Predictive genetic markers in neoadjuvant chemoradiotherapy for locally advanced esophageal cancer: a long way to go. Review of the literature.

The role of genetic molecular markers in neoadjuvant treatment for locally advanced esophageal cancer has been reviewed, focusing strictly on concurrent chemoradiation protocols followed by surgery. Eleven studies evaluated the role of mRNA expression profile; the end point was overall survival (OS) in two studies and different definitions of histological response in nine. Genes reported as significant were involved in cell cycle control (30), apoptosis (7), structural molecules (9), cell metabolism (6) and DNA repair (1). Seven studies reported about 15 microRNA (miRNA) molecules associated with OS (2) or histological response (13), however, defined with different classifications. Their target genes were prevalently involved in cell cycle control (4), apoptosis (1), cell adhesion (1), migration (1) and angiogenesis (1). Gene polymorphisms (single-nucleotide polymorphisms (SNPs)) have been evaluated in 8 studies reporting 10 variants associated with survival or pathological response. OS was the end point in six of these studies. SNPs reported as significant were involved in DNA repair system (4), detoxification (2), folate metabolism (6), drug efflux (2) and others (2). In a study, a panel including histology, pathological response and five SNPs discriminated two subsets of patients with 5-year survival rates of 79.3% and 26.3% (hazard ratio 6.25, P<0.0001). In another study, combination of stage, grade and 4 miRNAs improved prediction of pathological response (P=10-30). At present, given the great inconsistency of the data and the variability of the end points, definite conclusions are extremely difficult, if not impossible. More consistent data can derive only from analyses obtained from patients included in prospective randomized trials while panels combining genetic and clinical factors may improve prediction.

Safety and activity of sunitinib in elderly patients (≥ 70 years) with metastatic renal cell carcinoma: a multicenter study.

BACKGROUND: Actual tolerability of sunitinib is still poorly documented in elderly patients with metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Charts of elderly patients treated with sunitinib for mRCC were reviewed in six Italian centers to assess safety (primary objective), efficacy and correlation of toxicity with comprehensive geriatric assessment (CGA) (secondary objectives). RESULTS: Sixty-eight patients were eligible, and the median age was 74 years. CGA was carried out in 34 patients (41% fit, 41% vulnerable and 18.5% frail). The dose reduction to 37.5 mg was made upfront or soon after the first cycle in 69.1%. More frequent toxic effects were fatigue (80.9%), mucositis (61.8%) and hypertension (58.8%). Cardiac events occurred in nine patients. In 10 patients, therapy was interrupted early due to rapidly progressive disease (10.3%) or severe toxicity (4.4%: 1 cardiac failure, 1 fatigue, 1 febrile neutropenia). At a median follow-up of 27.1 months, the median OS was 18.3 months and the median PFS was 13.6 months. Correlation was not found between frailty at CGA with severe toxicity nor with response. CONCLUSIONS: Treatment with sunitinib is effective in elderly patients; yet early interruptions were frequent. Starting treatment at reduced dose and escalating in the absence of severe toxicity could be suggested.

Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to sunitinib in metastatic renal cancer.

BACKGROUND: Recently, we developed an apoptotic assay for expanding the monitoring capabilities of the circulating tumour cells (CTC) test during therapy. An automated platform for computing CTCs was integrated with a mAb (M30) targeting a neoepitope disclosed by caspase cleavage at cytokeratin 18 in early apoptosis; we showed that live CTCs were associated with progression, consistent with enhanced cell migration and invasion. The test was first applied here to mRCC. METHODS: Live/apoptotic CTCs changes were measured in mRCC patients receiving first-line Sunitinib and compared with circulating endothelial cell (CEC) levels. RESULTS: The presence of EpCAM-positive, live CTCs predicts progression in individual mRCC patient, being associated with distant metastasis under first-line Sunitinib. Synchronous detection of CTCs and CEC levels discloses for the first time an association between their dynamic changes and outcome: a rapid increase of the CEC number as early as the first cycle of therapy is associated with CTC decrease in non-progressed patients, whereas a delayed response of CECs is related to higher CTC values in the progressed group indicating treatment failure. CONCLUSION: We demonstrated that a delayed response to antiangiogenic treatment indicated by persistent detection of CECs correlates with persistent live CTCs and more aggressive disease.

Predictive value of hematological and phenotypical parameters on postchemotherapy leukocyte recovery.

BACKGROUND: Grade IV chemotherapy toxicity is defined as absolute neutrophil count <500/microL. The nadir is considered as the lowest neutrophil number following chemotherapy, and generally is not expected before the 7th day from the start of chemotherapy. The usual prophylactic dose of rHu-G-CSF (Filgrastim) is 300 microg/day, starting 24-48 h after chemotherapy until hematological recovery. However, individual patient response is largely variable, so that rHu-G-CSF doses can be different. The aim of this study was to verify if peripheral blood automated flow cytochemistry and flow cytometry analysis may be helpful in predicting the individual response and saving rHu-G-CSF. METHODS: During Grade IV neutropenia, blood counts from 30 cancer patients were analyzed daily by ADVIA 120 automated flow cytochemistry analyzer and by Facscalibur flow cytometer till the nadir. "Large unstained cells" (LUCs), myeloperoxidase index (MPXI), blasts, and various cell subpopulations in the peripheral blood were studied. At nadir rHu-G-CSF was started and 81 chemotherapy cycles were analyzed. Cycles were stratified according to their number and to two dose-levels of rHuG-CSF needed to recovery (300-600 vs. 900-1200 microg) and analyzed in relation to mean values of MPXI and mean absolute number of LUCs in the nadir phase. The linear regressions of LUCs % over time in relation to two dose-levels of rHu-G-CSF and uni-multivariate analysis of lymphocyte subpopulations, CD34(+) cells, MPXI, and blasts were also performed. RESULTS: In the nadir phase, the increase of MPXI above the upper limit of normality (>10; median 27.7), characterized a slow hematological recovery. MPXI levels were directly related to the cycle number and inversely related to the absolute number of LUCs and CD34(+)/CD45(+) cells. A faster hematological recovery was associated with a higher LUC increase per day (0.56% vs. 0.25%), higher blast (median 36.7/microL vs. 19.5/microL) and CD34(+)/CD45(+) cell (median 2.2/microL vs. 0.82/microL) counts. CONCLUSIONS: Our study showed that some biological indicators such as MPXI, LUCs, blasts, and CD34(+)/CD45(+) cells may be of clinical relevance in predicting individual hematological response to rHu-G-CSF. Special attention should be paid when nadir MPXI exceeds the upper limit of normality because the hematological recovery may be delayed.

Predictors of survival and toxicity in patients on adjuvant therapy with 5-fluorouracil for colorectal cancer.

The present study aimed at investigating whether the simultaneous evaluation of pharmacokinetic, pharmacogenetic and demographic factors could improve prediction on toxicity and survival in colorectal cancer patients treated with adjuvant 5-fluorouracil (5FU)/leucovorin therapy. One hundred and thirty consecutive, B2 and C Duke's stage colorectal cancer patients were prospectively enrolled. 5FU pharmacokinetics was evaluated at the first cycle. Thymidylate synthase (TYMS) 5'UTR and 3'UTR polymorphisms and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms were assessed in peripheral leukocytes. Univariate and multivariate analyses were applied to evaluate which variables could predict chemotherapy-induced toxicity, disease-free survival (DFS) and overall survival (OS). Multivariate analysis showed that: (a) low 5FU clearance was an independent predictive factor for severe toxicity (OR=7.32; P<0.0001); (b) high-5FU clearance predicted poorer DFS (HR=1.96; P=0.041) and OS (HR=3.37; P=0.011); (c) advanced age was associated with shorter DFS (HR=3.34; P=0.0008) and OS (HR=2.66; P=0.024); (d) the C/C genotype of the MTHFR C677T polymorphism was protective against grade 3-4 toxicity (P=0.040); (e) none of the TYMS polymorphisms could explain 5FU toxicity or clinical outcome.

Pharmacokinetic and demographic markers of 5-fluorouracil toxicity in 181 patients on adjuvant therapy for colorectal cancer.

BACKGROUND: The relationship between 5-fluorouracil (5-FU) pharmacokinetics and toxicity following i.v. bolus administration has not been extensively studied. PATIENTS AND METHODS: One hundred and eighty-one patients on adjuvant therapy with 5-FU plus leucovorin for colorectal cancer were the study population. 5-FU pharmacokinetics was determined on day 2 of the first, third, and fifth cycles; type and the grade of adverse reactions were recorded on the next cycle. RESULTS: The 5-FU area under the curve (AUC) measured at the first cycle ranged between 146 and 1236 mg x min/l and was significantly correlated with drug dose, patients' body weight (BW) and gender, females having higher AUCs. These covariates explained only 23% of AUC variability. AUC and age were the only covariates which discriminated between toxic (grade > or =2) and nontoxic cycles (grade <2), with an optimal AUC cut-off value of 596 mg x min/l. Such a correlation was lost during the next cycles following dose reduction because of toxicity in 80 patients. CONCLUSIONS: A method for calculating the initial 5-FU dose is proposed which takes into account patient BW, gender and a target AUC of 596 mg x min/l. Nevertheless, it appears that a substantial part of 5-FU toxicity is not linked to pharmacokinetic factors and dose adjustments must still be on the basis of careful clinical surveillance.

Role of 18F-FDG PET-CT imaging for the detection of an unknown primary tumour: preliminary results in 21 patients.

PURPOSE: Metastatic cancer of unknown primary origin is a syndrome characterised by a poor prognosis, with a typical survival rate from diagnosis of no longer than 1 year. Only 20-27% of primary tumours are identified by conventional radiological imaging. By contrast, it has been reported that 18F-fluorodeoxyglucose positron emission tomography (FDG PET) allows the identification of 24-40% of otherwise unrecognised primary tumours. To our knowledge, the studies on this topic have been conducted using 18F-FDG PET imaging alone. The aim of this study was to evaluate the potential additional diagnostic role of fused 18F-FDG PET-CT imaging for the detection of metastatic occult primary tumours. METHODS: The study population consisted of 21 consecutive patients with biopsy-proven metastatic disease and negative conventional diagnostic procedures. Each patient underwent a PET scan, carried out according to a standard procedure (6 h of fasting, i.v. injection of 370 MBq of 18F-FDG and image acquisition with a dedicated PET-CT scanner for 4 min per bed position). RESULTS: 18F-FDG PET-CT detected the occult primary tumour in 12 patients (57% of cases), providing a detection rate higher than that reported with any other imaging modality, including conventional 18F-FDG PET. CONCLUSION: The favourable results of this study need to be confirmed in larger patient populations with long-term follow-up.

Daily low-dose subcutaneous recombinant interleukin-2 by alternate weekly administration: antitumor activity and immunomodulatory effects.

A phase II clinical trial of subcutaneous recombinant Interleukin 2 (rIL-2) given by 5 days pulses followed by a 9 days rest has been performed in patients affected by renal cell carcinoma, malignant melanoma and colorectal cancer. A total of 25 patients entered the study, completed at least six courses of treatment, and were evaluable for toxicity and response to treatment. This schedule of subcutaneous rIL-2 was well tolerated and no World Health Organization grade 3 side effects were observed. A 33.3% response rate was recorded in patients affected by renal cell carcinoma, although no major responses were achieved in patients with malignant melanoma and colorectal cancer. A durable increase of natural killer activity retained by poeripheral blood mononuclear cells was demonstrated in these patients and was paralleled by increased serum levels of interferon gamma and tumor necrosis factor a without changes of circulating interleukin-1d. It is concluded that this schedule of pulse administration of subcutaneous rIL-2 has antitumor activity in renal cell carcinoma and produces durable biomodulatory effects.

Alpha-interferon induces depletion of intracellular iron content and upregulation of functional transferrin receptors on human epidermoid cancer KB cells.

We have demonstrated that interferon-alpha (IFN alpha) upregulates the epidermal growth factor receptor (EGF-R) on human epidermoid carcinoma cells. Here we report that IFN alpha induces growth inhibition and upregulation of transferrin receptor (TRF-R) on epidermoid cancer KB cells. IFN alpha does not alter TRF-R affinity for its ligand and induces a two-fold increase of TRF binding sites. IFN alpha does not modify receptor internalization and cycling. Intracellular iron levels are known to regulate TRF-R expression: we have, therefore, evaluated whether changes in the iron content could be determined by IFN alpha. Iron levels are transiently increased after addition of fresh growth medium in untreated controls but not in KB cells exposed for 48 h to IFN alpha. Iron depletion is however completely reversed 24 h later when maximal TRF-R upregulation occurs in IFN alpha-treated cells. We suggest that IFN alpha-induced iron depletion elicits a homeostatic cellular response through upregulation of TRF-R.

Phorbol 12-myristate 13-acetate (pma) induces neuroendocrine-like differentiation and reverses Doxorubicin-resistance of human colon-carcinoma cells in-vitro.

Human colon carcinoma LoVo/DX cells, which have been selected from parental LoVo for resistance to doxorubicin, express a typical multidrug resistant (MDR-1) phenotype. We have investigated whether phorbol 12-myristate 13-acetate (PMA) which often induces phenotypical changes in human tumor cells could, at the same time, modulate differentiation and sensitivity of LoVo/DX cells to doxorubicin. After 48 h exposure to 100 nM PMA, morphological changes became evident on LoVo/DX cells which showed elongated cytoplasm and dendritic-like structures: moreover immunocytochemical findings were suggestive of neuroendocrine-like differentiation. Under the same experimental conditions, LoVo/DX became sensitive to doxorubicin and showed enhanced intracellular drug-accumulation and reduced membrane expression of the 170 kD glycoprotein GP-170, which is the cellular product of the mdr1 gene. We conclude that pharmacological induction of tumor cell differentiation by PMA is paralleled by abrogation of drug resistance in a colon carcinoma MDR-1 cell line.

Cardiovascular monitoring of drug-resistant lymphoma patients treated with epoch chemotherapy plus high-dose verapamil in continuous-infusion.

High dose Verapamil (VP) infusion has been incorporated into cytotoxic chemotherapy in order to circumvent tumor cell drug-resistance. We have evaluated the cardiovascular side-effects produced by high dose VP associated to EPOCH chemotherapy in 12 patients with chemorefractory lymphoma. Continuous monitoring of right ventricular and pulmonary pressure and cardiac index was performed in three patients by a Swan-Ganz catheter. A slight reduction in cardiac index was observed 6 h after the beginning of VP infusion and was followed by spontaneous recovery within 12 h. First degree atrioventricular (AV) block was detected in 6/12 patients. Premature Ventricular Beats (PVB) occurred in one patient, and promptly disappeared after xylocaine administration. All patients experienced mild and transient hypotension, while severe hypotension was observed only in 1 patient, who promptly recovered when VP administration was discontinued. Hypokalemia was detected in 6 patients possibly as a consequence of transient activation of the renin-angiotensin system.

[Arterial complications of renal transplantation. Experience with 360 cases]. / Sulle complicanze arteriose dei trapianti di rene. Esperienza su 360 casi.

The Authors report the arterial complications observed in a 360 kidney transplantations experience. They analyze the etiological, diagnostic and therapeutic features.

[Venous complications of renal transplantation. Experience with 360 cases]. / Sulle complicanze venose dei trapianti di rene. Esperienza su 360 casi.

The Authors report three cases of renal vein thrombosis after transplantation. One of these cases has been successfully admitted to surgical treatment. They point out the pathogenetical features and underline the importance of surgery.

[Considerations on 12 cases of mesenteric embolism treated surgically]. / Considerazioni su 12 casi di embolia mesenterica trattati chirurgicamente.

Twelve cases of mesenteric artery embolism surgically treated with a surviving rate of 66% are reported. The Authors point out the diagnostic features and the various factors affecting the surgical result.

[Inflammatory aneurysms of the abdominal aorta]. / Aneurismi infiammatori dell'aorta addominale.

The Authors report their fifteen years experience, point out the clinical features of inflammatory abdominal aortic aneurysms and examine the different pathogenetic theories.

[Peripheral nerve injuries during carotid endarterectomy]. / Lesioni nervose periferiche durante l'endoarteriectomia della carotide.

Our experience with patients undergoing carotid endoarteriectomy over a 10 year period has been retrospectively reviewed. Nerve injuries were detected by reviewing postoperative progress and clinical notes. One hundred thirty-four procedures were performed on 120 patients, to 15 of whom (9%) occurred major nerve injuries. These included seven vagal nerve injuries causing ipsilateral vocal cord paralysis and hoarseness, five injuries of the marginal mandibular nerve and three injuries of the hypoglossal nerve. None of the patients with nerve injury had a stroke as a result of carotid operation. Vocal cord paralysis was documented by laryngoscopy. The incidence of cranial nerve injury during carotid endoarteriectomy appears to be higher than expected, particularly if asymptomatic patients are controlled.

[Follow-up in femoral artery embolectomy]. / Risultati a distanza nell'embolectomia dell'arteria femorale.

The results of 112 femoral embolectomies performed on 100 patients were reviewed. Operative mortality rate was 15% and early amputation (within 30 day-after the procedure) 18%. The role of early amputation was closely related to the time of leg ischemia. Current follow-up as established for 86 patients. 5 years and 10 years survival rates for the group were 49% and 40%. Although early survival is decreased after femoral embolectomy long term survivors can be expected to live independently with excellent limb salvage and function.

[Popliteal aneurysm. Our experience in 65 cases]. / Gli aneurismi poplitei. La nostra esperienza in 65 casi.

Fifty patients with 65 popliteal aneurysms underwent reconstructive procedures (mean age 64). Atherosclerosis is almost the exclusive cause of popliteal aneurysms. Most of the cases showed an acute ischemia, while he others were asymptomatic or presented a complication of venous occlusion or neural compression. Numerous cases were found incidentally at amputations (these were not included). The best operational method is ligation of the aneurysm sometimes with partial resection and autologous venous graft bypass. The immediate results were excellent in all cases, loss of limb was observed in only three.