of follow-up study in 34 patients with acute anterior myocardial infarction. Of these, 10 admitted to the coronary care unit within 4 h from the onset of symptoms were treated with recombinant tissue-type plasminogen activator (rt-PA) (Group A) and 24 admitted between 4 and 8 h after onset were randomly assigned to receive either rt-PA (Group B, n = 12) or conventional therapy (Group C, n = 12). Seven to 10 days after admission, all patients underwent cardiac catheterization and coronary angiography. Patency of the infarct-related vessel was 70% in Group A, 66% in Group B and 33% in Group C and the average Thrombolysis in Myocardial Infarction (TIMI) coronary perfusion grade was 1.9 +/- 0.8 for Group A, 1.6 +/- 1.0 for Group B and 0.84 +/- 0.95 for Group C (Group A versus Group C p less than 0.01; Group B versus Group C p less than 0.05). At predischarge evaluation, mean left ventricular end-systolic and end-diastolic volumes were higher in Group C than in Group B (p less than 0.001 and 0.05, respectively) and Group A (p less than 0.005 for both); mean left ventricular ejection fraction at rest was lower in Group C than in Group B and Group A (p less than 0.05 for both). At 1 year follow-up study, end-systolic and end-diastolic volumes remained higher in Group C than in Group B (p less than 0.05 for both) and Group A (p less than 0.005 for end-systolic volume and p less than 0.001 for end-diastolic volume); ejection fraction at rest was lower in Group C than in Groups A and B (p less than 0.05 for both); during exercise, it increased more in Group A than in Group C (p less than 0.01). Comparison of data obtained before discharge and at the 1 year follow-up study revealed a significant differences in end-systolic volume (p less than 0.05) in Group C patients and in end-diastolic volume in patients in Groups B (p less than 0.05) and C (p less than 0.001). The beneficial effect of late thrombolysis with rt-PA may be related to a reduction in myocardial expansion and thus to a favorable influence on postinfarction left ventricular remodeling.

Effects of captopril treatment on left ventricular remodeling and function after anterior myocardial infarction: comparison with digitalis.

The effects of captopril and digoxin treatment on left ventricular remodeling and function after anterior myocardial infarction were evaluated in a randomized unblinded trial. Fifty-two patients with a first transmural anterior myocardial infarction and a radionuclide left ventricular ejection fraction less than 40% were randomly assigned to treatment with captopril (Group A) or digoxin (Group B). The two groups had similar baseline hemodynamic, coronary angiographic, echocardiographic and radionuclide angiographic variables. Among the 40 patients (20 in each group) who were followed up for 1 year, echocardiographic end-diastolic and end-systolic volumes were unmodified in Group A and global wall motion index was improved (p less than 0.01); in Group B, end-diastolic and end-systolic volumes increased (p less than 0.001 for both) and global wall motion index was unchanged. Rest radionuclide ejection fraction increased significantly in both groups (p less than 0.001, Group A; p less than 0.005, Group B). A comparison of the changes in the considered variables between the two groups after 1 year of treatment showed a difference in end-diastolic (p less than 0.005) end-systolic volumes (p less than 0.001) and global wall motion index (p less than 0.005) without differences in radionuclide ejection fraction, which improved to a similar degree in both groups. The results of this study suggest that captopril therapy, started 7 to 10 days after symptom onset in patients with anterior myocardial infarction and an ejection fraction less than 40%, improves both left ventricular remodeling and function and prevents left ventricular enlargement and in these patients performs better than digitalis.