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Background: Many gastric cancer patients in Western countries are diagnosed as metastatic with a median overall survival of less than twelve months using standard chemotherapy. Innovative treatments, like targeted therapy or immunotherapy, have recently proved to ameliorate prognosis, but a general agreement on managing oligometastatic disease has yet to be achieved. An international multi-disciplinary workshop was held in Bertinoro, Italy, in November 2022 to verify whether achieving a consensus on at least some topics was possible., Methods: A two-round Delphi process was carried out, where participants were asked to answer 32 multiple-choice questions about CT, laparoscopic staging and biomarkers, systemic treatment for different localization, role and indication of palliative care. Consensus was established with at least a 67% agreement., Results: The assembly agreed to define oligometastases as a "dynamic" disease which either regresses or remains stable in response to systemic treatment. In addition, the definition of oligometastases was restricted to the following sites: para-aortic nodal stations, liver, lung, and peritoneum, excluding bones. In detail, the following conditions should be considered as oligometastases: involvement of para-aortic stations, in particular 16a2 or 16b1; up to three technically resectable liver metastases; three unilateral or two bilateral lung metastases; peritoneal carcinomatosis with PCI ≤ 6. No consensus was achieved on how to classify positive cytology, which was considered as oligometastatic by 55% of participants only if converted to negative after chemotherapy., Conclusion: As assessed at the time of diagnosis, surgical treatment of oligometastases should aim at R0 curativity on the entire disease volume, including both the primary tumor and its metastases. Conversion surgery was defined as surgery on the residual volume of disease, which was initially not resectable for technical and/or oncological reasons but nevertheless responded to first-line treatment., (© 2024. The Author(s).)

Introduction: The Italian Research Group for Gastric Cancer developed a prospective database about stage IV gastric cancer, to evaluate how a pragmatic attitude impacts the management of these patients., Materials and Methods: We prospectively collected data about metastatic gastric cancer patients thanks to cooperation between radiologists, oncologists and surgeons and we analyzed survival and prognostic factors, comparing the results to those obtained in our retrospective study., Results: Three-hundred and eighty-three patients were enrolled from 2018 to September 2022. We observed a higher percentage of laparoscopic exploration with peritoneal lavage in the prospective cohort. In the registry only 3.6 % of patients was submitted to surgery without associated chemotherapy, while in the retrospective population 44.3 % of patients were operated on without any chemotherapy. At univariate and multivariate analyses, the different metastatic sites did not show any survival differences among each other (OS 20.0 vs 16.10 vs 16.7 months for lymphnodal, peritoneal and hepatic metastases, respectively), while the number of metastatic sites and the type of treatment showed a statistical significance (OS 16,7 vs 13,0 vs 4,5 months for 1, 2 and 3 different metastatic sites respectively, p < 0.001; 24,2 vs 12,0 vs 2,5 months for surgery with/without chemotherapy, chemotherapy alone and best supportive treatment respectively, p < 0.001)., Conclusions: Our data highlight that the different metastatic sites did not show different survivals, but survival is worse in case of multiple localization. In patients where a curative resection can be achieved, acceptable survival rates are possible. A better diagnostic workup and a more accurate staging impact favorably upon survival., Competing Interests: Declaration of competing interest All authors have no competing interests to declare., (© 2023 Published by Elsevier Ltd.)

Background: Interest in the field of metastatic gastric cancer has grown in recent years, and the identification of oligometastatic patients plays a critical role as it consents to their inclusion in multimodal treatment strategies, which include systemic therapy but also surgery with curative intent. To collect sound clinical data on this subject, The Italian Research Group on Gastric Cancer developed a prospective multicentric observational register of metastatic gastric cancer patients called META-GASTRO., Methods: Data on 383 patients in Meta-Gastro were mined to help our understanding of oligometastatic, according to its double definition: quantitative/anatomical and dynamic., Results: the quantitative/anatomical definition applies to single-site metastases independently from the metastatic site ( p < 0.001) to peritoneal metastases with PCI ≤ 12 ( p = 0.009), to 1 or 2 hepatic metastases ( p = 0.024) and nodal metastases in station 16 ( p = 0.002). The dynamic definition applies to a percentage of cases variable according to the metastatic site: 8%, 13.5 and 23.8% for hepatic, lymphatic and peritoneal sites, respectively. In all cases, the OS of patients benefitting from conversion therapy was similar to those of cases deemed operable at diagnosis and operated after neoadjuvant chemotherapy., Conclusions: META-GASTRO supports the two-fold definition of oligometastatic gastric cancer: the quantitative/anatomical one, which accounts for 30% of our population, and the dynamic one, observed in 16% of our cases.

Background  Liquid biopsy is mainly used to identify tumor cells in pulmonary neoplasms. It is more often used in research than in clinical practice. The BL-MOL-AR study aims to investigate the efficacy of next-generation sequencing (NGS) and clinical interpretation of the circulating free DNA (cfDNA) levels. This study reports the preliminary results from the first samples analyzed from patients affected by various neoplasms: lung, intestinal, mammary, gastric, biliary, and cutaneous. Methods  The Biopsia Liquida-Molecolare-Arezzo study aims to enroll cancer patients affected by various malignancies, including pulmonary, intestinal, advanced urothelial, biliary, breast, cutaneous, and gastric malignancies. Thirty-nine patients were included in this preliminary report. At time zero, a liquid biopsy is executed, and two types of NGS panels are performed, comprising 17 genes in panel 1, which is already used in the routine tissue setting, and 52 genes in panel 2. From the 7th month after enrollment, 10 sequential liquid biopsies are performed up to the 17th month. The variant allele frequency (%) and cfDNA levels (ng/mL) are measured in every plasmatic sample. Results  The NGS results obtained by different panels are similar even though the number of mutations is more concordant for lung pathologies. There are no significant differences in the actionability levels of the identified variants. Most of the molecular profiles of liquid biopsies reflect tissue data. Conclusions  Preliminary data from this study confirm the need to clarify the limitations and potential of liquid biopsy beyond the lung setting. Overall, parameters related to cfDNA levels and variant allele frequency could provide important indications for prognosis and disease monitoring., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: Several studies report the useful therapeutic results of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer. Modulated electro-hyperthermia (mEHT) is a new hyperthermia technique that induces immunogenic death or apoptosis of pancreatic cancer cells in laboratory experiments and increases tumor response rate and survival in pancreatic cancer patients, offering beneficial therapeutic effects against this severe type of cancer., Aim: To assess survival, tumor response and toxicity of mEHT alone or combined with CHT compared with CHT for the treatment of locally advanced or metastatic pancreatic cancer., Methods: This was a retrospective data collection on patients affected by locally advanced or metastatic pancreatic cancer (stage III and IV) performed in 9 Italian centers, members of International Clinical Hyperthermia Society-Italian Network. This study included 217 patients, 128 (59%) of them were treated with CHT (no-mEHT) and 89 (41%) patients received mEHT alone or in association with CHT. mEHT treatments were performed applying a power of 60-150 watts for 40-90 min, simultaneously or within 72 h of administration of CHT., Results: Median patients' age was 67 years (range 31-92 years). mEHT group had a median overall survival greater than non-mEHT group (20 mo, range 1.6-24, vs 9 mo, range 0.4-56.25, P < 0.001). mEHT group showed a higher number of partial responses (45% vs 24%, P = 0.0018) and a lower number of progressions (4% vs 31%, P < 0.001) than the no-mEHT group, at the three months follow-up. Adverse events were observed as mild skin burns in 2.6% of mEHT sessions., Conclusion: mEHT seems safe and has beneficial effects on survival and tumor response of stage III-IV pancreatic tumor treatment. Further randomized studies are warranted to confirm or not these results., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

We read, with great interest, the article by Huang Ruo-Yi and colleagues entitled "Outcomes of Conversion Surgery for Metastatic Gastric Cancer Compared with In-Front Surgery Plus Palliative Chemotherapy or In-Front Surgery Alone", published on 1 April 2022 [...].

Background: An increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer; in particular, the use of modulated electro-hyperthermia (mEHT) results in increased survival and tumor response., Aim: To compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer., Methods: This was an observational retrospective study; data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019. A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals; 58 (37%) of these received CHT + mEHT and 100 (63%) CHT. CHT was mainly gemcitabine-based regimens in both groups., Results: Overall (19.5 mo vs 11.02 mo, P < 0.001) and progression-free (12 mo vs 3 mo, P < 0.001) survival were better for the CHT + mEHT group compared to the CHT group. The association of mEHT resulted also in an improvement of tumor response with disease control rate 95% vs 58% ( P < 0.001) at 3 mo. Toxicity was comparable in the two study groups, and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns., Conclusion: The addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity., Competing Interests: Conflict-of-interest statement: No conflict of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: To validate a nodal regression system for gastric cancer and to verify its impact on prognosis., Methods: This is an ancillary study which included 47 patients of the GASTRODOC trial. The dedicated pathologists of each Institute were invited to revise all the lymph nodes included in the surgical specimens in order to classify the regression according to the grading system proposed by Tsekrekos et al. The association of the nodal regression system and the clinico-pathological characteristics and prognosis were investigated., Results: According to the classification of Tsekrekos et al., there were 19 (40.4%) patients with grade a, 14 (29.8%) with grade b and 14 (29.8%) with grade c nodal regression. This regression system showed significant statistical associations with pathological N status (p < 0.001), residual tumor classification (p = 0.003) and Becker regression system (p = 0.011). At multivariable analysis only Tsekrekos' grading regression system was significantly associated with the PFS (HR 10.1, 95% CI 1.3-75.5; p = 0.025)., Conclusions: The analyzed nodal regression system is significantly associated with Becker's regression system and it has a strong correlation with prognosis., (Copyright © 2021. Published by Elsevier Ltd.)

Docetaxel associated with oxaliplatin and 5-fluorouracil (FLOT) has been reported as the best perioperative treatment for gastric cancer. However, there is still some debate about the most appropriate number and timing of chemotherapy cycles. In this randomized multicenter phase II study, patients with resectable gastric cancer were staged through laparoscopy and peritoneal lavage cytology, and randomly assigned (1:1) to either four cycles of neoadjuvant chemotherapy (arm A) or two preoperative + two postoperative cycles of docetaxel, oxaliplatin, and capecitabine (DOC) chemotherapy (arm B). The primary endpoint was to assess the percentage of patients receiving all the planned preoperative or perioperative chemotherapeutic cycles. Ninety-one patients were enrolled between September 2010 and August 2016. The treatment was well tolerated in both arms. Thirty-three (71.7%) and 24 (53.3%) patients completed the planned cycles in arms A and B, respectively ( p = 0.066), reporting an odds ratio for early interruption of treatment of 0.45 (95% confidence interval (CI): 0.18-1.07). Resection was curative in 39 (88.6%) arm A patients and 35 (83.3%) arm B patients. Five-year progression-free survival (PFS) was 51.2% (95% CI: 34.2-65.8) in arm A and 40.3% (95% CI: 28.9-55.2) in arm B ( p = 0.300). Five-year survival was 58.5% (95% CI: 41.3-72.2) and 53.9% (95% CI: 35.5-69.3) ( p = 0.883) in arms A and B, respectively. The planned treatment was more frequently completed and was more active, albeit not significantly, in the neoadjuvant arm than in the perioperative group.

Aims: A multicentre trial, ICOS-ONE, showed increases above the upper limit of normality of cardiac troponin (cTn) in 27% of patients within 12 months after the end of cancer chemotherapy (CT) with anthracyclines, whether cardiac protection with enalapril was started at study entry in all (prevention arm) or only upon first occurrence on supra-normal cTn (troponin-triggered arm). The aims of the present post hoc analysis were (i) to assess whether anthracycline-based treatment could induce cardiotoxicity over 36 month follow-up and (ii) to describe the time course of three cardiovascular biomarkers (i.e. troponin I cTnI-Ultra, B-type natriuretic peptide BNP, and pentraxin 3 PTX3) and of left ventricular (LV) function up to 36 months., Methods and Results: Eligible patients were those prescribed first-in-life CT, without evidence of cardiovascular disease, normal cTn, LV ejection fraction (EF) >50%, not on renin-angiotensin aldosterone system antagonists. Patients underwent echocardiography and blood sampling at 24 and 36 months. No differences were observed in biomarker concentration between the two study arms, 'prevention' vs. 'troponin-triggered'. During additional follow-up 13 more deaths occurred, leading to a total of 23 (9.5%), all due to a non-cardiovascular cause. No new occurrences of LV-dysfunction were reported. Two additional patients were admitted to the hospital for cardiovascular causes, both for acute pulmonary embolism. No first onset of raised cTnI-Ultra was reported in the extended follow-up. BNP remained within normal range: at 36 months was 23.4 ng/L, higher (N.S.) than at baseline, 17.6 ng/L. PTX3 peaked at 5.2 ng/mL 1 month after CT and returned to baseline values thereafter. cTnI-Ultra peaked at 26 ng/L 1 month after CT and returned to 3 ng/L until the last measurement at 36 months. All echocardiographic variables remained stable during follow-up with a median LVEF of 63% and left atrial volume index about 24 mL/m 2 ., Conclusions: First-in-life CT with median cumulative dose of anthracyclines of 180 mg/m 2 does not seem to cause clinically significant cardiac injury, as assessed by circulating biomarkers and echocardiography, in patients aged 51 years (median), without pre-existing cardiac disease. This may suggest either a 100% efficacy of enalapril (given as preventive or troponin-triggered) or a reassuringly low absolute cardiovascular risk in this cohort of patients, which may not require intensive cardiologic follow-up., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired., Methods: We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone versus first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported., Results: The overall effect of B across the two lines resulted in a HR = 0.80 (95% CI 0.68-0.95, p  = 0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR = 0.90, 95% CI 0.72-1.12, p  = 0.340) versus CT alone; B added to second-line CT produced a 36% risk reduction (HR = 0.64, 95% CI 0.49-0.84, p  = 0.0011) versus CT alone., Conclusion: Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Background: Pancreatic adenocarcinoma has a poor prognosis, resulting in a <10% survival rate at 5 years. Modulated electro-hyperthermia (mEHT) has been increasingly used for pancreatic cancer palliative care and therapy. Objective: To monitor the efficacy and safety of mEHT for the treatment of advanced pancreatic cancer. Methods: We collected data retrospectively on 106 patients affected by stage III-IV pancreatic adenocarcinoma. They were divided into 2 groups: patients who did not receive mEHT (no-mEHT) and patients who were treated with mEHT. We performed mEHT applying a power of 60 to 150 W for 40 to 90 minutes. The mEHT treatment was associated with chemotherapy and/or radiotherapy for 33 (84.6%) patients, whereas 6 (15.4%) patients received mEHT alone. The patients of the no-mEHT group received chemotherapy and/or radiotherapy in 55.2% of cases. Results: Median age of the sample was 65.3 years (range = 31-80 years). After 3 months of therapy, the mEHT group had partial response in 22/34 patients (64.7%), stable disease in 10/34 patients (29.4%), and progressive disease in 2/34 patients (8.3%). The no-mEHT group had partial response in 3/36 patients (8.3%), stable disease in 10/36 patients (27.8%), and progressive disease in 23/36 patients (34.3%). The median overall survival of the mEHT group was 18.0 months (range = 1.5-68.0 months) and 10.9 months (range = 0.4-55.4 months) for the non-mEHT group. Conclusions: mEHT may improve tumor response and survival of pancreatic cancer patients.

Background: There are interesting studies on glioma therapy with modulated electrohyperthermia (mEHT), which combines heat therapy with an electric field. Clinical researchers not only found the mEHT method feasible for palliation but also reported evidence of therapeutic response., Purpose: To study the efficacy and safety of mEHT for the treatment of relapsed malignant glioma and astrocytoma versus best supportive care (BSC)., Methods: We collected data retrospectively on 149 patients affected by malignant glioma and astrocytoma. Inclusion criteria were informed consent signed; >18 years old; histological diagnosis of malignant glioma or astrocytoma; relapsed after surgery, adjuvant temozolomide-based chemotherapy, and radiotherapy; and indication for treatment with mEHT in palliative setting. mEHT was performed with capacitive coupling technique keeping the skin surface at 26°C and the tumor temperature at 40°C to 42.5°C for > 90% of treatment duration (20-60 minutes). The applied power was 40 to 150 W using a step-up heating protocol. Results from patients treated with mEHT were compared with those treated with BSC., Results: A total of 149 consecutive patients were enrolled in the study, 111 (74%) had glioblastoma multiforme (GBM), and 38 (26%) had astrocytoma (AST). mEHT was performed for 28 (25%) of GBM and 24 (63%) of AST patients. Tumor response at the 3-month follow-up was observed in 29% and 48% of GBM and AST patients after mEHT, and in 4% and 10% of GBM and AST patients after BSC, respectively. The survival rate at first and second year in the mEHT group was 77.3% and 40.9% for AST, and 61% and 29% for GBM, respectively. The 5-year overall survival of AST was 83% after mEHT versus 25% after BSC and 3.5% after mEHT versus 1.2% after BSC for GBM. The median overall survival of mEHT was 14 months (range 2-108 months) for GBM and 16.5 months (range 3-156 months) for the AST group. We observed 4 long-term survivors in the AST and 2 in the GBM group. Two of the long survivors in AST and 1 in GBM group were treated by mEHT., Conclusions: mEHT in integrative therapy may have a promising role in the treatment and palliation of relapsed GBM and AST.

Background: Troponin changes over time have been suggested to allow for an early diagnosis of cardiac injury ensuing cancer chemotherapy; cancer patients with troponin elevation may benefit of therapy with enalapril. It is unknown whether a preventive treatment with enalapril may further increase the benefit., Methods: The International CardioOncology Society-one trial (ICOS-ONE) was a controlled, open-label trial conducted in 21 Italian hospitals. Patients were randomly assigned to two strategies: enalapril in all patients started before chemotherapy (CT; 'prevention' arm), and enalapril started only in patients with an increase in troponin during or after CT ('troponin-triggered' arm). Troponin was assayed locally in 2596 blood samples, before and after each anthracycline-containing CT cycle and at each study visit; electrocardiogram and echocardiogram were done at baseline, and at 1, 3, 6 and 12-month follow-up. Primary outcome was the incidence of troponin elevation above the threshold., Findings: Of the 273 patients, 88% were women, mean age 51 ± 12 years. The majority (76%) had breast cancer, 3% had a history of hypertension and 4% were diabetic. Epirubicin and doxorubicin were most commonly prescribed, with median cumulative doses of 360 [270-360] and 240 [240-240] mg/m 2 , respectively. The incidence of troponin elevation was 23% in the prevention and 26% in the troponin-triggered group (p = 0.50). Three patients (1.1%) -two in the prevention, one in the troponin-triggered group-developed cardiotoxicity, defined as 10% point reduction of LV ejection fraction, with values lower than 50%., Interpretation: Low cumulative doses of anthracyclines in adult patients with low cardiovascular risk can raise troponins, without differences between the two strategies of giving enalapril. Considering a benefit of enalapril in the prevention of LV dysfunction, a troponin-triggered strategy may be more convenient., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This article reports the guidelines for gastric cancer staging and treatment developed by the GIRCG, and contains comprehensive indications for clinical management, including radiological, endoscopic, surgical, pathological, and oncological paths.

Background: Although small-cell lung cancer is a chemosensitive malignancy, most patients rapidly relapse. Results of second-line treatment are generally poor. We conducted a phase II study to evaluate the activity and toxicity of a combination of gemcitabine and paclitaxel as second-line chemotherapy., Patients and Methods: Eligible patients were refractory or relapsed small-cell lung cancer, with an Eastern Cooperative Oncology Group performance status of 0-2 and measurable disease. Paclitaxel was administered at 135 mg/m(2) days 1 and 8 immediately followed by gemcitabine at 1000 mg/m(2) every 3 weeks up to 6 courses. Restaging of disease was scheduled every 3 courses., Results: Forty-one patients were enrolled. The median age was 65 years. Nineteen patients were considered refractory (progressive disease during or within 90 days from completion of first-line treatment), whereas 22 patients were chemotherapy sensitive. A total of 135 courses was administered (range, 1-6; median, 3). Nine patients achieved a partial remission (partial response, 22%), and 10 patients had stable disease (24%), with a disease control rate (partial response + stable disease) of 46%: in 12 (55%) of 22 patients who were sensitive and in 7 (37%) of 19 patients with refractory disease, respectively. All partial responses but one were observed in the sensitive group. The median duration of response was 5 months. The most-frequent severe toxicities were neutropenia grade 3-4 and neurologic grade 3 in 24% and 7% of delivered courses, respectively., Conclusions: The combination of gemcitabine and paclitaxel investigated in our study achieved a high disease control rate, but the schedule we adopted appeared to be quite toxic., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation., Methods: Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS)>60, gross total resection of stage IB-III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, α=.05 and β=.10, the study was to enroll 51 patients per arm., Results: A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS>80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities., Conclusions: The 4-drug regimen deserves further assessment in resectable pancreatic cancer.

Background/aims: Natural history of renal cell carcinoma includes metastases to the pancreas. The literature reports that selected patients may have benefits by pancreatic resection in terms of long term survival. We report patient outcome and considerations on immunotherapy approach., Methodology: From 2001 to 2010 eight patients underwent pancreatic resection for metastases from renal cancer. We reviewed surgical outcome and following treatment (conventional chemotherapy: 5FU-Vindesine; Immunotherapy: Interleukin 2 - Interferon - Dendritic cells) of these patients., Results: All patients underwent radical pancreatic resection (7 spleno-pancreatectomies; 1 segmental pancreatic resection) and were R0 after surgery. No postoperative mortality was reported. Morbidity was 37% (2 distal leakage; 1 pneumonitis). Two patients did not receive any further treatment; 2 patients received conventional chemotherapy; 2 patients received immunotherapy (interleukin2 + interferon); 2 patients received dendritic cells (DC) interleukin-2 infusion. Three years overall survival rate was 55%. Disease free survival after 3 years was 30%., Conclusions: Our data confirm that pancreatic resection should be offered to selected patients with no mortality and low morbidity. Long-term survival is achievable, but recurrence rate after surgery is high. Immunotherapy could be effective to control tumour progression especially in selected cases where DC may be used.

The liver is the primary site of metastases in most uveal melanoma patients. We retrospectively investigated intraarterial chemotherapy (IAC) as treatment for patients with hepatic melanoma metastases.Twenty-three patients (18 with uveal melanoma) received fotemustine (14 patients, 61.9%) or carboplatin (9 patients, 31.1%) via hepatic IAC delivery. The catheter was introduced through percutaneous access to the femoral artery with drugs delivered directly to the hepatic artery, and was removed at the end of each treatment cycle. A total of 3 cycles was planned, repeated every 21 days. However, patients with a clinical response could receive more than 3 cycles, provided that the toxic effects were acceptable.IAC was well tolerated and no catheter-related complications or grade 4 toxicities were reported. Considering only uveal melanoma patients, the overall response rate and disease control rate was 16.7% and 38.9%, respectively. Median time to progression was 6.2 months (95% CI 3.7-10.5) and median overall survival was 21 months (95% CI 8-39).IAC is well tolerated and is a valid choice for patients with a poor prognosis since median survival rates are among the longest reported.

Aim: To assess the activity and safety of non-pegylated liposomal doxorubicin (Myocet®) in combination with docetaxel and trastuzumab as first-line treatment of patients with HER-2/neu-positive metastatic breast cancer (MBC)., Patients and Methods: The maximum tolerated dose of the combination was defined in the phase I part of the study. In the phase II part, 45 HER-2/neu-positive MBC patients were enrolled to receive 6-8 cycles of Myocet® 50 mg/m2 (day 1), docetaxel 30 mg/m2 (days 2 and 9) plus trastuzumab (day 2, 4 mg/kg followed by 2 mg/kg/week) every 21 d until unacceptable toxicity or progression occurred. Objective response (primary end-point) and treatment tolerability were assessed according to World Health Organisation criteria. Cardiotoxicity was defined as signs and/or symptoms of congestive heart failure and/or a decrease in left ventricular ejection fraction (LVEF)., Results: The overall response rate was 55.6% (complete response 8.9%, partial response 46.7%), with a median time-to-progression of 10.9 months (C.I. 8.7-15.0). Median overall survival was not reached. The most frequent grade 3-4 adverse events were granulocytopaenia (60.0%), leukocytopenia (43.2%) and alopecia (35.6%). Grade 3-4 diarrhoea, pain, oral and skin toxicity (4.4%, each) and nausea/vomiting, thrombocytopenia and elevated alkaline phosphatase (2.2%, each) were also reported. In 2 patients LVEF fell to <50%, with a decrease from baseline>15%. LVEF median values remained stable from baseline to the end of the study (60%)., Conclusions: The combination of Myocet®, docetaxel and trastuzumab is safe and shows promising activity as first-line treatment of HER-2-positive MBC., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background/aims: The aim of this prospective phase II study was to evaluate the effect of neoadjuvant GEMOX plus helical tomotherapy on the resectability of locally advanced pancreatic cancer., Methodology: Between November 2004 and July 2008, 33 enrolled patients received gemcitabine (GEM) 1000 mg/m2 on day 1, and oxaliplatin (OX) 100 mg/m2 on day 2, every two weeks for 3-4 cycles. This was followed by radiotherapy (25 Gy, 5 fractions), 15 days after completion of GEMOX. Patients then received a further 3-4 cycles of GEMOX, underwent restaging and were evaluated for surgery. Potentially resectable patients were submitted to surgery, while unresectable responders received further GEMOX and radiotherapy., Results: Toxicity to GEMOX was similar to that reported elsewhere and radiotherapy was also well tolerated. After treatment, one patient achieved a complete response, 14 had a partial response, 11 showed a stable disease, 6 progressed, and one was not evaluable. Eight patients (24%) underwent surgical laparotomy (7 radical pancreatic resections and one explorative laparotomy)., Conclusions: Our study shows the feasibility and potential efficacy of the GEMOX plus helical tomotherapy regimen in unresectable locally advanced pancreatic cancer.

Introduction: We describe a case of acute hiatal hernia during chemotherapy, in a female patient previously treated with gastrectomy., Case Presentation: After gastric resection, the patient underwent chemotherapy, developing important emetic symptoms. A radiograph of the abdomen was performed because of acute epigastrial pain and it showed a marked left diaphragm elevation.A CT scan carried out 24 hours later identified an occlusion with herniation in the left hemi thorax. Subsequent surgical investigation resulted in a diagnosis of hiatal hernia with volvulus., Conclusions: This case represents a rare, late complication occurring after gastrectomy.

The response of pancreatic cancer to treatments remains unsatisfactory, highlighting the need for more effective therapeutic regimens. Sorafenib, an orally available multikinase inhibitor, is active against different tumors, including pancreatic cancer. We studied the antitumor efficacy of sorafenib in combination with different antitumor drugs currently used in clinical practice in in vitro and in vivo experimental models of human pancreatic cancer. The cytotoxic effect of sorafenib and conventional antitumor drug combinations was evaluated in vitro in human pancreatic cancer cell lines and the efficacy of the most active combination was tested on tumor-bearing mice. Flow cytometric, Western blot and immunohistochemistry analyses were performed to investigate the mechanisms involved in the activity of single drugs and in their interaction when used in combination. Sorafenib showed a strong sequence-dependent synergistic interaction in vitro with docetaxel, which was highly dependent on the drug sequence employed. In vivo, human pancreatic cancer-xenografted mice treated with docetaxel followed by sorafenib reduced and delayed tumor growth, with complete tumor regression observed in half of the mice. This marked antitumor effect resulted in an overall increase in mouse survival of about 70% and in a complete cure in 3 of the 8 treated mice. The strong activity was also accompanied by marked apoptosis induction, inhibition of tumor angiogenesis and downregulation of ERK signalling. Our results show that the docetaxel and sorafenib combination exerts high therapeutic efficacy in experimental models of human pancreatic cancer, indicating a promising antitumor strategy for clinical use.

Background: Docetaxel and gemcitabine combinations have proven active for the treatment of non-small cell lung cancer (NSCLC). The aim of the present study was to evaluate and compare two treatment schedules, one based on our own preclinical data and the other selected from the literature., Methods: Patients with stage IV NSCLC and at least one bidimensionally-measurable lesion were eligible. Adequate bone marrow reserve, normal hepatic and renal function, and an ECOG performance status of 0 to 2 were required. No prior chemotherapy was permitted. Patients were randomized to arm A (docetaxel 70 mg/m2 on day 1 and gemcitabine 900 mg/m2 on days 3-8, every 3 weeks) or B (gemcitabine 900 mg/m2 on days 1 and 8, and docetaxel 70 mg/m2 on day 8, every 3 weeks)., Results: The objective response rate was 20% (95% CI:10.0-35.9) and 18% (95% CI:8.6-33.9) in arms A and B, respectively. Disease control rates were very similar (54% in arm A and 53% in arm B). No differences were noted in median survival (32 vs. 33 weeks) or 1-year survival (33% vs. 35%). Toxicity was mild in both treatment arms., Conclusion: Our results highlighted acceptable activity and survival outcomes for both experimental and empirical schedules as first-line treatment of NSCLC, suggesting the potential usefulness of drug sequencing based on preclinical models., Trial Registration Number: IOR 162 02.

Background/aims: The main aim of the present work was to determine response rates and time to progression in patients with locally advanced or metastatic pancreatic cancer treated with intra-arterial chemotherapy., Methodology: Nineteen chemotherapy-naive patients with measurable lesions were treated with intra-arterial 5-fluorouracil 1000 mg/m2, leucovorin 100 mg/m2, carboplatin 300 mg/m2 and epirubicin 60 mg/m2 (FLEC regimen) every 21 days. Prophylactic granulocyte colony-stimulating factors were administered on days 4-10 of each cycle., Results: There were 16 patients evaluable for response, of whom 4 (25%) had a partial response, 7 (44%) showed stable disease, and 5 (31%) progressed. Marker response rate was 43%. Median time to progression was 4 months and median overall survival was 6 months. One-year overall survival was 16%. No grade 4 toxicity or severe complications relating to the angiographic procedure were observed., Conclusions: Our results show that intra-arterial FLEC is well tolerated and active against advanced pancreatic cancer.

Objective: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC., Methods: Pacl was infused at a fixed dose of 150 mg/m2 on day 1. UFT, at doses escalated by 50 mg/m2 starting from 200 mg/m2 . day, and LV, at a fixed dose of 90 mg/day, were given orally every 8 h for 11 days (days 3-13). Cohorts of at least 3 patients were treated at each dose level, and if 1 experienced dose-limiting toxicity (DLT), a maximum of 3 additional patients were added at the same dose level. MTD was reached if 2 out of the 6 patients experienced DLT., Results: Sixteen patients were enrolled in the study. The most important toxicity observed was hematological. Nonhematological toxicities were paresthesia and myalgia, asthenia, nausea, and mucositis. DLT occurred in only 1 patient (grade 3 hepatic toxicity)., Conclusions: The recommended dose for a subsequent phase II trial is Pacl 150 mg/m2 on day 1, and UFT 300 mg/m2 and LV 90 mg on days 3-13, every 2 weeks., (Copyright 2007 S. Karger AG, Basel.)

Limited information on salvage treatment in patients affected by pancreatic cancer is available. At failure, about half of the patients present good performance status (PS) and are candidate for further treatment. Patients >18 years, PS >or=50, with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-containing chemotherapy, and progression-free survival (PFS) <12 months received a combination of raltitrexed (3 mg m(-2)) and oxaliplatin (130 mg m(-2)) every 3 weeks until progression, toxicity, or a maximum of six cycles. A total of 41 patients received 137 cycles of chemotherapy. Dose intensity for both drugs was 92% of the intended dose. Main grade >2 toxicity was: neutropenia in five patients (12%), thrombocytopenia, liver and vomiting in three (7%), fatigue in two (5%). In total, 10 patients (24%) yielded a partial response, 11 a stable disease. Progression-free survival at 6 months was 14.6%. Median survival was 5.2 months. Survival was significantly longer in patients with previous PFS >6 months and in patients without pancreatic localisation. A clinically relevant improvement of quality of life was observed in numerous domains. Raltitrexed-oxaliplatin regimen may constitute a treatment opportunity in gemcitabine-resistant metastatic pancreatic cancer. Previous PFS interval may allow the identification of patients who are more likely to benefit from salvage treatment.

Background: Patients with metastatic breast cancer are frequently treated with anthracyclines and taxanes, which are among the most active agents in this disease. Gemcitabine is an interesting candidate for a three-drug combination because of its different mechanism of action and non-overlapping toxicity with respect to the other two drugs. We aimed to evaluate the activity and toxicity of the GAT (gemcitabine, doxorubicin and paclitaxel) regimen, derived from experimental preclinical studies, as first-line chemotherapy in patients with stage IIIB-IV breast cancer., Methods: Patients with locally advanced or metastatic breast cancer and at least one bidimensionally measurable lesion were included in the present study. Adequate bone marrow reserve, normal cardiac, hepatic and renal function, and an ECOG performance status of 0 to 2 were required. Only prior adjuvant non anthracycline-based chemotherapy was permitted. Treatment consisted of doxorubicin 50 mg/m2 on day 1, paclitaxel 160 mg/m2 on day 2 and gemcitabine 800 mg/m2 on day 6, repeated every 21-28 days., Results: Thirty-three consecutive breast cancer patients were enrolled onto the trial (7 stage IIIB and 26 stage IV). All patients were evaluable for toxicity and 29 were assessable for response. A total of 169 cycles were administered, with a median of 6 cycles per patient (range 1-8 cycles). Complete and partial responses were observed in 6.9% and 48.3% of patients, respectively, for an overall response rate of 55.2%. A response was reported in all metastatic sites, with a median duration of 16.4 months. Median time to progression and overall survival were 10.2 and 36.4 months, respectively. The most important toxicity was hematological, with grade III-IV neutropenia observed in 69% of patients, sometimes requiring the use of granulocyte colony-stimulating factor (27%). Non hematological toxicity was rare and mild. One patient died from sepsis during the first treatment cycle before the administration of gemcitabine., Conclusion: The strong synergism among the three drugs found in the preclinical setting was confirmed in terms of both clinical activity and hematological toxicity. Our results seem to indicate that the GAT regimen is effective in anthracycline-naïve metastatic breast cancer and provides a feasible chemotherapeutic option in this clinical setting.

Background: A phase III trial suggested that a PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) regimen might improve the outcome compared to gemcitabine in advanced pancreatic adenocarcinoma. The analysis of treatment impact on quality of life (QOL) is reported., Method: Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and PAN-26 questionnaires at baseline and every second month of treatment until disease progression., Results: The largest differences between arms favored PEFG. Expressed as improvement > or =10 points from baseline (PEFG/gemcitabine), these were: emotional function (43/18%), fatigue (41/17%), QOL (55/29%), pain (64/41%), and flatulence (50/26%). Only change in sexual function favored gemcitabine (19/42%). Physical function, fatigue, appetite, and satisfaction with healthcare improved in 40-46% of partial responders compared with 0-12% of patients with stable disease., Conclusion: Clinically relevant improvement in QOL from baseline was observed more often after PEFG than after gemcitabine, suggesting that the PEFG regimen did not impair QOL, Partial response was associated with improved QOL suggesting that effective treatment of pancreatic adenocarcinoma may have an important role in these patients., (Copyright (c) 2006 S. Karger AG, Basel and IAP.)

Background: Patients with advanced pancreatic adenocarcinoma have a poor response, progression-free survival, and overall survival with standard treatment. We aimed to assess whether a four-drug regimen could improve 4 month progression-free survival compared with gemcitabine alone., Methods: In a randomised multicentre phase III trial, 52 patients were randomly assigned to 40 mg/m2 cisplatin and 40 mg/m2 epirubicin both given on day 1, 600 mg/m2 gemcitabine given intravenously over 1 h on days 1 and 8, and 200 mg/m2 fluorouracil a day given by continuous infusion on days 1-28 of a 4-week cycle (PEFG regimen), and 47 were assigned to 1000 mg/m2 gemcitabine given intravenously over 30 min once a week for 7 of 8 consecutive weeks in cycle 1 and for 3 of 4 weeks thereafter. The primary endpoint was 4-month progression-free survival. Secondary endpoints were overall survival, objective response, safety, and quality of life. Analyses were by intention to treat., Findings: 51 patients assigned PEFG and 46 assigned gemcitabine alone had disease progression. 49 patients in the PEFG group and 46 in the gemcitabine group died from progressive disease. More patients allocated PEFG than gemcitabine alone were alive without progressive disease at 4 months (60% [95% CI 46-72] vs 28% [17-42]; hazard ratio [HR] 0.46 [0.26-0.79]). 1-year overall survival in the PEFG group was 38.5% (25.3-51.7) and in the gemcitabine group was 21.3% (9.6-33.0; HR 0.68 [0.42-1.09]). More patients assigned PEFG showed disease response than did those assigned gemcitabine (38.5% [25.3-51.7] vs 8.5% [0.5-16.5]; odds ratio 6.60 [2.11-20.60], p=0.0008). More patients in the PEFG group had grade 3-4 neutropenia and thrombocytopenia than in the gemcitabine group (p<0.0001)., Interpretation: The PEFG regimen could be considered for treatment of advanced pancreatic adenocarcinoma.

Colorectal cancer with peritoneal carcinomatosis is usually considered incurable. Intraperitoneal carcinomatosis accounts for 25-35% of recurrences of colorectal cancer. Studies demonstrate that peritoneal carcinomatosis is not necessarily a terminal condition with no options for treatment or cure. Encouraging results were obtained in many studies by cytoreductive surgery followed by hyperthermic intraoperative intraperitoneal chemotherapy (HIIC). Oxaliplatin is a new agent whose clinical use with intraperitoneal administration has been pioneered by Elias et al. Eight patients with peritoneal carcinomatosis (PC) of colo-rectal origin underwent complete cytoreductive surgery from March 2004 to January 2005. Six of them were submitted to HIIC with semi-closed technique; in one patient mitomycin C (2 mg/m2/l) was used for intraperitoneal perfusion at 41.5-42 degrees for 60 minutes; in five patients IPCH was carried out for 30 minutes at 41.5-42 degrees with intraperitoneal oxaliplatin (460 mg/m2). Patients received intravenous leucovorin (10 mg/m2) and 5-fluorouracil (400 mg/m2) just before HIIC to maximize the effect of oxaliplatin. Preliminary results are reported.

The ability of lonidamine (LND), a derivative of indazole-carboxylic acid, to modulate the cytotoxic activity of anticancer drugs was investigated in two human hepatocarcinoma (HCC) cell lines. The cytotoxicity of drugs used singly, in association or in sequence was evaluated using the Sulforhodamine B (SRB) assay. LND did not appreciably potentiate the effect of antitumor drugs when given before or simultaneously, in either cell line. Conversely, a synergistic interaction was observed in both cell lines when LND was given after conventional drugs. LND produced a moderate decrease in S-phase cell fraction and did not induce apoptosis. Conversely, paclitaxel (TAX) induced an important block in G2 and an increase in apoptosis. Following a 48-h TAX wash out, a progressive passage of cells from G2 to M phase was observed with a corresponding increase in apoptotic cells. Post-treatment with LND increased the cytotoxicity of some antitumor drugs, especially TAX, in hepatocarcinoma cells, possibly by preventing, as an energolytic drug, cell damage repair or by producing an additional effect on microtubule stabilization.

We report of the use of intra-arterial chemotherapy in one case of locally advanced breast cancer, that had been systemically pre-treated. Locoregional chemotherapy was delivered via percutaneous access. The catheter tip was placed into the subclavian artery and into origin of the internal mammary artery; it was removed after every cycle of treatment. The schedule of chemotherapy was: epirubicin 30 mg/m2, mitomycin 7 mg/m2 and 5 fluouracil 1000 mg. Three cycles were administered, and the treatment was well tolerated. The patient responded to intra-arterial chemotherapy, and she subsequently underwent complete surgical resection. Intra-arterial chemotherapy for breast cancer in an uncommon approach to the treatment of locally advanced disease. Nevertheless, in selected cases, it could be a more effective therapeutic option for patients with systemic chemotherapy-resistant disease.