Can the plasma PD-1 levels predict the presence and efficiency of tumor-infiltrating lymphocytes in patients with metastatic melanoma?

Background: The immune response in melanoma patients is locally affected by presence of tumor-infiltrating lymphocytes (TILs), generally divided into brisk, nonbrisk, and absent. Several studies have shown that a greater presence of TILs, especially brisk, in primary melanoma is associated with a better prognosis and higher survival rate. Patients and Methods: We investigated by enzyme-linked immunosorbent assay (ELISA) the correlation between PD-1 levels in plasma and the presence/absence of TILs in 28 patients with metastatic melanoma. Results: Low plasma PD-1 levels were correlated with brisk TILs in primary melanoma, whereas intermediate values correlated with the nonbrisk TILs, and high PD-1 levels with absent TILs. Although the low number of samples did not allow us to obtain a statistically significant correlation between the plasma PD-1 levels and the patients' overall survival depending on the absence/presence of TILs, the median survival of patients having brisk type TILs was 5 months higher than that of patients with absent and nonbrisk TILs. Conclusions: This work highlights the ability of measuring the plasma PD-1 levels in order to predict the prognosis of patients with untreated metastatic melanoma without a BRAF mutation at the time of diagnosis

Meaningful cut-off pain intensity for breakthrough pain changes in advanced cancer patients

Abstract OBJECTIVES: To assess the level of pain intensity at which patients feel the impetus to ask for a breakthrough cancer pain (BTcP) medication, and level of pain intensity at which patients consider they have achieved acceptable pain control after receiving a BTcP medication. METHODS: A consecutive sample of patients who were receiving oral morphine equivalents equal to or more than 60\u2009mg daily, and were prescribed rapid onset opioids for the management of episodes of BTcP, were included in the study. Focused educational activities regarding BTcP and numerical scales were established during hospital admission. At discharge patients were interviewed to find out what was the pain intensity level which gave the impetus to take the BTcP medication, what was the pain intensity for acceptable pain control after a BTcP medication had been given, and which factors prevented the patient calling for BTcP medication. A brief COPE (coping orientation to problems experienced) questionnaire was also administered. RESULTS: Fifty-two patients were recruited for this study. The meaningful pain intensity for asking for a BTcP medication was 7.1; 77% of patients had a pain intensity of 7-8 on a numerical scale of 0-10. The meaningful pain intensity for adequate analgesia after a BTcP medication was 3.5. Similarly, 77% of patients had a pain intensity of 3-4. There was no relationship with the variables examined. Concerns by patients about the use of BTcP medications were minimal. CONCLUSION: The meaningful BTcP intensity and pain intensity expected after BTcP medication can be useful in selecting patients in studies of BTcP. The principal limitation of this study was the specific setting of an acute unit with specific features and the relatively low number of patients. This observation should be followed up by further surveys with a larger number of patients and different settings

Morphine versus oxycodone in pancreatic cancer pain: a randomized controlled study.

Objective: According to experimental findings, oxycodone (OX) could have some advantages over morphine (MO) in clinical models of visceral pain. It was hypothesized that OX could have some advantages over MO in terms of efficacy and dose escalation in pancreatic cancer pain. Methods: Sixty patients with pancreatic cancer with a pain intensity rating of 4/10 who required opioids were included in the study. Patients were randomized to receive 30mg/d of sustained release oral MO or sustained release oral OX (20mg/d). Opioid doses were increased according to the clinical needs. Daily doses of opioids, pain and symptom intensity were recorded at admission (T0) and at weekly intervals for the subsequent 4 weeks (T1, T2, T3, and T4), with an extension at 8 weeks (T8). Opioid escalation index (OEI) as percentage (OEI %) and in mg (OEI mg) was calculated. Results: Nineteen and 20 patients in groups OX and MO, respectively, were followed for the entire period of study (T4). No differences between groups were found in age (P=0.400), Karnofsky (P=0.667), or escalation indexes at T4 and T8 (OEImg, P=0.945 and OEI %, P=0.295). No statistical differences in pain and symptoms intensity between the groups were observed. Conclusion: OX and MO provided similar analgesia and adverse effects with similar escalating doses in patients with pancreatic cancer pain, resembling observations reported in the general cancer pain population. The experimental hypothesis that OX would be superior to MO in the clinical model of pancreatic cancer pain was not confirmed. © 2010 by Lippincott Williams & Wilkins

Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers

BACKGROUND: Biliary tract cancers are uncommon tumors with a poor prognosis and most patients present with invasive and inoperable disease at diagnosis. Chemotherapy represents a palliative treatment, with poor response rates and a median survival of less than 6 months. Oxaliplatin and gemcitabine have shown an interesting activity as single agents in this group of patients. PATIENTS AND METHODS: We carried out a multicenter phase II study to evaluate the efficacy and safety of combined oxaliplatin and gemcitabine in locally advanced and metastatic biliary tract carcinoma. The schedule of chemotherapy included oxaliplatin 100 mg/m(2) on day 1 and gemcitabine 1000 mg/m(2) on days 1 and 8, every 21 days. RESULTS: All the 24 patients were evaluable for response and toxicity. According to RECIST criteria we observed one complete response and 11 partial responses for an overall response rate of 50%. Overall survival for all the patients on study was 12 months (range 2-30). According to WHO criteria, three patients (12.5%) suffered grade 3 neutropenia and three patients (12.5%) grade 3 thrombocytopenia. Only two patients (8%) suffered grade 3 neuropathy. CONCLUSIONS: Oxaliplatin and gemcitabine chemotherapy seems to be effective with a favorable safety profile in first-line chemotherapy of advanced biliary tract cancers

Early magnesium reduction in advanced colorectal cancer patients treated with cetuximab plus irinotecan as predictive factor of efficacy and outcome

Introduction: Magnesium plays a role in a large number of cellular metabolic reactions. Cetuximab is able to induce hypomagnesemia by interfering with magnesium (Mg2+) transport in the kidney.We designed this trial to investigate if Mg2+ serum level modifications may be related with clinical response andoutcome in advancedcolorectal cancer patients during treatment with cetuximab plus irinotecan. Experimental Design: Sixty-eight heavily pretreatedmetastatic colorectal cancer patients were evaluatedfor Mg2+ serum levels at the following time points: before; 6 hours; and1, 7, 14, 21, 50, and92 days after the start of treatment. Results: Basal Mg2+ median levels were significantly decreased just 7 days after the first anticancer infusion and progressively decreased from the 7th day onward, reaching the highest significance at the last time point (P < 0.0001).Twenty-five patients showeda reduction in median Mg2+ circulating levels of at least 20% within the 3rdweek after the first infusion. Patients with this reduction showed a response rate of 64.0% versus 25.6% in the nonreduced Mg2+ group. The median time to progression was 6.0 versus 3.6 months in the reduced Mg2+ group andin that without reduction, respectively (P < 0.0001). Overall survival was longer in patients with Mg2+ reduction than in those without (10.7 versus 8.9 months). Conclusions: Our results confirm that cetuximab treatment may induce a reduction of Mg2+ circulating levels andoffer the first evidence that Mg2+ reduction may represent a new predictive factor of efficacy in advanced colorectal cancer patients treated with cetuximab plus irinoteca

Gastrointestinal stromal tumors (GISTs): focus on histopathological diagnosis and biomolecular features

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors of the gastrointestinal tract that are believed to originate from a neoplastic transformation of the intestinal pacemaker cells (interstitial cells of Cajal) normally found in the bowel wall or their precursors. Although the microscopic features have been known for a long time, the defining characteristic of GIST is the presence of the cell-surface antigen CD117 (KIT), which is demonstrated by immunohistochemistry. KIT, which is a growth factor transmembrane receptor, is the product of the proto-oncogene c-kit (chromosome 4). Surgical removal remains the only curative treatment for patients with GISTs. Tumor size, mitotic index, anatomic location, tumor rupture and disease-free interval are the classic characteristics used to predict the clinical course of patients who undergo complete gross resection. Most GISTs express constitutively activated mutant isoforms of KIT or kinase platelet-derived growth factor receptor alpha (PDGFRA) that are potential therapeutic targets for imatinib mesylate. Imatinib mesylate is a rationally designed, molecularly specific oral anticancer agent that selectively inhibits several protein tyrosine kinases central to the pathogenesis of human cancer and which has demonstrated remarkable clinical efficacy in patients with chronic myeloid leukemia and malignant GISTs. More recently Sunitinib, a new KIT/PDGFRA kinase inhibitor, has been tested in patients with GIST resistant to imatinib, with promising results. Key words: gastrointestinal stromal tumors, histopathological diagnosis, molecular biology, novel therapie

Into the Wild of long non-coding RNAs in Gastrointestinal Stromal Tumors (GISTs) to explore new prognostic/predictive biomarkers

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Moving the target on the optimal adjuvant strategy for resected pancreatic cancers: A systematic review with meta-analysis

Combination regimens have shown superiority over single agents in the adjuvant treatment of resected pancreatic cancer (PC), but there are no data supporting definition of the best regimen. This work aimed to compare the efficacy and safety of mFOLFIRINOX, gemcitabine+capecitabine, and gemcitabine+nab/paclitaxel in PC patients. A meta-analysis was performed for direct comparison between trials comparing combination regimens and gemcitabine monotherapy. Subsequently, an indirect comparison was made between trials investigating the efficacy and safety of mFOLFIRINOX, gemcitabine+capecitabine, and gemcitabine+nab/paclitaxel because of the same control arm (gemcitabine). A total of three studies met the selection criteria and were included in our indirect comparison. Indirect comparisons for efficacy outcomes showed a benefit in terms of DFS (disease-free survival)/EFS (event-free survival)/RFS (relapse-free survival) for both mFOLFIRINOX versus gemcitabine+capecitabine (HR 0.69, 95% CI 0.52–0.91) and versus gemcitabine+nab/paclitaxel (HR 0.67, 95% CI 0.50–0.90). No significant advantage was registered for OS (overall survival). Indirect comparisons for safety showed an increase in terms of G3-5 AEs (with the exception of neutropenia) for mFOLFIRINOX versus gemcitabine+capecitabine (RR 1.24, 95% CI 1.03–1.50), while no significant differences were observed versus gemcitabine+nab/paclitaxel. According to our results, mFOLFIRINOX is feasible and manageable and could represent a first option for fit PC resected patients