Γδ T Cell-Based Immunotherapy in Melanoma: State of the Art.

Metastatic melanoma is still associated with a poor prognosis, and there is increasing interest in immunotherapy alone or in combination with other adjuvant therapies. Γδ T lymphocytes play a pivot role in the immune response against cancer, but while γδ-based immunotherapy is already a clinical reality for several solid tumors, data on melanoma are still limited and fragmented. This systematic review presents preclinical and clinical evidence for a role of γδ T lymphocytes in immunotherapeutic strategies for advanced melanoma and discusses research state of the art and future perspectives. Current strategies focus on in vivo stimulation, and ex vivo adoptive therapy and vaccination; results are promising, but further studies are needed to better investigate the interactions in tumoral microenvironment and to improve clinical efficacy of immunotherapeutic protocols.

Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Gastric cancer (GC) development is a multistep process, during which numerous alterations accumulate in nuclear and mitochondrial DNA. A deficiency of repair machinery brings about an accumulation of errors introduced within simple repetitive microsatellite sequences during replication of DNA. Aberrant methylation is related to microsatellite instability (MSI) by the silencing of the hMLH1 gene. The aim of this study is to investigate a possible relationship between the RUNX3 promoter methylation, nuclear microsatellite instability (nMSI) and mitochondrial microsatellite instability (mtMSI), in order to clarify its biological role in GC. PATIENTS AND METHODS: nMSI and mtMSI were evaluated in a consecutive series of 100 GC patients. For the analysis of the nMSI, we followed the National Cancer Institute guidelines. mtMSI was assessed by analyzing a portion of the displacement-loop region. The aberrant methylation of RUNX3 was analyzed in 40 GC patients by methylation-specific PCR. RESULTS: Overall, 55% of GC demonstrated methylation of the RUNX3 promoter; 82% of GC was classified as stable microsatellite instability, 5% as low-level microsatellite instability and 13% as high-level microsatellite instability (MSI-H); mtMSI was detected in 11% of GC. A significant association was found between mtMSI and tumor-node-metastasis staging, furthermore an interesting association between MSI-H status, mtMSI and RUNX3 methylation. CONCLUSION: These data suggest that RUNX3 is an important target of methylation in the evolution of mtMSI and nMSI-H GC.

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.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ): run dental management designs and issues in diagnosis.

Recently, jawbone osteonecrosis has been largely reported as a potential adverse effect of bisphosphonate (BP) administration. Because of the peculiar pharmacokinetic and pharmacodynamic features of the BF (mainly for i.v. administration), their efficacy and large use, some major issues have to be taken into account extendedly both by oncologists and by dentists: 1) therapeutic dental protocol for patients with diagnosis of bisphosphonate-related osteonecrosis of the jaw (BRONJ); 2) dental strategies for patients in former or current i.v. BF treatment and in absence of BRONJ signs; 3) strategies for patients before i.v. BF treatment. Clinical features and guidelines for the management of this condition have been investigated and reported, sometimes with unclear indications; hence, on the basis of the literature and our clinical experience, major end points of this paper are providing our run protocols for the issues above described and, finally, focusing on a crucial, but not extensively investigated point: the early and correct diagnosis of BRONJ versus metastatic jaw lesions in cancer patients.

A case of Guillain-Barré syndrome in a patient with non small cell lung cancer treated with chemotherapy.

Guillain-Barré Syndrome (GBS) is a demyelinating polyneuropathy of probable autoimmune pathogenesis characterized by rapidly progressive symmetric paralysis. In the literature some cases of GBS associated with anticancer chemotherapy are reported. We present a case of a 55-year old woman who complained of progressive motor deficit in four limbs, areflexia in lower limbs and facial nerve paralysis one week after beginning cisplatin-gemcitabine chemotherapy for metastatic lung cancer. The cerebrospinal fluid analysis showed a strong positive Pandy reaction with 435 mg/dl total protein. The electromyography and the electroneuronography established the diagnosis of inflammatory demyelinating polyneuropathy. Specific therapy with intravenous immunoglobulin 25 g/day in 5 administrations for 5 days was started with complete benefit.

Detection and quantification of mammaglobin in the blood of breast cancer patients: can it be useful as a potential clinical marker? Preliminary results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study.

BACKGROUND: Mammaglobin is expressed mainly in mammary tissue, overexpressed in breast cancer (BC) and rarely in other tissue. The aim of this study was to assess the sensitivity and specificity of transcript MGB1 detection and to evaluate the role of MGB1 as potential clinical marker for the detection of disseminated cancer cells in the blood of BC patients. PATIENTS AND METHODS: A consecutive series of 23 BC tissues, 36 peripheral blood BC samples and 35 healthy peripheral blood samples was prospectively recruited to investigate MGB1 expression by means of a quantitative Real Time RT-PCR assay. RESULTS: MGB1 overexpression in tissue samples of BC patients is significantly associated only with high level of Ki67 (P <0.05). None of the samples from peripheral blood of 35 healthy female individuals were positive for MGB1 transcript. In contrast MGB1 mRNA expression was detected in three of 36 (8%) peripheral blood of BC patients. CONCLUSIONS: Our preliminary results demonstrate that the detection of MGB1 transcript in peripheral blood of BC patients was specific but with low sensitivity. MGB1 overexpression by itself or in combination with Ki67 might be considered an index of BC progression.

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.

A phase II study of pegylated liposomal doxorubicin oxaliplatin and cyclophosphamide as second-line treatment in relapsed ovarian carcinoma.

We carried out a phase II nonrandomized study to examine the level of activity of oxaliplatin, pegylated liposomal doxorubicin, and cyclophosphamide in a patient population with relapsed ovarian cancer pretreated with platinum derivatives and paclitaxel. Patients received oxaliplatin (85 mg/m2), pegylated liposomal doxorubicin (30 mg/m2), and cyclophosphamide (750 mg/m2). A total of 49 patients (39 assessable for toxicity and response) were enrolled in this trial. Neutropenia grade 3 was observed in six patients (15%) and anemia grade 3 in one patient (0.2%). Fatigue grade 1-2 occurred in 26 patients (66%), nausea/vomiting grade 1 in 23 patients (58%), and alopecia grade 1-2 in 19 patients (48%). Twenty-one (53%) patients experienced grade 1-2 peripheral neuropathy. The overall response rate was 46% (95% CI 23.6-68.7). Median progression-free survival was 28 weeks (range 12-52 weeks) and median survival was 45 weeks (range 26-136+ weeks). The mean duration of response was 34 weeks (range 16-52 weeks). In platinum-resistant and -refractory ovarian cancer patients, the overall response rate was 37% (CI 95% 14.4-60.8) with a progression-free survival of 28 weeks (range 12-52 weeks) and a median survival of 42 weeks (range 28-84 weeks). This combination chemotherapy is generally well tolerated and is an active second-line regimen against ovarian cancer.

The use of zoledronic acid in patients with bone metastases from prostate carcinoma: effect on analgesic response and bone metabolism biomarkers.

Zoledronic acid is a bisphosphonate that is effective in the treatment of complications of metastatic bone disease. We have carried out a perspective study on 24 consecutive patients with prostate cancer metastatic to bone to verify the effect of zoledronic acid on analgesic response and a possible relationship with the levels of bone metabolism biomarkers. Eligibility for this study required prostate cancer patients with metastatic bone disease and pain not controlled by analgesics. Patients were excluded from the study if they were receiving cytotoxic chemotherapy or radiation therapy within three months. Eighteen patients (75%) were considered responder to acid zoledronic, only 6 patients did not respond. Before starting treatment (T0) mean Visual Analogue Scale was 7.8 (SE +/- 0.29), after 1 month therapy (T1) was 3.6 (SE +/- 0.3) and after three months (T2) was 3.1 (SE +/- 0.4) with a significant difference between T0 and T1 (p<0.0005) and between T0 and T2 (p<0.0005). Visual Analogue Scale improvement was positively correlated with decrease of C-telopeptide and bone phosphatase alkaline (p<0.05) serum levels.

Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients.

Outpatient treatment of deep vein thrombosis (DVT) has become a common practice in uncomplicated patients. Few data are still present in patients with comorbidity (such as cancer) or concomitant symptomatic pulmonary embolism. Cancer patients with DVT are often excluded from home treatment because they have a higher risk of both bleeding and recurrent DVT. We tested the feasibility and safety of the Home Treatment (HT) program for acute DVT a PE in cancer patients. Patients were treated as outpatients unless they required admission for other medical problems, were actively bleeding or had pain that requires parenteral narcotics. Outpatient treatment was with low molecular weight heparin (LMWH) followed by warfarin or with LMWH alone. An educational program for patients was implemented. Two-hundred and seven patients with cancer were evaluated, 36 (17.4%) of whom had metastatic disease. Treatment with LMWH and warfarin was prescribed to 106 (51.2%) and LMWH alone to 102 (48.8%). One hundred and twenty-seven patients (61.3%) were entirely treated at home. There were no differences between patients treated at home and hospitalized patients with regard to gender, mean age, site of cancer, presence of metastases, and treatment. After 6 months, recurrent thrombo-embolism occurred in 8.7% of patients treated at home and in 5.6% of hospitalized patients (P=0.58); major bleeding in 2.0% and 1.5%, respectively (P=0.06). Twenty-seven patients (33%) in the hospitalized, and 33 (26%) in the home-treatment group, died after a follow-up of 6 months. These results indicate that, regarding cancer patients with acute DVT and/or PE, there is no difference between hospitalised and home-treated patients in terms of major outcomes.

Antiblastic drug combinations with ifosfamide: an update.

Ifosfamide is an alkylating agent that is widely used in the treatment of various neoplasms, such as sarcomas, lymphomas, pediatric malignancies, germ cell tumors, lung, breast and ovarian cancer. The clinical toxicity of ifosfamide depends on the dose and administration schedules. The pharmacologic features of this drug enable its combination with other antiblastic agents, such as vinorelbine, gemcitabine, paclitaxel and docetaxel. Moreover, the pharmacologic profile of ifosfamide allows the use of this antiblastic drug in patients who have previously failed many other treatments, and a large percentage of responses has already been obtained. There is some concern about the optimal scheduling of the drug with other novel chemotherapeutics. Clinical trials that include pharmacokinetic and pharmacodynamic studies may be the most efficient way to optimize the therapeutic efficacy of ifosfamide and define the dosing and scheduling.

Opioid plasma concentration during switching from morphine to methadone: preliminary data.

Opioid switching is often used to improve the opioid response in cancer patients experiencing poor analgesia or adverse effects. However, no data are available on plasmatic changes of opioids and their metabolites during these phases, and whether there exists a relationship with the clinical events. In a prospective study of 10 consecutive cancer patients on oral morphine but with uncontrolled pain (greater >4 on a numerical scale of 0 to 10) and/or moderate to severe opioid adverse effects (on a level of 2 and 3 of a verbal scale) and not responsive to adjuvant medications, switching to oral methadone was performed using a fixed ratio of 5:1, leaving extra-doses of 1/5 of the daily dose of methadone calculated as needed. Blood samples were obtained at the same hour for four days, before the switching, and then on day 1, 2, and 3. The intensity of pain and the adverse effects were assessed daily to calculate the switching score before and after switching. Completed blood samples were obtained in 9 patients. One patient was separately considered, because of his renal impairment. Significant improvements in pain intensity as well as adverse effects within an average period of 1-2 days were observed. Morphine, morphine-6-glucuronide, and morphine-3-glucuronide were progressively cleared from plasma to almost disappear within three days. Methadone rapidly achieved a stable concentration in 1-2 days. The doses of methadone were changed, but not significantly, and tended to decrease in the following days, according to the clinical situation. The results of this study confirm the need to stop rapidly morphine, and to use a priming dose of methadone, rather than using progressive decrements and increments of morphine and methadone, respectively, during opioid switching. This method allows for a rapid clearance of morphine and its metabolites are rapidly cleared, except in patients with renal failure. Opioid plasma changes substantially overlap the clinical changes observed in these patients, in terms of benefit between analgesia and adverse effects.

DNA ploidy and S-phase fraction, but not p53 or NM23-H1 expression, predict outcome in colorectal cancer patients. Result of a 5-year prospective study.

PURPOSE: The aim of this study was to determine TP53 and NM23-H1 immunoreactivity, DNA ploidy, and S-phase fraction (SPF) in a series of 160 patients undergoing resective surgery for primary operable colorectal cancer (CRC) and to establish whether these alterations have any clinical value in predicting CRC patients' prognosis. METHODS: TP53 and NM23-H1 expressions were evaluated on paraffin-embedded tissue by immunohistochemistry and DNA-ploidy and SPF on frozen tissue by flow-cytometric analysis. RESULTS: The median follow-up time in our study group was 71 months (range 34-115 months). P53 protein expression was associated with distal tumors (P<0.05) and DNA aneuploid tumors (P<0.05) tumors. DNA-aneuploidy was associated with distal tumors (P<0.01), histological grade (G3) (P<0.05), advanced Dukes' stage (C and D) (P<0.01), lymph node metastases (P<0.01) and high SPF (>18.3%) (P<0.01). The major significant predictors for both disease relapse and death were advanced Dukes' stage, DNA-aneuploidy, and high SPF, while lymphohematic invasion was the only independent factor for relapse and non-curative resection for death. CONCLUSIONS: Our results indicate that DNA aneuploidy and high SPF are associated in CRC with a poor clinical 5-year outcome, while in contrast the prognostic role of TP53 and NM23-H1 expression is still to be clarified.

A randomised controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: effects on dose-escalation and a pharmacoeconomic analysis.

The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cancer pain has been well established in the treatment of mild pain and in association with opioids in the treatment of moderate to severe pain. The aim of this study was to verify the effects of NSAIDs on morphine escalation in advanced cancer patients with pain followed-up at home and to assess the pharmacoeconomic implications. A prospective randomised controlled study was carried out in 156 consecutive advanced cancer patients with pain followed-up at home in the period December 1999-December 2000. In this group of patients, 47 were selected with pain progression after 1 week of opioid stabilisation. Patients were randomly assigned to one of two groups: group 'O' patients were treated with continuing opioid escalation according to their clinical needs; group 'OK' received ketorolac 60 mg/daily orally (p.o.) in three doses and then continued opioid escalation according to their clinical situation. Performance status, doses of morphine before and after starting treatment, mean weekly pain intensity (assessed by means of a numerical scale from 0 to 10), mean weekly symptoms intensity, adverse effects and pain mechanisms were recorded. Moreover, drug costs per day in both groups were calculated. Patients who received ketorolac in addition to morphine showed a better analgesia after a week in comparison to the group treated with morphine only (P=0.005). Thereafter, morphine escalation was slower and the maximum morphine dose was lower in the group treated with ketorolac. The incidence and the severity of gastric discomfort was more evident in patients treated with ketorolac, while constipation was significantly increased in patients who received morphine only. Drug costs per day were similar in both groups; statistical differences were observed in patients who started on lower morphine doses (<100 mg/daily) in the two groups (4.3 in the ketorolac-morphine group versus 3.4 in the morphine group; P=0.012). The use of NSAIDs reduces the need for an opioid dose escalation or allows the use of lower doses. Their use is associated with a more intense gastric discomfort, but results in less opioid-related constipation. The eventual additive cost for NSAIDs therapy is negligible, especially in patients taking high doses of morphine.

Rifampicin in opioid-induced itching.

Pruritus is prevalent in 5-12% of palliative care patients. Rifampicin has been shown to be useful both as initial treatment and as salvage treatment after failure of other agents to control the pruritus associated with the cholestatic jaundice of malignancy. We report the case of a 65-year-old woman who complained of severe pruritus after morphine treatment. The use of rifampicin 300 mg twice a day by the i.v. route was successful, and after opioid switching it was no longer necessary to maintain rifampicin in the therapeutic regimen. Controlled clinical trials are warranted to confirm this preliminary observation.

The use of corticosteroids in home palliative care.

Evidence for the effectiveness of corticosteroids in palliative care is anecdotal, and more information is required. From January to December 1999 a total of 376 consecutive patients admitted to a home palliative care program were longitudinally surveyed. Patients who started a corticosteroid treatment after admission on the basis of common indications prescribed by their home care physicians were selected. Fifty patients were enrolled in the study. Dexamethasone, in doses ranging from 4 to 16 mg, was the drug of choice. Corticosteroids were found to be effective in anorexia, weakness, headache, and nausea and vomiting. The reduction of symptom intensity was achieved in less than 3 days on average. However, no great advantages were found in terms of controlling drowsiness or confusional states associated with advanced illness because of cerebral involvement. It can be concluded from this study that: (a) corticosteroids may be effective in controlling anorexia, weakness, headache, and nausea and vomiting associated with cerebral involvement or bowel obstruction; (b) they should be stopped if no therapeutic effect has become evident within 3-5 days; (c) the treatment is not useful when given in the presence of severe neurological impairment resulting from the advanced stage of disease; (d) the range of adverse effects was acceptable for limited periods and in the circumstances in which the preparations were used in this study; and (e) corticosteroids may have an adjuvant role in potentiation of analgesic drugs. These findings will be very useful in the planning of future controlled studies designed to yield evidence-based data on the role of corticosteroids in the relief of specific symptoms.

Pathogenesis and pharmacological treatment of bone pain in skeletal metastases.

Sixty-five percent of patients with advanced cancer present bone metastases and most of them present a rather slow clinical course characterized by pain, mobility deficiencies and skeletal complications such as fractures and spinal cord compression. Metastatic involvement of the bone is one of the most frequent causes of pain in cancer patients and represents one of the first signs of widespread neoplastic disease. The pain may originate directly from the bone, from nerve root compression or from muscle spasms in the area of the lesions. The mechanism of metastatic bone pain is mainly somatic (nociceptive) even though, in some cases, neuropathic and visceral stimulations may overlap. The conventional symptomatic treatment of metastatic bone pain requires the use of multidisciplinary therapies such as radiotherapy in association with systemic treatment (hormonotherapy, chemotherapy, radioisotopes) with the support of analgesic therapy. Recently, studies have indicated the use of bisphosphonates in the treatment of pain and in the prevention of skeletal complications in patients with metastatic bone disease. In some patients pharmacological treatment, radiotherapy, radioisotopes administered alone or in association are not able to manage pain adequately. The role of neuroinvasive techniques in treating metastatic bone pain is debated. The clinical conditions of the patient, his life expectancy and quality of life must guide the physician in the choice of the best possible therapy.