Sacral neuromodulation for the treatment of faecal incontinence following proctectomy.

AIM: This study assessed the effectiveness of sacral neuromodulation (SNM) for faecal incontinence (FI) following proctectomy with colorectal or coloanal anastomosis. METHODS: An Institutional Review Board (IRB)-approved database identified patients treated for FI following proctectomy (SNM-P) for benign or malignant disease, who were matched 1:1 according to preoperative Cleveland Clinic Florida Faecal Incontinence Scores (CCF-FIS) with patients without proctectomy (SNM-NP). Primary outcome was change in CCF-FIS. RESULTS: Twelve patients (seven women) were in the SNM-P group and 12 (all women) were in the SNM-NP group. In the SNM-P group, six patients underwent proctectomy for low rectal cancer and five received neoadjuvant chemoradiation. Five patients had handsewn anastomosis, and one had stapled coloanal anastomosis. One lead explantation occurred after a failed 2-week SNM percutaneous trial. Six patients underwent proctectomy for benign conditions. Within-group analyses revealed significant improvement in CCF-FIS in the SNM-P group (reduction from a score of 18 to a score of 14; P = 0.02), which was more profound for benign disease (reduction from 14.5 to 8.5) than for rectal cancer (reduction from 19.5 to 15). SNM was explanted in 66% and 33% of patients after proctectomy for malignant and benign conditions, respectively. In the SNM-NP group, 41% underwent overlapping sphincteroplasty. One patient received chemoradiation for anal cancer. Within-group analysis for the SNM-NP group showed significant improvement in CCF-FIS (a reduction from 17.5 to 4.0; P = 0.003). There was significant improvement in CCF-FIS in patients without previous proctectomy (mean delta CCF-FIS: 11.1 vs 4.7; P = 0.011). Analysis of covariance (ANCOVA) reaffirmed that controls outperformed proctectomy patients (P = 0.006). CONCLUSION: SNM for FI after proctectomy appears less effective than SNM in patients without proctectomy, with high device explantation rates, particularly after neoadjuvant chemoradiation and proctectomy for low rectal cancer.

Regional lymph node status after neoadjuvant chemoradiation of rectal cancer producing a complete or near complete rectal wall response.

AIM: Transanal excision of the tumour site after complete response to chemoradiotherapy can determine the rectal wall response to treatment. This study was designed to assess whether the absence of tumour in the rectal wall corresponds to the absence of tumour in the mesorectum (true pathological complete response). METHOD: A retrospective review identified patients who underwent preoperative chemoradiation therapy for advanced mid and low rectal cancer followed by routine pre-planned radical surgery with total mesorectal excision. Patients in whom the pathology specimen showed no residual tumour in the rectal wall (ypT0) or a ypT1 lesion were assessed for tumour involvement in the mesorectum. RESULTS: Seventy-eight patients who underwent pelvic chemoradiation followed by radical surgery were reviewed. The rectal wall tumour disappeared in eight (ypT0). Of these, residual tumour was found in the mesorectum (ypT0N1) in one (12%) patient. Eleven patients were found to have ypT1 residual tumour. Of these, two (18%) had a final post-surgical staging of ypT1N1. CONCLUSION: Complete rectal wall tumour eradication was achieved in 10% of the patients, and downstaging to ypT1 was achieved in 14%. In 15% (12% in ypT0 and 18% in ypT1) of these patients, residual tumour cells were evident in the mesorectum. This would probably have rendered these patients with residual disease had a nonradical approach of transanal excision of the original tumour site been employed. Caution should be taken when considering the avoidance of radical surgery.

Heparanase procoagulant activity is elevated and predicts survival in non-small cell lung cancer patients.

BACKGROUND: Heparanase is implicated in angiogenesis and tumor progression. We had earlier demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. It forms a complex and enhances the activity of the blood coagulation initiator- tissue factor (TF). Although increased heparanase antigen level in the plasma and biopsies of cancer patients was previously demonstrated, in the present study we evaluated, for the first time, the heparanase procoagulant activity in the plasma of patients with lung cancer. MATERIALS AND METHODS: Sixty five patients with non-small cell lung cancer at presentation and twenty controls were recruited. Plasma was studied for TF / heparanase procoagulant activity, TF activity and heparanase procoagulant activity using chromogenic assay and heparanase antigen levels by ELISA. RESULTS: Heparanase antigen levels were higher in the study group compared to control (P=0.05). TF / heparanase activity, and even more apparent, heparanase procoagulant activity were significantly higher in the study group compared to controls (P=0.008, P<0.0001, respectively). No significant difference was observed in the TF activity between the groups. Survival of patients with heparanase procoagulant activity higher than 31 ng/ml predicted a mean survival of 9 ± 1.3 months while heparanase procoagulant activity of 31 ng/ml or lower predicted a mean survival of 24 ± 4 months (P=0.001). Heparanase procoagulant activity was higher than 31 ng/ml in the four cases of thrombosis detected during the follow-up period. CONCLUSIONS: Elevated heparanase procoagulant activity in patients with lung cancer reveals a new mechanism of coagulation system activation in malignancy. Heparanase procoagulant activity can potentially be used as a predictor for survival.

International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer.

BACKGROUND: Guidelines addressing the management of venous thromboembolism (VTE) in cancer patients are heterogeneous and their implementation has been suboptimal worldwide. OBJECTIVES: To establish a common international consensus addressing practical, clinically relevant questions in this setting. METHODS: An international consensus working group of experts was set up to develop guidelines according to an evidence-based medicine approach, using the GRADE system. RESULTS: For the initial treatment of established VTE: low-molecular-weight heparin (LMWH) is recommended [1B]; fondaparinux and unfractionated heparin (UFH) can be also used [2D]; thrombolysis may only be considered on a case-by-case basis [Best clinical practice (Guidance)]; vena cava filters (VCF) may be considered if contraindication to anticoagulation or pulmonary embolism recurrence under optimal anticoagulation; periodic reassessment of contraindications to anticoagulation is recommended and anticoagulation should be resumed when safe; VCF are not recommended for primary VTE prophylaxis in cancer patients [Guidance]. For the early maintenance (10 days to 3 months) and long-term (beyond 3 months) treatment of established VTE, LMWH for a minimum of 3 months is preferred over vitamin K antagonists (VKA) [1A]; idraparinux is not recommended [2C]; after 3-6 months, LMWH or VKA continuation should be based on individual evaluation of the benefit-risk ratio, tolerability, patient preference and cancer activity [Guidance]. For the treatment of VTE recurrence in cancer patients under anticoagulation, three options can be considered: (i) switch from VKA to LMWH when treated with VKA; (ii) increase in LMWH dose when treated with LMWH, and (iii) VCF insertion [Guidance]. For the prophylaxis of postoperative VTE in surgical cancer patients, use of LMWH o.d. or low dose of UFH t.i.d. is recommended; pharmacological prophylaxis should be started 12-2 h preoperatively and continued for at least 7-10 days; there are no data allowing conclusion that one type of LMWH is superior to another [1A]; there is no evidence to support fondaparinux as an alternative to LMWH [2C]; use of the highest prophylactic dose of LMWH is recommended [1A]; extended prophylaxis (4 weeks) after major laparotomy may be indicated in cancer patients with a high risk of VTE and low risk of bleeding [2B]; the use of LMWH for VTE prevention in cancer patients undergoing laparoscopic surgery may be recommended as for laparotomy [Guidance]; mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated [2C]. For the prophylaxis of VTE in hospitalized medical patients with cancer and reduced mobility, we recommend prophylaxis with LMWH, UFH or fondaparinux [1B]; for children and adults with acute lymphocytic leukemia treated with l-asparaginase, depending on local policy and patient characteristics, prophylaxis may be considered in some patients [Guidance]; in patients receiving chemotherapy, prophylaxis is not recommended routinely [1B]; primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic pancreatic [1B] or lung [2B] cancer treated with chemotherapy and having a low risk of bleeding; in patients treated with thalidomide or lenalidomide combined with steroids and/or chemotherapy, VTE prophylaxis is recommended; in this setting, VKA at low or therapeutic doses, LMWH at prophylactic doses and low-dose aspirin have shown similar effects; however, the efficacy of these regimens remains unclear [2C]. Special situations include brain tumors, severe renal failure (CrCl<30 mL min(-1) ), thrombocytopenia and pregnancy. Guidances are provided in these contexts. CONCLUSIONS: Dissemination and implementation of good clinical practice for the management of VTE, the second cause of death in cancer patients, is a major public health priority.

International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer.

BACKGROUND: Although long-term indwelling central venous catheters (CVCs) may lead to pulmonary embolism (PE) and loss of the CVC, there is lack of consensus on management of CVC-related thrombosis (CRT) in cancer patients and heterogeneity in clinical practices worldwide. OBJECTIVES: To establish common international Good Clinical Practices Guidelines (GCPG) for the management of CRT in cancer patients. METHODS: An international working group of experts was set up to develop GCPG according to an evidence-based medicine approach, using the GRADE system. RESULTS: For the treatment of established CRT in cancer patients, we found no prospective randomized studies, two non-randomized prospective studies and one retrospective study examining the efficacy and safety of low-molecular-weight heparin (LMWH) plus vitamin K antagonists (VKAs). One retrospective study evaluated the benefit of CVC removal and two small retrospective studies were on thrombolytic drugs. For the treatment of symptomatic CRT, anticoagulant treatment (AC) is recommended for a minimum of 3 months; in this setting, LMWHs are suggested. VKAs can also be used, in the absence of direct comparisons of these two types of anticoagulants in this setting [Guidance]. The CVC can be kept in place if it is functional, well-positioned and non-infected and there is good resolution under close surveillance; whether the CVC is kept or removed, no standard approach in terms of AC duration has been established [Guidance]. For the prophylaxis of CRT in cancer patients, we found six randomized studies investigating the efficacy and safety of VKA vs. placebo or no treatment, one on the efficacy and safety of unfractionnated heparin, six on the value of LMWH, one double-blind randomized and one non randomized study on thrombolytic drugs and six meta-analyses of AC and CVC thromboprophylaxis. Type of catheter (open-ended like the Hickman(®) catheter vs. closed-ended catheter with a valve like the Groshong(®) catheter), its position (above, below or at the junction of the superior vena cava and the right atrium) and method of placement may influence the onset of CRT on the basis of six retrospective trials, four prospective non-randomized trials, three randomized trials and one meta-analysis. In light of these data: use of AC for routine prophylaxis of CRT is not recommended [1A]; a CVC should be inserted on the right side, in the jugular vein, and distal extremity of the CVC should be located at the junction of the superior vena cava and the right atrium [1A]. CONCLUSION: Dissemination and implementation of these international GCPG for the prevention and treatment of CRT in cancer patients at each national level is a major public health priority, needing worldwide collaboration.

Systemic and renal growth hormone-IGF1 axis involvement in a mouse model of type 2 diabetes.

AIMS/HYPOTHESIS: In previous studies we have shown a significant involvement of the growth hormone (GH)-IGF axis in animal models of type 1 diabetes mellitus, but the role of this endocrine system in type 2 diabetes mellitus is less well characterised. We therefore examined the endocrine and renal GH-IGF axis changes in db/db mice, a model of type 2 diabetes mellitus and nephropathy. MATERIALS AND METHODS: Obese and lean animals were followed, beginning at hyperglycaemia onset, for 4 weeks. Albuminuria and creatinine clearance, as well as kidney and glomerular morphology were assessed. Tissue protein levels were determined by western blotting and mRNA levels by RT-PCR. RESULTS: Serum GH and IGF1 levels immediately prior to killing were decreased and liver mRNA levels of insulin-like growth factor binding protein 1 (Igfbp1) were increased in obese animals. Kidney weight was increased in obese animals, associated with hyperfiltration, albuminuria and glomerular hypertrophy. Administration of a somatostatin analogue (PTR-313) did not improve any of these parameters of diabetic renal involvement. Renal Igf1 mRNA was decreased and renal Igfbp1 mRNA and protein were significantly increased in obese animals. Renal insulin-driven levels of phosphorylated forkhead box O1 (FOXO1) were decreased in obese animals. CONCLUSIONS/INTERPRETATION: Diabetic db/db mice show significant renal changes (and IGFBP1 renal accumulation), similar to the findings in models of type 1 diabetes mellitus. A decreased signalling through the insulin receptor and decreased FOXO1 phosphorylation may allow Igfbp1 gene transcription. These renal changes are associated with low circulating IGF1 and GH levels and unchanged hepatic growth hormone receptor expression, unlike the condition in type 1 diabetes mellitus. This suggests that further GH inhibition to modulate renal complications in type 2 diabetes mellitus is not indicated.

[Cancer in Israel: mass mediated reality vs. real reality].

BACKGROUND: Cancer, being a terminal and often incurable disease, is a source of fear and concern for human beings. One of the most important sources of medical information in general, and cancer specifically, is the mass media. The media can shape beliefs regarding health and influence people's decision-making. The main hypothesis guiding this study, based on the theoretical framework of cultivation research, is that there will be considerable differences between media coverage and medical data regarding cancer in the Israeli population. METHOD: A systematic content analysis was applied to test this hypothesis, examining all the press reports (650 articles) published during the year 2000 in three of Israel's most popular daily newspapers--"Yedioth Ahronot", "Maariv" and "Haaretz". Data from the Israeli Ministry of Health was used for comparison with media reports to the population in terms of the types of cancer reported, the emphasis on death in the context of the disease, reports concerning treatment, and the age of cancer patients. RESULTS: The findings of the study are in accordance with the main hypothesis and show that the media's portrayal of cancer does not always reflect the medical reality regarding the above mentioned aspects. Several possible explanations are proposed in analyzing these findings, focusing mainly on the nature of news making and media selection, as well as on the impact of various interest groups such as pharmaceutical companies, hospitals. laboratories, oncology departments, and various organizations trying to promote awareness and raise funds for research. CONCLUSION: The findings of this study enhance a wide range of research in different areas of human knowledge that have documented processes of constructing "mass-mediated realities", but in the case of a fatal disease, the findings may have acute implications.

Adverse interaction between capecitabine and warfarin resulting in altered coagulation parameters and bleeding: case report and review of the literature.

Capecitabine can interact with warfarin, resulting in altered coagulation parameters and bleeding. Four cases have been reported. We describe a fifth case with life-threatening interaction between these two drugs. A 67-year-old female with metastatic breast cancer developed hemorrhagic blisters, purpura and ecchymoses. She had been well controlled on long-term warfarin (5 mg/day). Capecitabine was initiated 4.5 weeks prior to the bleeding episode. Laboratory work-up revealed an international normalized ratio of 8.56, partial prothrombin time of 61 seconds and prothrombin time of 5.2%. The coagulation parameters gradually normalized within 4 days following vitamin K administration and discontinuation of capecitabine and warfarin. Careful monitoring of coagulation parameters and proper adjustment of the warfarin dose are required in patients taking warfarin and capecitabine concomitantly.

Primary lymphoma of the liver: clinical features and outcome of 9 patients.

PURPOSE: Primary liver lymphoma (PLL) is a rare lymphoproliferative disorder of unknown etiology. The prognosis in affected patients is poor, consisting of brief remissions, rapidly developing resistance to chemotherapy, early recurrence, and short survival. Most studies related to PLL are based on case reports. The aim of this retrospective study was to review our experience with PLL. PATIENTS AND METHODS: From 1985 to 2000, 9 patients who fulfilled the diagnostic criteria for PLL were treated at our hospital. All patients underwent a thorough work-up and were staged accordingly. RESULTS: The disease occured in middle and higher-aged patients (median age 63 years). Primary presenting complaints were abdominal pain, mainly in the right upper quadrant, and hepatomegaly. Liver function tests and lactate dehydrogenase (LDH) levels were elevated. Liver imaging (computed tomography-CT) and isotopic methods (gallium scan) demonstrated liver involvement either as solitary or multiple space-occupying lesions. Pathologic examination demonstrated diffuse, large cell (DLCL), B-type lymphoma in 7/9 (78%) patients. Doxorubicin-based chemotherapy was the mainstay of treatment. Good partial or complete remission rates were achieved in 7 patients, albeit for a brief period of time. CONCLUSION: Most patients with PLL succumb to their illness, despite its being relatively chemotherapy-sensitive. The introduction of intensive chemotherapy, plus/minus radiotherapy, and/or surgery has been considered in some studies.

Vinorelbine/VP-16 (etoposide) in metastatic breast cancer: a phase II study.

PURPOSE: This phase II study was conducted to evaluate the efficacy and tolerability of vinorelbine (navelbine) and oral VP-16 (etoposide) in pretreated metastatic breast cancer (MBC) patients. PATIENTS AND METHODS: Twenty-two female patients with therapy-resistant metastatic breast cancer were treated with vinorelbine 25 mg/m(2) i.v. on days 1 and 8 and oral VP-16 50 mg/m(2)/day for 14 days. Cycles were repeated every 28 days. Treatment was given until clear evidence of disease progression. RESULTS: Complete remission was observed in 3 (14%) patients, and partial remission or stable disease in 10 (45%) patients. Median duration of response was 4 months (range 2-8). Symptomatic improvement, irrespective of imaging methods results, as evaluated through improved performance status (PS), the lack of requirement for urgent palliative radiotherapy, and a decrease in steroids and analgesics doses was demonstrated in 10 (45%) patients through a special questionnaire completed by all patients. Side effects were manageable. Dose modification due to leucopenic fever were necessary in only 3 patients. Previous radiation therapy did not mitigate the application of full doses of chemotherapy. CONCLUSION: Vinorelbine/VP-16 combination is active and tolerable in relapsed and heavily pretreated MBC patients.

Primary lymphoma of bone--a retrospective study. Experience at the Northern Israel Oncology Center (1979-2000).

OBJECTIVE: This retrospective study describes our experience with the diagnosis, treatment, results and long-term follow-up of primary bone lymphoma (PBL). PATIENTS AND METHODS: Nineteen patients diagnosed with PBL were reviewed. Seven patients presented with stage I(E) disease, four with stage II(E) (regional lymphadenopathy), and eight with stage IV disease (disseminated bone involvement). Only one stage IV patient exhibited 'B' symptoms. The majority (72%) demonstrated diffuse, large cell, B-type lymphoma. All patients were treated with adriamycin-based chemotherapy and consolidation radiotherapy to the primary site (8 patients: early PBL) or the most bulky area (3 patients: stage IV PBL). RESULTS: Ten stage I(E)/II(E) patients are alive with no evidence of disease (NED) and only one died due to metastatic secondary lung cancer while with NED from his PBL. Eight stage IV patients are alive with NED. Median follow-up for all living patients: 77 months. Side effects were mild and did not necessitate delay in treatment. CONCLUSIONS: Our departmental policy of treating PBL patients with an anthracycline-based regimen and involved field radiotherapy proved to be successful in achieving excellent long-term, disease-free survival. Phase III randomized, controlled, clinical trials will determine the true role of consolidation radiotherapy in PBL, when considering severe late side effects, including radiation-induced bone tumors.

Etoposide, doxorubicin and cisplatin alternating with 5-fluorouracil, doxorubicin and high-dose methotrexate in patients with advanced adenocarcinoma of the stomach or the gastroesophageal junction.

Both the etoposide, doxorubicin, cisplatin (EAP) and 5-fluorouracil, doxorubicin, high-dose methotrexate (FAMTX) schedules have been reported to be active in advanced gastric cancer. Since these regimens include non-cross resistant agents, a regimen that consists of EAP alternating with FAMTX may have an advantage over each regimen alone. We undertook a phase II trial to evaluate EAP/FAMTX in patients with advanced adenocarcinoma of the stomach or gastroesophageal junction. Of the 56 patients treated, an objective response was observed in 34%, including complete response in 7%. Median response duration was 8 months and median survival for the entire group was 9 months. The main toxicity was myelosuppression. Hospitalization for granulocytopenic fever was required in 32% of patients and 34% required red blood cells (RBC) transfusion. Non-hematological toxicity was moderate. There were three drug-related deaths associated with granulocytopenic fever. We conclude that the alternating EAP/FAMTX regimen is associated with occasional lethal events and has no obvious advantage over either regimen alone.

Diagnosis and treatment of primary non-Hodgkin's lymphoma of the parotid gland: a retrospective study - Experience at the Northern Israel Oncology Center (1977-1999).

PURPOSE: The treatment and outcome of primary parotid gland non-Hodgkin's lymphoma (PGL) has rarely been described. This retrospective study documents the clinicopathologic features and treatment results in this relatively rare entity. PATIENTS AND METHODS: This study was conducted on 11 patients diagnosed and treated for primary PGL over a period of 22 years. RESULTS: Of the 4 male and 7 female patients, only one presented with the classic pattern of Sjögren's syndrome (SS) simultaneous with PGL, and only 4 patients demonstrated a low-grade Maltoma type. None of the patients had evidence of disease at the end of the primary treatment; 4 patients are alive and well from 6 months to 10 years after the end of treatment. Four patients relapsed and died due to therapy-resistant disease and 3 patients died of nonmalignant causes while in complete remission. CONCLUSION: The majority of patients with primary non- Hodgkin's lymphoma of the parotid gland present with early- stage disease. Accurate staging is mandatory. Low-grade, localized PGL can be treated successfully with primary radiotherapy alone. The aggressive type of PGL should be treated with combined chemoradiotherapy-based regimens.

Cancer and thrombosis revisited.

Remarkable progress has been made since the first description of the association between cancer and thrombosis by Trousseau over 100 years ago. Now, it is clear that there is a two-way connection between coagulation and cancer as tumor results in alterations in hemostatic balance, and thrombosis may promote tumor cell growth. A variety of clinical thrombotic syndromes may present in cancer patients including local and systemic venous and arterial thromboses. More evidence is now being gathered on the potential of antithrombotic regimens to prolong survival of cancer patients. Whether the use of novel antithrombotic drugs may result in a better outcome remains to be determined.

Octreotide in the treatment of severe chemotherapy-induced diarrhea.

BACKGROUND: Chemotherapy-induced diarrhea (CID) is a common side effect of a number of chemotherapeutic agents. Conventional therapy for severe CID with opioids or loperamide is moderately effective. A prospective trial was conducted using octreotide acetate for treatment of severe CID refractory to loperamide. PATIENTS AND METHODS: Thirty-two patients with grade 2 and 3 CID refractory to loperamide were treated with octreotide at a dosage of 100 microg subcutaneously 3x/day for three days followed by 50 microg 3x/day for three days. Previous chemotherapy consisted of regimens containing fluorouracil, leucovorin, CPT-11, cyclophosphamide, methotrexate and cisplatin. Primary tumors were colorectal (n = 23), gastric (n = 3), and other cancers (n = 6). RESULTS: Complete resolution of diarrhea was obtained in 30 of 32 patients (94%); 5 within 24 hours, 14 within 48 hours, and 11 within 72 hours of treatment. Nineteen patients were treated as outpatients. Thirteen were hospitalized for a median of three days. Response was unaffected by age, gender, performance status, previous chemotherapy or primary tumor site. No side effects related to octreotide were observed. CONCLUSIONS: Octreotide 100 microg subcutaneously 3x/day for three days is an effective, safe treatment for CID given primarily or as a second-line therapy after loperamide failure.

[The chemotherapeutic treatment of advanced Hodgkin's disease].

Between 1972 and 1994, 121 adult patients with advanced Hodgkin's disease received MOPP (M) combination chemotherapy, MOPP alternating with ABVD (M-A) or MOPP and ABV hybrid (M/A). Radiation therapy was given to 1/3 of them. The median age was 35 years, 58% had stage III and 42% had stage IV disease. Failure-free survival at 10 years was 43.9%. It was 66.7%, 48.4% and 29.9% for patients treated by M/A, M-A and M, respectively. Overall survival at 10 years was 40.8%, and 78.2%, 48% and 27.7% for patients treated by M/A, M-A and M, respectively. Multivariate analysis found age (above or below 65 years) and combination chemotherapy (with or without adriamycin) to be significant prognostic factors. M/A combination was more myelotoxic, while M combination caused more second primaries. Today, 80% of patients with advanced Hodgkin's disease may be cured, with low rate of long-term toxicity.