A phase II study to evaluate LY2603618 in combination with gemcitabine in pancreatic cancer patients.

BACKGROUND: The aim of this study was to determine whether checkpoint kinase 1 inihibitor (CHK1), LY2603618, and gemcitabine prolong overall survival (OS) compared to gemcitabine alone in patients with unresectable pancreatic cancer. METHODS: Patients with Stage II-IV locally advanced or metastatic pancreatic cancer were randomized (2:1) to either 230 mg of LY2603618/1000 mg/m2 gemcitabine combined or 1000 mg/m2 gemcitabine alone. OS was assessed using both a Bayesian augment control model and traditional frequentist analysis for inference. Progression-free survival (PFS), overall response rate (ORR), duration of response, pharmacokinetics (PK), and safety (Common Terminology Criteria for Adverse Events [AEs] v 3.0) were also evaluated. RESULTS: Ninety-nine patients (n = 65, LY2603618/gemcitabine; n = 34, gemcitabine) were randomized (intent-to-treat population). The median OS (months) was 7.8 (range, 0.3-18.9) with LY2603618/gemcitabine and 8.3 (range, 0.8-19.1+) with gemcitabine. Similarly, in a Bayesian analysis, the study was not positive since the posterior probability that LY2603618/gemcitabine was superior to gemcitabine in improving OS was 0.3, which did not exceed the prespecified threshold of 0.8. No significant improvements in PFS, ORR, or duration of response were observed. Drug-related treatment-emergent AEs in both arms included nausea, thrombocytopenia, fatigue, and neutropenia. The severity of AEs with LY2603618/gemcitabine was comparable to gemcitabine. The LY2603618 exposure targets (AUC(0-∞) ≥21,000 ng∙hr/mL and Cmax ≥2000 ng/mL) predicted for maximum pharmacodynamic response were achieved after 230 mg of LY2603618. CONCLUSIONS: LY2603618/gemcitabine was not superior to gemcitabine for the treatment of patients with pancreatic cancer. TRIAL REGISTRATION: NCT00839332 . Clinicaltrials.gov. Date of registration: 6 February 2009.

Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial.

BACKGROUND: We report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT). PATIENTS AND METHODS: mCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups. RESULTS: Between November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2-10.3] and 8.4 (95% CI 7.2-9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70-1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. CONCLUSIONS: The addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population. CLINICAL TRIAL NUMBER: NCT01878422.

Phase II study of capecitabine-based concomitant chemoradiation followed by durvalumab as a neoadjuvant strategy in locally advanced rectal cancer: the PANDORA trial.

BACKGROUND: This study investigated the efficacy of chemoradiotherapy (CRT) followed by durvalumab as neoadjuvant therapy of locally advanced rectal cancer. PATIENTS AND METHODS: The PANDORA trial is a prospective, phase II, open-label, single-arm, multicenter study aimed at evaluating the efficacy and safety of preoperative treatment with durvalumab (1500 mg every 4 weeks for three administrations) following long-course radiotherapy (RT) plus concomitant capecitabine (5040 cGy RT in 25-28 fractions over 5 weeks and capecitabine administered at 825 mg/m2 twice daily). The primary endpoint was the pathological complete response (pCR) rate; secondary endpoints were the proportion of clinical complete remissions and safety. The sample size was estimated assuming a null pCR proportion of 0.15 and an alternative pCR proportion of 0.30 (α = 0.05, power = 0.80). The proposed treatment could be considered promising if ≥13 pCRs were observed in 55 patients (EudraCT: 2018-004758-39; NCT04083365). RESULTS: Between November 2019 and August 2021, 60 patients were accrued, of which 55 were assessable for the study's objectives. Two patients experienced disease progression during treatment. Nineteen out of 55 eligible patients achieved a pCR (34.5%, 95% confidence interval 22.2% to 48.6%). Regarding toxicity related to durvalumab, grade 3 adverse events (AEs) occurred in four patients (7.3%) (diarrhea, skin toxicity, transaminase increase, lipase increase, and pancolitis). Grade 4 toxicity was not observed. In 20 patients (36.4%), grade 1-2 AEs related to durvalumab were observed. The most common were endocrine toxicity (hyper/hypothyroidism), dermatologic toxicity (skin rash), and gastrointestinal toxicity (transaminase increase, nausea, diarrhea, constipation). CONCLUSION: This study met its primary endpoint showing that CRT followed by durvalumab could increase pCR with a safe toxicity profile. This combination is a promising, feasible strategy worthy of further investigation.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Microbiological evaluation of environmental cleanliness in haematopoietic cell transplant patient rooms: implementing JACIE standards.

BACKGROUND: Environmental hygiene is one of the most important strategies to prevent hospital-acquired infections by reducing pathogens in haematopoietic cell transplant (HCT) patient rooms. This study was designed in response to JACIE requirements for microbiological monitoring, and aimed to assess environmental hygiene in protective isolation rooms. METHODS: Environmental cleanliness was assessed by measuring microbial loads in at-rest and operational conditions sampled from target surfaces, and in passive and active air from rooms occupied by patients with different grades of neutropenia. The study also evaluated whether microbial loads were influenced by isolation precautions. RESULTS: The failure rate of cleanliness on target surfaces in at-rest conditions was 0% compared with 37% for surfaces and 13% for passive and active air samples in operational conditions. Differences in failure rates were observed in the rooms of patients with different levels of neutropenia (P=0.036 for surfaces, 0.028% for passive air). No relationship was found between infections and microbial loads. CONCLUSIONS: Microbiological assessment integrated with an enhanced monitoring programme for hospital hygiene provides invaluable information to drive infection control policies in HCT patients. These results highlight the need to set and validate strict standards for the assessment of cleanliness in a clinical setting.

Treatment of squamous cell carcinoma of the anal canal: A new strategies with anti-EGFR therapy and immunotherapy.

The incidence of squamous cell carcinoma of the anal canal (SCAC) is increasing in both sexes but the standard treatment remains that of 20 years ago. However, interesting data have recently emerged on the use of anti-epidermal growth factor receptor (EGFR) agents and immunotherapy in advanced disease. Thus, new avenues of research are opening up that will hopefully lead to more effective therapeutic strategies. We provide an overview of the latest studies published on this tumor and discuss the possible future therapeutic options for combination therapy, anti-EGFR treatment and radiotherapy.

Clinical and laboratory evaluation of the myeloprotective effect of medroxyprogesterone acetate in head and neck cancer.

The action of high-dose medroxyprogesterone acetate (MPA) was studied by analysing the behaviour of colony-forming-unit granulocyte-macrophage (CFU-GM) during chemotherapy. 21 non-pretreated men with locally advanced carcinoma of the head and neck were randomised into two arms: A (11 patients) received three alternating cycles of cisplatin, 5-fluorouracil (CF)/cisplatin, methotrexate, bleomycin, vincristine and then CF every 4 weeks and B (10 patients) were treated with the same schedule plus 1000 mg per day of MPA. MPA was administered 14 days before the start of chemotherapy (day 0) and continued daily up to the 90th day. Bone marrow was harvested in arm A on days 0, +14 and +90, and in B, also on day -14. There was diverse CFU-GM behaviour in the two arms on the 14th day. These data support the hypothesis that the myeloprotective effect of MPA is due to induction of a mitotic rest in the stem cells, which protects them from drug action.

A phase II study of gemcitabine in patients with transitional cell carcinoma of the urinary tract previously treated with platinum. Italian Co-operative Group on Bladder Cancer.

The aim of this study was to evaluate the efficacy and safety of gemcitabine, a pyrimidine antimetabolite, in the treatment of advanced transitional cell carcinoma of the urinary tract. 35 patients with unresectable or metastatic transitional cell carcinoma of the urinary tract previously treated with a platinum-based regimen were studied. Gemcitabine was administered at a dosage of 1200 mg/m2 as a 30-min intravenous infusion on days 1, 8 and 15, repeated every 28 days. 31 patients were evaluable for efficacy. 4 patients achieved a complete response (12.9%), 3 a partial response (9.6%) and 13 (42%) were stable for at least 4 weeks (overall response 22.5%; 95% confidence interval 8-37%). The median response duration was 11.8 months (range 3.6-17.7 + months) and median survival for all patients entered was 5 months (range 2-21 + months). 2 patients with complete response are still alive with no evidence of disease after 14 and 21 months. Gemcitabine also provided subjective symptomatic relief from pain, cystitis, dysuria, haematuria and peripheral oedema. Patients experienced little WHO grade 3-4 toxicity, with anaemia in 8 patients (23%), thrombocytopenia in 5 (14.2%), leucopenia in 4 (11.4%) and neutropenia in 7 (20%). WHO grade 3-4 hepatic toxicity occurred in 4 patients (11.4%) and transient elevations of transaminase was noted in 3 (8.6%). No patient had WHO grade 3-4 elevation of serum creatinine level. There was no WHO grade 4 symptomatic toxicity and no alopecia was noted. Transient influenza symptoms with gemcitabine occurred in 18 patients (51.4%) with 13 patients (37.1%) experiencing fever (2.9% WHO grade 3). In conclusion, gemcitabine is an new active agent for the treatment of transitional cell carcinoma of the urinary bladder with a mild toxicity profile; it warrants further investigation in combination with cisplatin in chemotherapy naive patients.

A phase I/II study of sequential doxorubicin and paclitaxel in the treatment of advanced breast cancer.

Based on preclinical data, we designed a phase I/II clinical trial to determine the efficacy and toxicity of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer (either untreated or relapsed after adjuvant therapy). In the phase I study, 19 enrolled patients received bolus doxorubicin (50 mg/m2) and, after a 16-hour interval, escalating doses of paclitaxel (from 130 to 250 mg/m2 in 30-mg/ m2 increments) by 3-hour infusion every 3 weeks for a maximum of eight cycles. Paclitaxel doses were increased if the maximum tolerated dose (MTD; defined by dose-limiting toxicities) had not been reached. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (< 500/microL) in 20% of cycles with no significant clinical events. No relevant clinical cardiotoxicity was observed. Other toxicities included mild peripheral neuropathy and mild myalgia/arthralgia (In 37.5% and 30.4% of cycles, respectively). The maximum tolerated paclitaxel dose was not reached at the 250 mg/m2 dose level. In the second phase, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2, the dose level immediately preceding the highest paclitaxel dose used in phase I). Grade 4 neutropenia occurred in 36 of the 87 cycles but was complicated by fever in only eight cycles (9%); three patients needed granulocyte colony-stimulating factor. Peripheral neuropathy (grades 1 and 2 in 41.3% and 5.7% of cycles, respectively) and a myalgic syndrome (grades 1 and 2 in 24.1% and 17.2% of cycles, respectively) were observed. No significant clinical cardiotoxicity was observed in 12 of the 13 patients. One patient experienced a decrease in left ventricular ejection fraction (from 60% to 43%) at a cumulative doxorubicin dose of 400 mg/m2. Antitumor efficacy was evaluated in both phase I and phase II. Overall clinical responses included 10 complete (31.3%) and 15 partial (46.9%) responses, for an objective response rate of 78.1%. Six patients (18.8%) had stable disease. The median durations of objective and complete response were 9 and 7 months, respectively. The 78.9% objective response rate in the phase I trial (31.6% complete and 47.3% partial responses) suggests a dose response relationship: at paclitaxel dose > or = 190 mg/m2, all patients had an objective response (six complete and nine partial responses). These results confirm that doxorubicin followed by paclitaxel is active and should be tested as adjuvant treatment and in patients treated previously with anthracyclines.

Paclitaxel plus doxorubicin in breast cancer: an Italian experience.

Based on preclinical data, phase I/II clinical trials were performed at Istituto Oncologico Romagnolo (IOR) Operative Units (Medical Oncology Departments of Forlì, Rimini, and Ravenna, Italy) to determine the efficacy and toxicity of sequential administration of doxorubicin followed by paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in the treatment of patients with advanced breast cancer that either had been previously untreated or that had relapsed after adjuvant therapy. In the phase I trial, 19 patients received bolus doxorubicin (50 mg/m2) followed after a 16-hour interval by paclitaxel (given at dose levels ranging from 130 to 250 mg/m2) by 3-hour infusion every 3 weeks, for a maximum of eight cycles. Paclitaxel doses were escalated in 30-mg/m2 increments if the maximum tolerated dose had not been reached in the previous dose level. Analysis of the 128 cycles assessable for toxicity demonstrated neutropenia (<500/microL) in 26 courses (20.3%), with no significant clinical events. No relevant clinical cardiotoxicity was observed. The paclitaxel maximum tolerated dose was not reached at the 250-mg/m2 dose level (no grade 3 or 4 extramedullary toxicity). In the IOR phase II trial, 13 patients were treated with fixed doses of both drugs (doxorubicin 50 mg/m2 and paclitaxel 220 mg/m2). Grade 4 neutropenia occurred in 39 of the 95 cycles, but was complicated by fever in only eight cycles (8.4%); three cycles required granulocyte colony-stimulating factor support. Peripheral neurotoxicity was the most common extramedullary side effect noted. Overall clinical responses in the IOR trials included 10 complete responses (31.3%) and 15 partial responses (46.9%), with an objective response rate of 78.1%. Comparison of these results with those obtained from a phase I trial using the opposite drug sequence showed comparable overall response rates, but IOR's sequence was associated with a higher complete response rate, as well as less frequent and less severe nonhematologic toxicity.

The sequential administration of combined doxorubicin and paclitaxel in the treatment of advanced breast cancer.

In phase I and II studies we administered fixed doses of doxorubicin by intravenous bolus 16 hours before escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) for the treatment of patients with advanced breast cancer who had received no prior treatment or who had relapsed after adjuvant therapy. Nineteen patients were entered in the study from April 1994 to February 1995. The median age of participants was 54 years; the median disease-free interval was 328 days. Eleven patients had undergone prior adjuvant chemotherapy, seven had undergone prior hormonal therapy, and six had undergone chest radiotherapy. A total of 128 courses of fixed-dose doxorubicin 50 mg/m2 by intravenous bolus and paclitaxel (doses escalated from 130 to 250 mg/m2, through dose escalations of 30 mg/m2 if maximum tolerated dose was not reached) were repeated every 21 days for a median of seven cycles per patient. Toxicities encountered in this trial included grade 4 neutropenia (20% of courses) and grade 4 thrombocytopenia (3% of courses). No grade 3 or 4 nonhematologic toxicities were observed (World Health Organization grade I peripheral neuropathies and mild myalgias in 37.5% and 30% of courses, respectively). No cardiac toxicity was observed. Responses included six complete responses (31.6%), nine partial responses (47.2%), and three stable disease (15.8%), for an overall response rate of 78.8%. Median duration of overall and complete response was 8+ months and 7+ months, respectively. At dose levels > or = 190 mg/m2, all patients had achieved a response (six complete responses and six partial responses). A phase II trial using fixed doses of doxorubicin (50 mg/m2) and paclitaxel (220 mg/m2) is ongoing. Preliminary data on 71 courses report no cardiac toxicity. Treatment with paclitaxel has been well tolerated at each dose level. The maximum tolerated dose was not reached at 250 mg/m2. No cardiac toxicity was reported. The dosing sequence of doxorubicin followed by paclitaxel is a highly active regimen and needs to be tested in anthracycline patients and in an adjuvant setting.

A Phase I/II study of paclitaxel and doxorubicin in the treatment of advanced breast cancer.

We designed a clinical study in which fixed doses of doxorubicin were infused by intravenous bolus 16 hours before escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, princeton, NJ) for the treatment of patients with advanced breast cancer, an interval selected to allow systemic clearance of doxorubicin before administration of paclitaxel in an outpatient setting. Courses of fixed-dose doxorubicin 50 mg/m2 by intravenous bolus and paclitaxel (doses escalated from 130 mg/m2 to 250 mg/m2 via dose escalation of 30 mg/m2) were repeated every 21 days, to a maximum of eight cycles. Maximum tolerated dose was reached if two or more of six patients at a given dose level were affected by the following events: absolute neutrophil count less than 500/microliter for > or = 7 days, absolute neutrophil count less than 100/microliter for > or = 3 days, insufficient hematopoietic recovery with absolute neutrophil count less than 1,500/microliter on day 21, febrile neutropenia, grade 4 thrombocytopenia, any World Health Organization grade 3 nonhematologic toxicity for more than 7 days. There were 19 patients enrolled; the patients received a total of 128 treatment courses. Grade 4 neutropenia was the main side effect, occurring in 20% of courses but generally not associated with clinical events. No relevant clinical cardiac toxicity or alteration of left ventricular ejection fraction was observed. Other toxicities included complete alopecia, mild peripheral neuropathy, and mild myalgia. There was a reduction of one dose level for moderate myalgia in one patient (190 mg/m2 level). Complete alopecia was always present. Maximum tolerated dose was not reached at paclitaxel 250 mg/m2. Ultimately, the introduction of this combination in the adjuvant setting is warranted.

Doxorubicin and paclitaxel (sequential combination) in the treatment of advanced breast cancer.

Based on preclinical data, we designed a phase I/II clinical trial to determine the efficacy and toxicity of doxorubicin followed by paclitaxel in the treatment of advanced breast cancer (either untreated or relapsed after adjuvant therapy). In the phase I dose-finding study, 19 enrolled patients received bolus doxorubicin (50 mg/m2) and, after a 16-hour interval, a three-hour infusion of paclitaxel in escalating doses from 130 to 250 mg/m2, increased by 30-mg/m2 increments for each dose-level group. The first dose level group (paclitaxel 130 mg/m2) included three patients. The other dose level groups included four patients. Treatment was repeated every three weeks for a maximum of eight cycles. The paclitaxel dose was escalated to 250 mg/m2 without reaching the maximum tolerated dose. In the 128 cycles assessable for toxicity, there were no relevant clinical signs or symptoms of cardiotoxicity. This absence of significant cardiotoxicity required confirmation in a phase II trial. Since a maximum tolerated dose of paclitaxel had not been reached during the first study and an increasing risk of neutropenia and peripheral neurotoxicity was feared if doses continued to escalate, a phase II confirmatory study was begun to evaluate treatment with fixed doses of doxorubicin (50 mg/m2) and paclitaxel (220 mg/m2), using the same schedule and interval as in phase I. The 13 patients enrolled in phase II received a total of 95 cycles of therapy; in 10 cycles (three patients) dose reductions were necessary because of toxicity. However, no significant clinical cardiotoxicity was observed in 12 of the 13 patients. One patient experienced an asymptomatic, transient decrease in left ventricular ejection fraction at a cumulative doxorubicin dose of 400 mg/m2. Overall clinical responses included 10 complete remissions (31.3%) and 15 partial remissions (46.9%) for an objective response rate of 78.1%. At 16 months' median follow-up, the median time to progression for all patients is nine months. The high response rate obtained in the phase I/II studies and, in particular, the absence of significant cardiotoxicity require confirmation in further clinical trials. To date, two confirmatory phase II trials are ongoing in our institutions.

Doxorubicin, paclitaxel and gemcitabine: a Phase I study of a new sequential treatment in stage III B - IV breast cancer.

Based on the synergistic interactions of the sequence doxorubicin-paclitaxel-gemcitabine obtained in our preclinical study, a Phase I trial was conducted to evaluate the feasibility of this new sequence in breast cancer. Patients with stage IIIB-IV breast cancer received doxorubicin on day 1, paclitaxel on day 2 and gemcitabine on day 6 and 13 (steps IIa, III and V) in cohorts of 3 patients. From March 1999 to December 2000, 9 patients were treated. The most important toxicity was hematological. The maximum tolerated dose was reached at the second level because dose-limiting toxicity occurred in 3 patients. Non hematological toxicities were alopecia, diarrhea, asthenia, nausea, mucositis, paresthesia and myalgia. A Phase II trial is ongoing to further investigate the activity of this new sequential treatment with doxorubicin (50 mg/m2 day 1), paclitaxel (160 mg/m2 day 2) and gemcitabine (800 mg/m2 day 6) in advanced breast cancer.

Potentiation of antiproliferative drug activity by lonidamine in hepatocellular carcinoma cells.

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.

Lanreotide-induced modulation of 5-fluorouracil or mitomycin C cytotoxicity in human colon cancer cell lines: a preclinical study.

The effect on growth of the long-acting somatostatin analogue lanreotide (LAN), alone or in combination with 5-fluorouracil (5-FU) and mitomycin C (MIT), was investigated in three human colon cancer lines. Cell survival inhibition induced by LAN alone, as evaluated by sulforhodamine B assay, ranged from 20% to 40% as a function of cell line and concentration. The IC50, the concentration inhibiting cell survival by 50%, was never reached. The antiproliferative effect produced by a 48 h exposure to 5-FU or MIT was synergistically enhanced in all cell lines by a subsequent 48 h exposure to LAN. The synergistic interaction was not related to specific cell cycle perturbations or to the somatostatin receptor 2 (sst2) mRNA abundance. In conclusion, our study seems to indicate that LAN is a potentially useful modulating agent for enhancing 5-FU and MIT activity in colorectal cancer patients.

Challenge in differential diagnosis of a liver mass histologically defined as a metastatic lesion from an occult primary intestinal tumour. The importance of clinical findings and the limitations of histology and molecular profiles. A case report.

Differential diagnosis of liver lesion in the absence of proven primary tumor is still a challenge. We experienced a case of an asymptomatic 14 cm lesion of right hemiliver in a 67 year-old man submitted to right hepatectomy in December 2010. One year before the patient underwent to endoscopic removal of a tubular adenoma of the right colon. Preoperative diagnosis was supported by ultrasound, CT scan, PET and liver biopsy. The patient received 6 cycles of preoperative chemotherapy (FOLFOX) with down-staging of the lesion diameter. Immunohistochemistry on the surgical specimen showed positivity for cytokeratins 19 and 20, CEA, MUC-2, negativity for cytokeratin 7 and a-fetoprotein. Moreover, the neoplastic cells showed a focal positivity with lower intensity for MUC-1 and MUC-5AC. The immunohistochemical profile suggested the possibility of a metastatic tumour from the large bowel, without excluding a primitive mucinous cholangiocarcinoma with intestinal phenotype. At 6 months after intervention, the patient was submitted to chemotherapy (FOLFOX). At present he is in good condition, without radiological signs of recurrence. Oncologists must evaluate the possible benefits of further adjuvant treatments based on the differential diagnosis between a primitive or metastatic liver tumour. In conclusion, correct diagnosis of liver masses is mandatory and remains a challenge that can differentiate either follow-up or surgical and adjuvant treatment. Histology and immunohistochemistry must be related to clinical findings as they may not always be sufficient to reach a correct final diagnosis, and can even be confusing. At present, molecular biology cannot be considered a helpful for diagnosis in these cases.

Activity of endovesical gemcitabine in BCG-refractory bladder cancer patients: a translational study.

Intravesical gemcitabine (Gem) has shown promising activity against transitional cell carcinomas (TCC) of the bladder, with moderate urinary toxicity and low systemic absorption. The present phase II study evaluated the activity of biweekly intravesical treatment with Gem using a scheme directly derived from in vitro preclinical studies. Patients with Bacille Calmette-Guérin (BCG) -refractory Ta G3, T1 G1-3 TCC underwent transurethral bladder resection and then intravesical instillation with 2000 mg Gem diluted in 50 ml saline solution on days 1 and 3 for 6 consecutive weeks. Thirty-eight (95%) of the 40 patients showed persistent negative post-treatment cystoscopy and cytology 6 months after Gem treatment, while the remaining 2 patients relapsed at 5 and 6 months. At a median follow-up of 28 months, recurrences had occurred in 14 patients. Among these, four had downstaged (T) disease, three had a lower grade (G) lesion and three had a reduction in both T and G. Urinary and systemic toxicity was very low, with no alterations in biochemical profiles. In conclusion, biweekly instillation of Gem proved active in BCG-refractory Ta G3, T1 G1-3 TCC. Our results highlight the importance of preclinical studies using in vitro systems that adequately reproduce the conditions of intravesical clinical treatment to define the best therapeutic schedule.

RT-PCR determination of maspin and mammaglobin B in peripheral blood of healthy donors and breast cancer patients.

BACKGROUND: The aim of the present study was to evaluate the accuracy of two markers, maspin and mammaglobin B, singly or in combination, to detect breast cancer. To define better the potential and limits of the two markers for diagnostic purposes, blood positivity was analyzed in relation to clinical, pathological and biological tumor characteristics. PATIENTS AND METHODS: The markers were determined in peripheral blood (PB) samples from 27 healthy donors and 140 previously untreated patients using nested reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: Positivity for maspin in blood samples was observed in 24% of patients with an 89% specificity. For mammaglobin B, positivity was observed in 7% of patients and never in healthy donors. The presence of maspin was correlated with cell proliferation of the primary tumor (P = 0.015), whereas mammaglobin B positivity correlated with pathological stage (P = 0.013). The presence of either marker was significantly related to nodal status. CONCLUSIONS: Our results indicate that the two markers in association could represent a potentially useful non-invasive tool to detect breast cancer. The validation of these markers as indicators of high risk of relapse is ongoing in a series of patients with an adequate follow-up.