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Obesity is associated with many significant physiological changes. These considerations are important to surgery, especially in urological procedures. Obese patients often undergo surgical procedures and are at higher risk of complications. This investigation reviews physiological and anaesthesia considerations for obese and morbidly obese patients. In addition, urological surgeries and procedures should be considered for these higher risk patients. Clinical anaesthesiologists must use detailed assessment and, when appropriate, consultation in developing safe anaesthesia plans for these patients. Newer technologies have improved safety related to airway management, advanced airway devices, and regional anaesthesia with ultrasound-guided nerve blocks, which can reduce the need for opioids postoperatively. Recent developments in drug and monitoring technologies have also been developed and can be effective for obese and morbidly obese patients undergoing urological procedures and perioperative surgery, thus improving the likelihood of safety in this higher risk population., Competing Interests: Declaration of Interests: The authors have no conflict of interest to declare., (©Copyright 2024 by the Turkish Anesthesiology and Reanimation Association / Turkish Journal of Anaesthesiology & Reanimation is published by Galenos Publishing House.)

Extracellular vesicles are considered a novel therapeutic tool, due to their ability to transfer their cargoes to target cells. Different strategies to directly load extracellular vesicles with RNA species have been proposed. Electroporation has been used for the loading of non-active vesicles; however, the engineering of vesicles already carrying a therapeutically active cargo is still under investigation. Here, we set up a coincubation method to increase the anti-tumor effect of extracellular vesicles isolated from human liver stem cells (HLSC-EVs). Using the coincubation protocol, vesicles were loaded with the anti-tumor miRNA-145, and their effect was evaluated on renal cancer stem cell invasion. Loaded HLSC-EVs maintained their integrity and miR transfer ability. Loaded miR-145, but not miR-145 alone, was protected by RNAse digestion, possibly due to its binding to RNA-binding proteins on HLSC-EV surface, such as Annexin A2. Moreover, miR-145 coincubated HLSC-EVs were more effective in inhibiting the invasive properties of cancer stem cells, in comparison to naïve vesicles. The protocol reported here exploits a well described property of extracellular vesicles to bind nucleic acids on their surface and protect them from degradation, in order to obtain an effective miRNA loading, thus increasing the activity of therapeutically active naïve extracellular vesicles.

Background: In a previous study, the authors tested the combination of fotemustine (FM) 100 mg/m(2) intravenously (i.v.) on Day 1, dacarbazine (DTIC) 250 mg/m(2) i.v. on Days 2-5, and interferon alpha (IFNalpha) 3 MIU intramuscularly three times per week in 43 patients with advanced melanoma. An overall response rate of 40% and a median survival of 40 weeks were obtained. To evaluate whether the addition of cisplatin (CDDP) to this regimen could improve these results, the authors conducted a preliminary Phase I study and concluded that CDDP 25 mg/m(2) i.v. for 2 days can be combined safely with DTIC, FM, and IFNalpha. Herein, the authors report the results of a Phase II trial with this regimen., Methods: From June 1996 to February 1999, 64 patients with metastatic melanoma who were not amenable to surgery were enrolled in this study. Sixty eligible patients (32 males and 28 females; median age, 53 years) were treated with a combination of FM 100 mg/m(2) i.v. on Day 1, DTIC 300 mg/m(2) i.v. on Days 2-4, and CDDP 25 mg/m(2) i.v. on Days 3 and 4 recycled every 3 weeks. IFN alpha2b was administered at a dose of 3 MIU intramuscularly 3 times per week until disease progression., Results: A total of 189 courses were administered, with a median number of 3 courses per patient (range, 1-8 courses per patient). Eleven complete responses and 12 partial responses were observed, for an overall response rate of 38.3% (95% exact confidence interval, 26.1-51.8%). The median survival was 36 weeks. Neutropenia and thrombocytopenia affected 85% of patients and 68% patients and was World Health Organization Grade 3-4 in 40% and 50%, respectively. The side effects attributable to IFN alpha2b were mild and manageable. The other side effects were moderate and well controlled by supportive therapy., Conclusions: The schedule used in this study demonstrated significant activity in patients with advanced, untreated melanoma. The addition of CDDP in the management of the patients in this series seemed to increase significantly both the proportion of patients who achieved a complete response and the probability of long term survival compared with a previous series of patients who were treated by the authors. However, considering the currently available therapies, this regimen does not seem to offer a special advantage in the treatment of patients with this disease. New agents and new protocols are needed., (Copyright 2000 American Cancer Society.)

A phase II trial was performed to evaluate the efficacy and toxicity of a double modulation of 5-fluorouracil (5-FU) by methotrexate (MTX) and L-leucovorin (L-LV) in patients with advanced recurrent (inoperable) or metastatic colorectal carcinoma (ACC). Between July 1993 and October 1995, 41 patients with ACC received a regimen that consisted of MTX 150 mg/m2 i.v., infused over a 20-minute period at hour 0, followed 19 hours later by L-LV 250 mg/m2 in a 2-hour i.v. infusion. 5-FU, 900 mg/m2, was administered by i.v. push injection at hour 20. Beginning 24 hours after MTX administration, all patients received four doses of L-LV, 15 mg/m2 i.m., every 6 hours. Cycles were repeated every 15 days. Two patients were not assessable for response. Objective regression was observed in 11 of 39 (28%) patients, [95% confidence interval (CI), 14-42%]. One (2%) patient achieved complete response (CR) and 10 (26%) partial response (PR). No change was recorded in 15 (39%) patients and progressive disease was noted in 13 (33%) patients. The median time to treatment failure was 6 months and the median survival time was 10 months. Toxicity was within acceptable limits, but one therapy-related death due to severe leukopenia was observed. The dose-limiting toxicity was mucositis. Eight episodes of grade 3 or 4 stomatitis were observed, and were responsible for dosage modifications of MTX and 5-FU. In conclusion, further in experimental and clinical studies are clearly necessary in order to design the best modulatory strategy of 5-FU.

A phase II study of advanced FIGO III and IV ovarian cancer treated with carboplatin and ifosfamide was performed to define the efficacy and tolerability of this regimen as first-line chemotherapy. From November 1990 to December 1994, 30 women with advanced ovarian cancer or residual disease after initial surgery were treated with carboplatin (300 mg/m(2) intravenously on day 1) and ifosfamide (1,500 mg/m(2) intravenously on days 1-3, with MESNA) every 3 weeks. The overall response rate was 67% (complete response 27%, partial response 40%) and the median duration of response was 14 months (range, 6-36). After a median follow-up of 31 months, the median survival was 24.9 months. Time to progression (p<0.05) and overall survival were longer in the patient group subjected to debulking. This regimen was easily manageable with good activity and acceptable toxicity, and most patients were treated on an outpatient basis.

The management of metastatic renal cell carcinoma (RCC) constitutes a therapeutic challenge and no standard therapy has yet been established. This phase II study aimed to verify the efficacy and tolerability of subcutaneous low dose recombinant interleukin-2 (IL-2) plus alpha interferon (IFN) and vinblastine (VLB) in patients with metastatic RCC. Twenty-three evaluable adult patients were enrolled in the study. A total of 19 patients were previously subjected to radical nephrectomy and four had been treated with adjuvant immunotherapy. The I-nest frequent metastatic sites were lung/pleura, bone, liver, lymph nodes, and abdominal mass. The following treatment schedule was administered: VLB at 6 mg/m(2) on day 1: IL-2 at 4.5 million IU twice daily from day 1 to 5 and day 8 to 12; IFN at 3 million IU three times weekly intramuscularly. The therapy was recycled every 21 days, except for the IFN which was administered continuously. Five patients demonstrated remission (21.6%) including one complete response persisting for 6 months, and four partial responses with a duration of 41+, 20, 8, and 18+ months. Moreover, 15 patients (65%) showed stable disease for 4-20 months (median 6 months), and three patients progressed. Overall median survival of the 23 patients was 11 months, with 27+ months for responders, 11 months for patients with stable disease, and 8 months for patients with rapid progression. Regressions occurred in lung, pleura, bone, and abdominal mass. Treatment was relatively well tolerated and easily manageable. This study was mainly administered as outpatient care. This study confirms the manageability and tolerability of subcutaneous IL-2 used in association with IFN alpha and chemotherapy. Even though a minority of patients responded, the duration of responses and the high percentage of long stable diseases represent the most interesting aspect of this study.

The aim was to compare the efficacy of ondansetron and a combination of ondansetron plus dexamethasone in the prophylaxis of cisplatin-induced delayed emesis over three consecutive courses of chemotherapy. Cancer patients scheduled to receive for the first time cisplatin (>50 mg/m(2)) in combination with other cytotoxic agents, were recruited in a multicentre, randomised, double-blind study and treated with ondansetron 8 mg i.v. and dexamethasone 20 mg i.v. Twenty-four hours after the start of chemotherapy, patients were randomised to treatment either with oral ondansetron 8 mg bd plus placebo on days 2-5 (group A) or with oral ondansetron 8 mg bd plus oral dexamethasone 8 mg bd on days 2-3, and 4 mg bd on days 4 and 5 (group B). Two hundred and thirty-six cancer patients were recruited into the study. Complete protection from delayed vomiting/nausea in group A and group B was Obtained in 50/39% and in 63/42% of patients, respectively in the first course; in 55/34% and in 64/40% in the second and in 49/31% and 60/37% in the third. Logistic regression analysis reveals a statistically significant difference in incidence of emesis between the combination of ondansetron plus dexamethasone and ondansetron alone (P<0.05). The same model, however, shows no difference in incidence of nausea between the two treatment regimens. Ondansetron plus dexamethasone reduces the risk of delayed emesis following cisplatin chemotherapy as compared to ondansetron alone.

The aim of the study was to verify the possibility of treating patients with poor prognosis early-intermediate Hodgkin's disease with a combined modality therapy consisting of three cycles of ABVD followed by extended field irradiation (EFRT). No patient had bulky mediastinum or had previously been administered chemo- or radiotherapy. At pathological restaging, 40/44 (91%) evaluable patients achieved complete responses (CR). After a ten-year followup, freedom from progression (FFP), relapse-free survival (RFS) and overall survival (OS) were 80%, 83% and 81%, respectively. Of the prognostic factors, univariate analysis showed that only stage III negatively influenced RFS, but not OS. Toxicity was mild except for subclinical mediastinal fibrosis in 32.5% of CR patients. No patient reported reduced fertility. Two cases of second neoplasms were recorded: one ameboid glioma and one thymoma, both occurring within five years after discontinuing chemo-radiotherapy. Our data suggest that three cycles of ABVD preceeding EFRT is an effective treatment for poor prognosis early-intermediate stage Hodgkin's disease; nevertheless, stage III patients and some stage II patients with unfavorable prognostic factors should be treated with a more aggressive approach.

Thirty patients with marginally resectable stage IIIA or stage IIIB NSCLC were treated with cisplatin (80 mg/ m(2)/i.v./dl), ifosfamide (4,000 mg/m(2)/i.v./dl) and vinorelbine (30 mg/m(2)/i.v./dl) plus G-CSF 300 mu g/s.c. on days 7-12 every 14 days for three cycles before surgery. In 26 evaluable patients, the radiographically assessed response rate to chemotherapy was 77% (8% complete). Three septic deaths (10%) occurred in spite of G-CSF and 1 patient refused to continue after the first cycle. Thoracothomy was performed in 23 patients including 19 complete resections. At 15 months median follow-up (range 10-22+), 11/19 (57%) completely resected patients relapsed. The overall median time to treatment failure was 11 months (range 0-17). Actuarial survival probability at 12, 18 and 24 months are 56%, 43% and 36%, respectively. In conclusion, the combination of cisplatin, ifosfamide and vinorelbine in full doses at a 14 day interval (accelerated chemotherapy) was very effective in neoadjuvant NSCLC setting. Nevertheless, relevant toxicity was demonstrated with a 10% death rate probably due to the overlapping toxicity of chemotherapy cycles, suggesting the need for a more intense supportive care or longer interval between cycles.

The hormone receptor status and proliferative activity characteristics of inflammatory breast cancer (IBC) were studied in a series of 46 patients. ER and PgR were measured by the DCC method and proliferative activity was by the H-3-thymidine autoradiographic labeling index (H-3-Tdr-LI). Tumors were ER and PgR positive in 42% and 38% of cases, respectively, whereas median H-3-Tdr-LI was 3.8%. With regard to clinical aspects, overall survival (OS) was not affected by either ER status (36 cases) or H-3-Tdr-LI value (33 cases). On the contrary, PgR(+) status was able to individualize women with a significantly higher probability of OS (X(2) by long rank test, p=0.03) after 35 months of follow-up. In the subgroup of 14 patients subjected to double biopsy performed before and after administration of primary polychemotherapy, the tumor proliferative activity variations were not related to clinical outcome.

From July 1992 to December 1993, 62 patients with non-small cell lung cancer (NSCLC) were admitted to a multicentric randomized study. The patients were treated with vinorelbine (V) alone at a dose of 25 mg/m(2)/i.v. weekly or with V at a dose of 25 mg/m(2)/i.v. on day 1 and 8 plus cisplatin at a dose of 80 mg/m(2)/i.v. on day 1 every 3-4 weeks (VP). An objective response was observed in 42% of patients treated with VP versus 12.5% of those treated with vinorelbine alone (p=0.038). There was no significant difference in the median survival duration between the two groups (38 versus 30 weeks for VP and V, respectively). Toxicity was tolerable but more severe in the VP regimen. These data suggest that V is an active agent in NSCLC and that the VP regimen may yield results comparable to other cisplatin combinations for treatment of these tumors.

HER-2/neu status and t-PA, u-PA, and PAI-1 cytosol content were evaluated in 88 primary breast cancer patients to determine the relationships between these parameters. HER-2/neu was amplified in 24% (20/84) of tumor samples and overexpressed in 28% (14/50). In the overall series, median t-PA, u-PA and PAI-1 contents, measured by the enzyme-linked immmunoassay (ELISA), resulted in 1.7, 1.1 and 1.0 ng/mg cytosol protein (cyt prot), respectively. HER-2/neu overexpressed cases showed higher u-PA levels than those normally expressed whereas t-PA and PAI-1 levels did not vary in HER-2/neu altered and non altered cases. The t-PA levels did not differ in cases with or without HER-2/neu alterations, when separately considering the node-negative and node-positive cases. A significant relationship between t-PA levels and HER-2/neu alterations was observed only in the ER(+) tumors: t-PA levels were lower in amplified and overexpressed cases (1.4 versus 2.5 ng/mg cyt prot in amplified and single copy gene, respectively; 1.6 versus 2.3 ng/mg cyt prot in overexpressed and normally expressed cases, respectively). Therefore, t-PA and HER-2/neu could provide additional prognostic information for ER-negative patients.

Twenty-two women with metastatic breast cancer, previously submitted to one or more lines of chemotherapy, were treated with mitoxantrone as single agent delivered at full dosage (14 mg/m(2)) every other week (accelerated chemotherapy). This dose was possible with concomitant subcutaneous administration of granulocyte colony stimulating factor (G-CSF) on days 5 to 12 of each 14 day cycle. Although grade III-IV leukopenia, anemia and thrombocytopenia were observed in 50%, 13%, and 27% of cases, respectively, a complete recovery of neutrophils, due to G-CSF administration, permitted on time cycle delivery in the majority of cases. Partial response was observed in 6/22 patients (27%). In conclusion, accelerated chemotherapy with mithoxantrone plus G-CSF is both feasible and effective for patients with previously treated breast cancer.

Sixty-eight patients with previously untreated metastatic breast cancer were randomly assigned to receive either 'classical CMF' (orally administered cyclophosphamide) or new intravenous administration of all drugs every 3 weeks. Overall response rates of 44.5% (95% CI: 28-62%) and 39% (95% CI:24-54%) were observed with classical and new CMF, respectively. The time to progression and overall survival were also similar: hematologic toxicity was mild in both groups, but the tolerance and patient compliance was generally better for the new CMF. The patients treated with classical CMF received a significantly higher drug intensity; dose intensity, however, had no impact on clinical results. In conclusion, our data suggest that the new CMF schedule has comparable activity to classical CMF but better patient compliance. A brief review of recent clinical studies regarding dose-effect relationships in breast cancer is included.

The metastatic potential of cancer cells has been associated to their ability to elaborate and secrete basement membrane degradative enzymes. In this process a major role appears to be played by a protease known as gelatinase A (72 kDa type IV collagenase, MMP-2). In an effort to assess the significance of these findings to breast cancer progression, we have evaluated the gelatinase A/MMP-2 serum levels in a cohort of 80 breast cancer patients, 27 subjects affected by benign breast disease and 27 healthy controls. Although differences between the three groups were observed, with the highest values monitored in benign breast disease, they were not statistically significant. On the contrary, within the breast cancer cohort, the patients presenting clinical evidence of distant metastases (M+, n=40) had statistically elevated enzyme serum levels (p<0.03) compared to those without nodal involvement and distant metastases (N-M-, n=20). The statistical significance was still evident when considering the overall M- cohort (including N+ and N- patients, n=40) compared to the M+. Although indicating that, in general, gelatinase A/MMP-2 is not a useful serum marker for breast cancer screening and diagnosis, the findings point toward its involvement in the breast cancer metastatic process and suggest a possible value in monitoring the outcome of the disease.

Immunostimulating and immunosuppresive events have been noted during rIL-2 immunotherapy and cell-mediated immune deficiencies have been reported in the neutrophil and monocyte functions, determining a high incidence of infections in patients during intravenous rIL-2 treatment. The phagocytic activity of monocytes/macrophages and granulocytes was evaluated in 10 advanced solid tumor patients treated with subcutaneous rIL-2. Several indirect parameters of phagocytosis were also considered, such as Neopterin, Beta2 microglobulin, IL-2 soluble receptor, and the C3 and C4 fractions of the complement system. A decreased phagocytosis was demonstrated after subcutaneous rIL-2 administration together with an increase of indirect parameters of granulocyte/macrophage activity. Therefore, cellular activation does not seem to correspond to actual phagocytosis which is probably due to IL-2-induced secondary cytokines or to rIL-2 inhibitory effects.

Seven patients with inflammatory and 11 with metastatic breast cancer were treated with high dose FEC chemotherapy plus GM-CSF; 5-fluorouracil and cyclophosphamide were administered at 500 mg/m2/iv/day 1, epirubicin at three dose levels: 100 mg, 120 mg and 140 mg/m2/iv/day 1 every three weeks (six patients per level). GM-CSF was administered at a dosage of 5 mg/kg/sc from day 5 to 12 of each cycle. The overall response rate was 83% (95% CI: 66%-100%) with 22% complete response. The median response duration for patients with metastatic disease was 7 months (range: 4-10). The hematological toxicity was moderate but reversible due to GM-CSF rescue; mucositis represented the dose limiting toxicity. In conclusion, the increase of dose intensity resulted in a higher response rate but not longer response duration, which must be taken into account when administering high-dose chemotherapy with growth factor rescue.

Immunotherapy represents a promising biological approach to cancer treatment. Important haemato-immunological modifications during rIL-2 treatment have been demonstrated in all patients treated, independently of the schedule and mode of rIL-2 administration. Generally, there is a lack of correlation between treatment-related modifications and clinical response. rIL-2 cell-mediated responses have been extensively studied but the role of humoral immunity is still unclear. We evaluated the peripheral blood CD4, CD8, CD19 and CD25 lymphocyte subset modifications and serum levels of immunoglobulin, IL-6 and IL-2 in 19 patients with malignant melanoma and renal cell carcinoma undergoing subcutaneous administration of IL-2. Our results suggest that humoral immunity is only marginally involved; however, the parameter variations observed suggest that further studies are necessary.

A multicentric randomized study was conducted to compare the CNF regimen (cyclophosphamide at 600 mg/m2/iv, mitoxantrone at 10 mg/m2/iv, 5-fluorouracil at 600 mg/m2/iv) with the CMF regimen (methotrexate at 40 mg/m2/iv instead of mitoxantrone) administered every 3 weeks to previously untreated locally advanced or metastatic breast cancer patients. In 119 patients evaluable for therapeutic response, complete plus partial response rate was 44% for CNF and 29% for CMF (p>0.05; 95% C.I.: CNF=32%-56%, CMF=18%-40%). No statistically significant difference regarding time to progression, over survival or response to second-line chemotherapy with Epidoxorubicin was observed between the two regimens. Both regimens were well tolerated, but the percent of alopecia and leucopenia was significantly higher in the CNF patient group (31% versus 5% and 18% versus 0%, respectively; p<0.01). In conclusion, CNF was demonstrated to be slightly more toxic but more effective as compared to CMF (global response: 44% versus 29%, respectively). These findings should be taken into consideration when planning future studies of adjuvant chemotherapy.

The aim of the present study was to verify the efficacy and tolerability of a treatment protocol using subcutaneous administration of rIL-2. Eighteen patients with metastatic disease were treated: 10 with renal carcinoma and 8 with malignant melanoma. The drug was administered as follows: 9 million UI/mq twice daily for two days followed by 1.8 million UI/mq twice daily for five days/week for six consecutive weeks. Of the 15 patients evaluated for clinical response, all completed treatment without rIL-2 dose modifications. No complete response was obtained. One patient with malignant melanoma and 1 with renal carcinoma (13%) had partial response (soft tissue and lymph nodes respectively) which lasted 3 and 4 months. Six patients with renal carcinoma and 3 melanoma patients had stable disease (60%) which lasted 6 months (median). Toxicity was moderate and spontaneously reversing after stopping treatment. Haemato-immunological modifications and pharmacokinetic study of this modality of rIL-2 treatment were also examined.

In stage IV non-Hodgkin's lymphomas, CVP (cyclophosphamide, vincristine, and prednisone) was randomly compared to ABP (adriamycin, bleomycin, and prednisone). Of 62 patients entered into the study, 57 (CVP 27, ABP 30) were considered evaluable for comparison. In patients with liver and/or marrow involvement a second biopsy was performed to define complete remission (CR). CR occurred in 48% of patients treated with CVP and in 50% of those given ABP. The median duration of CR was 10.5 and 20.5 months, respectively. The difference is not statistically significant. Also, the survival of complete responders was not significantly different between the two treatment groups. After cross-over, secondary treatment with CVP produced an overall response rate of 40% (six of 15), compared to 50% (six of 12) obtained with ABP. In the ABP group, four patients developed a reversible interstitial penumonia. In two other patients, cardiomyopathy (fatal in one) was observed. In conclusion, although complete remission was similar in both groups, cumulative toxicity occurred in few patients given ABP. However, this combination could represent an effective alternative treatment to be used either in CVP failures or sequence with CVP.