THE ROLE OF TUMOR-SEEKING RADIOPHARMACEUTICALS IN THE DIAGNOSIS AND MANAGEMENT OF ADRENAL TUMORS.

CONTEXT: The variety of tumor-seeking radiopharmaceuticals, which are currently in clinical use, may have a potential role as imaging agents for adrenal gland tumors, due to physiological characteristics of this organ. OBJECTIVE: The purpose of this study was to evaluate the diagnostic potential of 99mTc-HYNIC-TOC, 99mTc(V)-DMSA, and 99mTc-MIBI in the assessment of adrenal tumors, by correlating with imaging findings and histopathologic results. DESIGN: The research is designed as a cross-sectional prospective study. PATIENTS AND METHOD: The study included 50 patients with adrenal tumors (19 hormone-secreting and 31 nonfunctioning) and 23 controls without adrenal involvement. In all patients, single-photon emission computed tomography (SPECT) was performed, using qualitative and semiquantitative analysis. The tumor to non-tumor tracer uptake was conducted by using a region-of-interest technique. Adrenal to background (A/B) ratio was calculated in all cases. RESULTS: 99mTc-HYNIC-TOC scintigraphy showed a high statistical significance between A/B ratios, while other two tracers resulted in a lower sensitivity, specificity and accuracy. Futhermore, 99mTc-HYNIC-TOC could have a high diagnostic yield to detect adrenal tumors (the receiver-operating-characteristic curve analysis, A/B ratio cut-off value of 8.40). CONCLUSION: A semiquantitative SPECT analysis showed that 99mTc-HYNIC-TOC is a highly sensitive tumor-seeking agent for the accurate localization of adrenal tumors.

Glucose and lipid abnormalities in patients with adrenal incidentalomas.

Adrenal incidentalomas (AI), defined as masses detected during imaging procedures of non-adrenal disorders, have become a common clinical problem that appear to have impairment of glucose and lipid metabolism. PATIENTS AND METHODS: One hundred and ten patients (mean 53.5 age; 24-72), who were diagnosed with functioning and non-functioning AI, were assessed. Patients with hormone-secreting AI underwent biochemical evaluation regarding metabolic disorders. Data about hormone status (cortisol profile and DEX screening test), lipid profile, glycemia, insulinemia were evaluated. RESULTS: This prospective study included 41 (37.28%) patients with non-functional and 69 (62.72%) with functional AI. Tumors associated with (sub)clinical Cushing's syndrome (functional AI) are considered to have higher cortisol concentration at 8h (p=0.027), 16h (p=0.025) and after DEX screening (p<0.010), compared to the controls. Patients with cortisol-secreting AI have significantly higher concentrations of cholesterol (p=0.040), triglycerides (p=0.027) and insulin (p<0.01) than controls. The patients with metabolic disorders have a significantly higher total cholesterol, triglyceride and insulin concentration (p<0.001) compared to controls. There was significant positive correlation between cortisol concentration after DEX screening and total cholesterol (r=0.727, p=0.007), triglycerides (r=0.564, p=0.041) and insulin (r=0.957, p=0.043) in the group with metabolic disorders. CONCLUSION: The present study demonstrates the patients with functional AI have significantly higher lipid, glucose and insulin concentration than controls. There was a significant positive correlation between metabolic parameters and cortisol concentration.

A phase II study on the efficacy and safety of procedural analgesia with fentanyl buccal tablet in cancer patients for the placement of indwelling central venous access systems.

BACKGROUND: Pain in cancer patients is often related to oncologic therapies and diagnostic procedures. The placement of fully implantable venous access systems is a very common procedure in oncology patients. Local anaesthesia is the method most commonly used to overcome pain related to this surgical procedure, but the local anaesthetic may be unable to completely eradicate all pain. This study investigates the effectiveness and safety of fentanyl buccal tablet (FBT), administered by OraVescent® technology, in reducing procedural pain related to the placement of indwelling central venous access systems (Ports) in opioid-naïve cancer patients. METHODS: Inpatients who required an indwelling vascular access (Port) were preoperatively assessed with a self-assessment questionnaire on anxiety and pain. A 100 µg FBT was administered 10 min before preparation of the operating field. A self-assessment scale for pain experienced during the procedure was administered at the end of the procedure. Vital signs and the presence of any side effects or bothersome symptoms were monitored during the procedure, at the end, and 4 h later. RESULTS: From October 2012 to June 2014, 65 patients were enrolled in the study. A total of 61 (93.9 %) patients perceived no or a little pain during the procedure. Four patients (6.2 %) reported a lot of pain. No patient reported very severe pain. This data is significant in terms of the lower than expected presence of pain (Fisher test p = 0.0018) as assessed in our previous experience without procedural analgesia. The most common side effects of FBT was drowsiness, experienced by 28 patients at the end of the procedure (43.1 %), significantly reduced (p < 0.01) to 8 patients after 4 h (12.5 %). Nausea was present in 6 cases at the end of the procedure (9.2 %) and in 7 cases 4 h later (10.9 %). Vomiting was present in 3 cases at the end (4.7 %) and in 2 other patients after 4 h (7.8 %). No significant change of vital parameters was observed between the baseline and the subsequent measurements in all patients studied. CONCLUSIONS: The significant improvement in the number of patients experiencing little or no pain, accompanied by a lower number of non-severe side effects, suggests that FBT is a valid, practical and safe method of procedural analgesia. It will be necessary to perform further studies, taking into account the need for standard antiemetic pre-medication to minimise the incidence of nausea and vomiting.

Early and short-term acenocumarine or dalteparin for the prevention of central vein catheter-related thrombosis in cancer patients: a randomized controlled study based on serial venographies.

BACKGROUND: We evaluated efficacy and safety of early and short-term prophylaxis with acenocumarine or dalteparin in the prevention of non-occlusive or occlusive central vein catheter-related thrombosis (CVCrT). PATIENTS AND METHODS: Consecutive cancer patients scheduled for chemotherapy randomly received: acenocumarine 1 mg/day for 3 days before and 8 days after central vein catheter (CVC) insertion; dalteparin 5000 IU 2 h before and daily for 8 days after CVC insertion; no anticoagulant treatment (NT). All patients underwent venography on days 8 and 30, some of them on days 90, 150 and 210 after CVC. RESULTS: A total of 450 patients were randomized, 348 underwent at least two venography. Both acenocumarine and dalteparin reduced venography-detected CVCrT rate [21.9% acenocumarine versus 52.6% NT, odds ratio (OR) 0.3, P < 0.01; 40% dalteparin versus 52.6% NT, OR 0.6, P = 0.05]. Acenocumarine was more effective than dalteparin (OR 0.4, P = 0.01). The rate of occlusive CVCrT was not different in the three groups (0.9% acenocumarine, 3.3% dalteparin, 1.8% NT; P = 0.40). Most CVCrTs (95.6%) were observed on day 8 after CVC insertion and were non-occlusive. CONCLUSIONS: In this study of early and short-term prophylaxis, acenocumarine was more effective than dalteparin on non-occlusive and asymptomatic CVCrT events. The first days following CVC insertion represent the highest risk for CVCrT.

Central venous thrombosis: an early and frequent complication in cancer patients bearing long-term silastic catheter. A prospective study.

Studies on catheter-related central venous thrombosis (CRCVT) have been focused mainly on clinically evident CRCVT due to occlusive thrombi, underestimating therefore the actual thrombosis prevalence. This prospective study was aimed at evaluating prevalence, timing and evolution of thrombosis, and identifying involved veins and risk factors in cancer patients (pts) undergoing percutaneous subclavian central venous catheterization (CVC) for chemotherapy, parenteral nutrition or both. We enrolled 127 consecutive pts requiring partially or totally implanted central venous silastic catheters. The study protocol included peripheral phlebography (P) at day 8, 30 and every two months following CVC and/or when clinically indicated, along with peripheral and pullout P on catheter withdrawal. A quantitative scale was developed to evaluate thrombus grading in subclavian, innominate and cava veins. Age, sex, coagulation profile tumor histotype, metastases, therapy, catheter type, and catheter insertion side were also investigated. Only pts who underwent at least two P were evaluated, and chi 2 test was adopted for statistical analysis. Altogether, 95 pts were evaluable. CRCVT was observed in 63/95 (66%) pts. At day 8, 30 and 105 (representing the median days in which first, second and last P were performed) CRCVT was evidenced in 64%, 65% and 66% of the pts, respectively. Thrombus grading did not differ among first, second and last P. CRCVT was symptomatic in 4/63 (6%) pts. Thrombosis prevalence was higher in subclavian (97%) with respect to innominate (60%) or cava (13%) veins (p < 0.001). Thrombosis was higher in left subclavian catheters (14/16; 87.5%) than in right ones (49/79; 62%), p < 0.01. No associations were established between CRCVT and other investigated parameters. Our data show a very high actual frequency of CRCVT in cancer pts, and emphasize that first days following CVC are at the highest risk for CRCVT development. Based on our results, a study on short-term antithrombotic prophylaxis in cancer pts requiring CVC is warranted. Finally, our data indicate that left subclavian vein catheterization represents a risk factor for CRCVT.

Antithrombin III deficiency as a risk factor for catheter-related central vein thrombosis in cancer patients.

The fibrin sleeve of venous catheters (VC) and parietal thrombi represent frequent and dangerous side-effects of central venous catheterization (CVC), due to the risk of embolism. Reduced levels of coagulation clotting factors inhibitors (such as Antithrombin III) are known to be associated with increased thrombogenic risk. The aim of this study was to evaluate the role of Antithrombin III (AT III) deficiency as a risk factor for thrombosis in cancer patients undergoing CVC. The study groups included patients with a reduced AT III activity (< 70%, 20 consecutive patients) and with normal AT III values (> 70%, 20 randomly selected patients), requiring a VC for chemotherapy and/or total parenteral nutrition. The study protocol included evaluation of Hb, PLTs, PT (INR), aPTT, Fibrinogen and AT III at days 0, 1, 3 and 8 after CVC and upon VC removal. Peripheral and pullout phlebographies were performed in all patients on catheter withdrawal. A quantitative scale was developed to evaluate both VC and parietal thrombus degree in each catheter-containing venous segment (subclavian, innominate, superior vena cava); the sum of the mean values was defined as overall thrombus. The average VC dwelling time was similar in both groups. There were no significant differences in Hb, PLTs, PT (INR), aPTT, Fibrinogen and in the remaining parameters of the study between the two groups. The group with AT III deficiency presented a higher degree of both parietal (p < 0.05) and overall thrombus (p < 0.02). Data showed a higher severity of CVC-related thrombosis in patients with AT III deficiency than in the control group. Further studies are needed to evaluate whether the therapeutically-induced normalization of AT III levels can reduce the thrombosis degree.

Central venous catheter-related thrombosis in clinically asymptomatic oncologic patients: a phlebographic study.

Fifty-seven oncologic patients with short- or long-term central venous catheters (CVCs) and without clinical signs of axillary-subclavian thrombosis were evaluated phlebographically. Different degrees of incomplete thrombosis were found in 26 patients (45.5%) and complete thrombosis, clinically silent, was found in six patients (10.5%). A fibrin sleeve around the CVC was radiologically demonstrated in 45 (78%) patients, 21 of them (46%) with negative standard venogram. Only in four patients there was no evidence of fibrin sleeve or parietal thrombosis. There were no significant differences between patients with long-term and short-term CVCs. We conclude that parietal thrombosis of the axillary-subclavian veins is a frequent event, even if there is no clinical evidence of flow obstruction and we confirm in vivo that a fibrin coating of the CVCs is present in the majority of the cases.

Carboplatin and etoposide in patients with advanced gastric cancer.

Thirty-six patients with advanced gastric cancer were treated with combination chemotherapy following surgery. Chemotherapy consisted of carboplatin (CBDCA) 300 mg/m2, days 1-3, and etoposide (VP 16) 100 mg/m2, days 1-5. 10/36 (28%) patients had objective response. The median duration of response was 8 months. Currently 26/36 patients have shown progressive disease at a median of 4 months. Three patients remain progression-free 7, 14, and 15 months after study entry, respectively. 26/36 patients have died and 10/26 remain alive at a median time of 16 months. Estimated survival for all patients is 7 months. Two groups of toxicities were observed: hematological and gastrointestinal. They were generally assessed as mild with only two grade 3 (ECOG) toxicities and with no grade 4 toxicity observed during this study.

Cisplatin and 5-fluorouracil as induction chemotherapy followed by radiation therapy in metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck. A phase II study.

12 patients with metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck were treated with induction chemotherapy and radiotherapy. Median age was 54 years (range, 39-68 years) and male to female ratio was 2:1. Five (42%) patients had N3 disease and 7 (58%) had N2 disease. Induction chemotherapy consisted of cisplatin 60 mg/m2, days 1 and 2 and 5-fluorouracil (5-FU), 500 mg/m2, days 3 and 4. Cycles were repeated every 4 weeks to a total of 3 cycles. After 4 weeks rest, patients underwent radiation therapy. It was given to all possible sites of the primary tumor (nasopharynx, pyriform sinus, and the base of the tongue). The radiation therapy dosage planned to the whole neck, nasopharynx, and supraclavicular area was 45 Gy in 24 daily fractions in 5 weeks, increasing to 60-70 Gy to the metastatic site. We observed 9 (75%) complete responses and 1 (8%) partial response. 7 (58%) patients are currently with no evidence of disease. Median survival time for all patients is 36 months (range, 14+ to 56 months), while median survival time for N3 patients was 32 months (range, 26-56 months). Toxicities were predominantly mild to moderate nausea and vomiting and mucositis. This combined modality appears to be effective and feasible in treatment of metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck.

[Chemotherapy protocol "8 drugs in 1 day" in patients with recurrent malignant glioma]. / Hemoterapijski protokol "osam lekova u jednom danu" kod bolesnika s recidivom malignog glioma.

22 patients with recurrent malignant gliome were treated with "8 drugs in 1 day" chemotherapy protocol. 3 patients achieved partial response, 7 achieved stable disease, while 12 had progressive disease. Median time to tumor progression for all patients was 13 weeks, while median survival time for all patients was 35 weeks. Hematological toxicities were the most common, resulting in treatment refusal in two patients. Other toxicities included gastrointestinal, nephrotoxicity and ototoxicity.

Incidence and growth of methylcholanthrene-induced tumors in mice with altered immunological status.

BALB/c mice were treated s.c. with 3-methylcholanthrene (MCA), and tumor incidence and growth were followed for 9 months. Immunological status of mice was altered by various treatments. Thymectomized, lethally irradiated, bone marrow reconstituted mice served as T-cell deficient recipients. In order to suppress natural killer (NK)-cell/macrophage functions some mice were injected with silica particles; to enhance these functions some mice were given Corynebacterium parvum (CP). Silica and CP were given simultaneously with MCA to test their influence on the presumed function of surveillance of tumor incidence, and also 2 months after MCA to test their influence on the growth of greater numbers of transformed host cells. Almost all mice developed tumors at the inoculation site and at the end of the observation period there was no difference in tumor incidence among 9 experimental groups. However, in T-cell deficient mice we observed shorter tumor duration and earlier death than in normal mice. Silica particles appeared to enhance tumor growth but the differences compared to normal controls were not significant. A single injection of CP simultaneously with MCA caused earlier tumor appearance but also slowed its growth. In contrast, CP given 2 months after MCA significantly delayed the appearance of the tumors. In regard to the tumor growth immunosuppression had stronger effects in males than in females; the opposite was true for immunostimulation treatments. We concluded that immunological status does not influence long-term tumor incidence, but that both T-cell and NK-cell/macrophage compartments strongly influence the parameters of growth of chemically induced tumors, i.e., the immune and natural resistance mechanisms do not influence the frequency of de novo arising tumors but both can slow down tumor growth.

Sensitization of rat gastrointestinal tract to acetylcholine and histamine produced by X-radiation.

Abdominal x-radiation produces both acute and chronic disturbances of gastrointestinal motility. Anaesthetized Albino-Oxford rats received one-session x-radiation (absorbed dose 10 Gy) of whole abdomen. Two hours after irradiation the rats were sacrificed and segments of their gastrointestinal tract (gastric fundus, jejunum, ileum and ascending colon, were mounted in isolated organ bath. Acetylcholine and 5-hydroxytryptamine produced tonic contractions of all gut segments, while histamine did so only with gastric fundus. While contractile effect of 5-hydroxytryptamine was not affected by x-radiation, the responses of all gut segments on acetylcholine were potentiated and shifted towards lower concentrations. After x-radiation histamine produced concentration-dependent tonic contraction of previously unresponsive jejunum and ascending colon. The results of our study suggest that x-radiation produces acute sensitization of rat gastrointestinal tract to acetylcholine and histamine.

[Quantitative analysis of gallbladder function using quantitative dynamic radionuclide cholecystography]. / Kvantitativna analiza funkcije holeciste metodom kvantitativne dinamicke radionuklidne holecistografije.

The aim of the study is to demonstrate general function of the cholecyst through selected quantitative parameters derived from the quantitative radionuclide cholecystography method, using our own computer software HIDATA, and to evaluate values of specific quantitative parameters in 15 patients presenting with chronic calculous and 15 with chronic acalculous cholecystitis. A control group comprised 10 subjects with no changes on the cholecyst. Of four quantitative parameters calculated during cholecyst filling, the only significant one was the ascending segment slope of the curve from specific ROI, that is, K1 derived from it, because it shows its functional status, depending on the changes in its wall and the lumen content. The most significant parameters which maintain motor function of the cholecyst are ejection fraction (EF) and ejection rate (ER) which are always decreased in chronic cholecystitis, regardless of the presence of calculosis and the number of calculi in the lumen. The ejection fraction is especially decreased in the multiple sclerosis group; it is significantly decreased when compared with acalculous chronic cholecystitis. Our results indicate that a selection of parameters used in clinical practice for the assessment of the cholecyst function is necessary. Our program HIDATA included a large number of parameters of which three were classified as important for the assessment of the cholecyst function (K1, EF, ER), reflecting the process of filling and emptying of the cholecyst and offering reliable and valuable data for the treatment.

[Long-term oral administration of etoposide in the treatment of patients with advanced non-small-cell carcinoma of the lung. The second phase of a clinical study]. / Produzena oralna primena etopozida u lecenju bolesnika s napredovalim nemikrocelulnim karcinomom pluca. Druga faza klinicke studije.

Over the period from May 1989 to May 1992 thirty-four patients with advanced non-small cell lung cancer (NSCLC) were treated with prolonged administration of oral etoposide. Etoposide was administered in a dose of 50 mg/m2 a day for 21 days. Nine (26%) patients partially responded to the treatment that lasted 2-7 months (median 5 months). Median survival time was 6 months, and 1-year survival was 32%. The most common toxic events were alopecia and myelosuppression. No patient died of treatment-related toxicity. Results of this study demonstrate moderate efficiency of the prolonged administration of oral etoposide to patients with advanced NSCLC.

Single-needle celiac plexus block: is needle tip position critical in patients with no regional anatomic distortions?

BACKGROUND: The "single-needle" celiac plexus block is becoming a popular technique. Despite different approaches and methods used to place the needle, the success of the block depends on adequate spread of the injectate in the celiac area. In the present retrospective study, the influence of needle tip position in relation to the celiac artery on injectate spread was evaluated. METHODS: Among 138 cancer patients subjected, via an anterior approach, to computed tomography (CT)-guided single-needle neurolytic celiac plexus block, a radiologist, blinded to the aim of the study, retrospectively selected 53 cases with normal anatomy of the celiac area as judged by CT. The decision was based on images obtained before the block. Patients were then classified into either group A (29 patients), in whom the needle tip was caudad to the celiac artery, and group B (24 patients), in whom it was cephalad. To evaluate CT patterns of neurolytic (mixed with contrast) spread, the celiac area was divided on the frontal plane into four quadrants: upper right and left and lower right and left, as related to the celiac artery. Patient assessments by visual analog scale were reviewed to evaluate the degree of pain relief. Pain relief 30 days after block was judged as long-lasting. The patterns of contrast spread in relation to the needle position and pain relief according to the number of quadrants with contrast were analyzed. RESULTS: The percentage of cases with four quadrants with contrast was higher when the needle tip was cephalad (58%, group B) than when it was caudad (14%, group A) to the celiac artery (P < 0.01). The percentage of patients with four and three quadrants with contrast was also higher in group B at 79% than in group A at 38% (P < 0.01). A significant difference in long-lasting pain relief was observed between patients with four quadrants with contrast (18 of 18, 100%; 95% confidence interval [CI], 81-100%) and patients with three quadrants with contrast (5 of 12, 42%; 95% CI, 15-72%) (P < 0.01). No patients showing two or one quadrant with contrast had long-lasting pain relief. CONCLUSIONS: These findings suggest that, when the celiac area is free from anatomic distortions, and the single-needle neurolytic celiac plexus block technique is used, the needle tip should be positioned cephalad to the celiac artery to achieve a wider neurolytic spread. It also appears that only a complete (four quadrants) neurolytic spread in the celiac area can guarantee long-lasting analgesia.

The effects of excitatory amino acids on isolated gut segments of the rat.

Glutamate and aspartate are excitatory neurotransmitters in both central and peripheral nervous systems, acting on ionotropic and metabotropic receptors. In our study we have examined the effects of glutamate, aspartate, N-methyl-d-aspartate (NMDA), kainic acid and (+/-)-1-aminocyclopentane-cis-1,3-dicarboxylic acid (ACPD) on tone and spontaneous activity of isolated rat gastric fundus, jejunum, ileum, ascending colon and rectum. Both glutamate and aspartate produced concentration-dependent tonic contractions of rat fundus and rectum; the other gut segments used in the study were not responsive. While only NMDA and kainic acid produced concentration-dependent tonic contractions of isolated rat gastric fundus, all three type-selective agonists of glutamate receptors (NMDA, kainic acid and ACPD) produced tonic contractions of isolated rat rectum. The results of our study suggest that glutamate and aspartate in rat gastric fundus activate excitatory intrinsic neurons through only ionotropic receptors (NMDA and non-NMDA receptors), while the same action in rat rectum is mediated through both ionotropic and metabotropic receptors.

[Carboplatin-etoposide-bleomycine chemotherapy protocol in the treatment of patients with metastatic non-seminomatous germ-cell testicular tumours with good prognosis]. / Hemoterapijski protokol karboplatini-etopozid-bleomicin u lecenju bolesnika s metastatskim neseminomskim tumorima germinacionih celija testisa s dobrom prognozom.

Fifteen patients with metastatic non-seminomatous germ-cell tumours with good prognosis were treated with carboplatin-etoposide-bleomycine chemotherapy. Patients were followed-up from 8 to 56 months (median 32 months). In 13 patients there was no evidence of the disease and in 2 patients recurred, but recovered after the subsequent secondary chemotherapy (cisplatin-bleomycine-vincristine). Signs and symptoms of toxicity included alopecia in 93% of patients, nausea and vomiting in 40%, while in respect of haematological toxicity, leucopenia was observed in all 15 patients, thrombocytopenia in 80%, and decrease of haemoglobinaemia in 60% of patients. Other toxicities were not observed. Carboplatin-etoposide-bleomycine chemotherapy is effective and little toxic, but a greater number of patients and a longer follow-up are needed for definitive evaluatin of this therapy in the treatment of patients with metastatic non-seminomatous germ-cell testicular tumours with good prognosis.