Treatment of peritoneal surface malignancies with hyperthermic intraperitoneal chemotherapy-current perspectives.

Peritoneal carcinomatosis (ptc) represents advanced malignant disease and has generally been associated with a grim prognosis. Peritoneal surface malignancy is often the major source of morbidity and mortality; it is of major concern in cancer management. Although ptc is categorized as metastatic disease, it represents a special disease pattern considered to be a locoregional disease limited to the abdominal cavity. The combination of cytoreductive surgery (crs) and intraoperative hyperthermic intraperitoneal chemotherapy (hipec) has successfully been used as locoregional treatment for selected patients with ptc from gastric, colorectal, and ovarian cancer; with mesothelioma; and with pseudomyxoma peritonei. In the prophylactic setting, hipec can also be used to prevent ptc in high-risk patients, and the first results of the "second-look" approach are promising. Patient selection-in which the risks of perioperative morbidity and mortality, which are analogous to those for any other major gastrointestinal surgery, are assessed-is of utmost importance. Those risks have to be weighed against the anticipated survival benefit, which depends mainly on tumour biology, extent of disease, and probability of achieving complete crs. The present review discusses the principles of crs and hipec, the most significant recent clinical data, and current perspectives concerning the application of this treatment modality in various malignancies. Ongoing trials and future directions are noted. It appears that the combination of crs and hipec is an indispensable tool in the oncologist's armamentarium.

Adipose tissue fatty acids in breast cancer patients versus healthy control women from Crete.

BACKGROUND: Few studies have implemented biomarkers of fatty acid intake in relation to breast cancer. AIMS: To examine possible differences in adipose tissue fatty acid composition between breast cancer patients and healthy control women. The relationship between tumor promotion and adipose tissue fatty acid synthesis was also investigated. METHODS: The study was conducted at the University of Crete. Subjects included 94 women with clinically diagnosed cancer of the breast and 131 healthy control women. Histological tumor grading and breast cancer staging were assessed. Fatty acids were determined by gas chromatography in gluteal adipose tissue. RESULTS: Conditional logistic regression analysis controlling for potential confounders indicated that elevated adipose monounsaturated fatty acids and oleic acid are associated with reduced odds of breast cancer [OR (T2 vs. T1) 0.15; 95% CI 0.03-0.64, and OR (T2 vs. T1) 0.18; 95% CI 0.04-0.71, respectively]. Adipose myristic acid was associated with an increase in breast cancer risk [OR (T3 vs. T1) 5.66; 95% CI 1.3-23.9]. CONCLUSIONS: Adipose oleic acid is inversely related, whereas adipose myristic acid is positively related to breast cancer risk. These relations could be mediated by Her-2/neu and FAS oncogenes.

Preoperative computed tomography and selection of patients with colorectal peritoneal carcinomatosis for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

AIM: A survival benefit has been observed for colorectal cancer patients with peritoneal carcinomatosis treated by cytoreductive surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC). However, this treatment modality is associated with a considerable morbidity and mortality and in a significant number of patients survival is not improved. We studied whether poor survivors could be identified on preoperative computed tomography (CT), in order to avoid unnecessary surgery. PATIENTS AND METHODS: Films of abdominopelvic CT scans from 25 such patients treated by cytoreductive surgery and HIPEC were retrospectively analysed by two radiologists separately. A simplified peritoneal cancer index (SPCI) was used to determine the extent of peritoneal involvement. Correlation between the on preoperative CT based SPCI-scores as well as number of involved abdominopelvic areas (N) and survival was examined with the log-rank test. The relation between each affected region and survival was evaluated with Cox regression analysis. RESULTS: The preoperative SPCI- and N-scores of one of the radiologists had no statistically significant prognostic value, while for the second radiologist SPCI > or = 7 and N > or = 4 were associated with particularly poor outcome. Additionally, the presence of ileocaecal region involvement and, depending on the radiologist, the occurrence of tumour deposits in the left subdiaphragmatic area on CT appeared to be unfavourable prognostic signs. CONCLUSIONS: The prognostic value of preoperative conventional CT appeared to be radiologist dependent and may, therefore, be of limited value in selecting colorectal cancer patients with peritoneal carcinomatosis who will not benefit from extensive cytoreductive surgery followed by HIPEC.

Intraperitoneal chemotherapy with taxanes for ovarian cancer with peritoneal dissemination.

Paclitaxel and docetaxel are currently the two clinically available taxanes. The combination of a taxane and a platinum compound has become the systemic chemotherapy of choice for primary ovarian cancer. Despite the high activity of these drugs in systemic chemotherapy, the majority of patients with advanced ovarian cancer will develop recurrent disease and ultimately decease of this disease. Therefore, more effective systemic chemotherapy regimens or alternative treatment modalities are warranted. Intraperitoneal chemotherapy is such an alternative treatment option. Pharmacokinetic studies on intraperitoneal administration of paclitaxel and docetaxel demonstrated very high locoregional drug concentrations and exposure. Their activity and response seem to be dose-dependent and hence higher efficacy with limited systemic toxicity is to be expected. Intraperitoneal chemotherapy may be combined intraoperatively with hyperthermia, which enhances tissue penetration and cytotoxic activity of many drugs. The data concerning thermal enhancement of taxanes are inconsistent, but at the high locoregional concentrations provided by intraperitoneal drug administration such a thermal enhancement seems to exist. Clinical studies have clearly demonstrated the feasibility and efficacy of intraperitoneal instillation chemotherapy with taxanes in patients with ovarian cancer. Preliminary results of a phase III study demonstrated improved outcome with the addition of intraperitoneal instillation chemotherapy to systemic chemotherapy after optimal primary cytoreductive surgery. Intraoperative hyperthermic intraperitoneal chemotherapy with docetaxel has been performed in a single study, in which promising results were observed. Further clinical investigations with an adequate follow-up period are needed to confirm the promising initial results and to determine the exact efficacy of intraperitoneal chemotherapy with these drugs.

Rationale and techniques of intra-operative hyperthermic intraperitoneal chemotherapy.

BACKGROUND: In recent years surgical cytoreduction followed by intra-operative hyperthermic intraperitoneal chemotherapy (HIPEC) was introduced as treatment modality in patients with peritoneal surface malignancy. In the current review the rational for this approach, the prerequisites and the different techniques used are discussed. METHODS: A literature search through PubMed was performed. RESULTS: Pharmacokinetic studies have shown an important dose advantage for intraperitoneal versus intravenous application. Hyperthermia enhances the penetration of cytostatic drugs into tumour tissue and also shows synergism with various cytostatic drugs. The penetration depth of drugs into tissue is limited, therefore HIPEC can only be effective in patients with minimal residual disease after (aggressive) surgery. HIPEC can be conducted in various ways, without clear proven advantage of one method over the others. Local complications after this combined treatment approach are mainly surgery related. Intraperitoneal chemotherapy may cause systemic toxicity, dependent on the drug used. In randomised studies cytoreductive surgery followed by HIPEC has proven its value in the prevention of peritoneal dissemination in gastric cancer. Phase II data on HIPEC in peritoneal carcinomatosis of colorectal origin and pseudomyxoma peritonei are promising, but randomised studies are still not available. CONCLUSION: Aggressive surgical cytoreduction and HIPEC in patients with peritoneal surface malignancy has a clear rational and seems to have clinical value.

Extensive cytoreductive surgery followed by intra-operative hyperthermic intraperitoneal chemotherapy with mitomycin-C in patients with peritoneal carcinomatosis of colorectal origin.

Peritoneal seeding from colorectal cancer has a very poor prognosis and is relatively resistant to systemic chemotherapy. We performed a phase I/II trial to investigate the feasibility and effectiveness of extensive cytoreductive surgery in combination with intra-operative hyperthermic intraperitoneal chemotherapy (HIPEC) in these patients. 29 patients with peritoneal carcinomatosis of colorectal origin without evidence of distant metastases underwent cytoreductive surgery and intra-operative HIPEC with mitomycin-C (MMC), followed by systemic chemotherapy with 5-fluorouracil (5-FU)/leucovorin. Surgical complications occurred in 11 patients (38%). One patient died directly related to the treatment, resulting in a mortality rate of 3%. MMC toxicity existed mainly of leucocytopenia (in 15 patients; 52%). After a median follow-up of 38 months (range 26-52 months) we found a 2- and 3-year survival rate (Kaplan-Meier) of 45 and 23%, respectively. Extensive cytoreductive surgery and HIPEC is feasible in patients with peritoneal seeding of colorectal cancer. First results suggest that a higher median survival could be achieved compared with conventional palliative surgery and systemic chemotherapy, therefore a randomised phase III study is now being conducted.

Staple-line disruption following vertical banded gastroplasty.

BACKGROUND: The purpose of this study was to determine the frequency with which staple-line disruption occurs following vertical banded gastroplasty (VBG) in morbidly obese patients, to investigate the effect of this complication on weight loss, and to identify any clinical symptoms that might be associated with staple-line disruption. METHODS: From April of 1992 to June of 1994, 60 patients with morbid obesity underwent VBG. Double-contrast radiographic examination of the upper gastrointestinal tract was performed on all patients at 6, 12, 24, and 36 months postoperation to assess the integrity of the staple line. At these same times, the weight of each patient was measured, so that the patients found to have staple-line disruption could be compared to those without disruption in terms of weight loss. RESULTS: Over the duration of the study, staple-line disruption was found in 12 patients (20%). All of these patients demonstrated satisfactory weight loss. Between the group of patients with staple-line disruption versus the group without disruption, weight loss did not differ significantly at any time up to 3 years postoperation. In addition, in the patients with staple-line disruption, no clear symptomatology that might be associated with this complication was discovered. CONCLUSIONS: Our results lead to the conclusion that small disruptions in the staple line lack clinical importance and do not significantly affect weight loss for at least the first 3 postoperative years. Furthermore, staple-line disruption does not seem to be associated with any specific clinical symptoms. Follow-up of all patients via barium meal is the correct approach for discovering the exact incidence of this complication.

Peritoneal expansion by artificially produced ascites during perfusion chemotherapy.

HYPOTHESIS: In cases of peritoneal carcinomatosis, continuous hyperthermic peritoneal perfusion chemotherapy (CHPPC) accomplishes homogeneous distribution of the drug and heat to the entire peritoneal cavity and exposure of the visceral and parietal surfaces to the perfusate. A new closed technique for expansion that produces artificial ascites is safer for medical personnel because of less heat and drug loss and more efficacious in its hemodynamic effect on the patient. DESIGN: Prospective study. SETTING: University hospital. PATIENTS: Twenty-one patients with peritoneal carcinomatosis. INTERVENTIONS: We performed 23 continuous hyperthermic peritoneal perfusion chemotherapy (CHPPC) procedures with peritoneal cavity expansion to an intra-abdominal pressure up to 26 mm Hg, using artificially produced ascites with 4 to 9 L normal saline solution. MAIN OUTCOME MEASURES: Intraoperative and postoperative complications and hemodynamic changes during CHPPC. RESULTS: No intraoperative complications were recorded. The artificially produced ascites did not cause significant hemodynamic changes. During the immediate postoperative period, 1 patient died of intra-abdominal hemorrhage and leakage of a colorectal anastomosis, resulting in a mortality rate of 4% in our series. Minor complications were seen in 14 patients. The complications were not attributable to the expansion technique. CONCLUSIONS: Our proposed modification of closed-circuit CHPPC appears to be well tolerated and safe in patients with a high tumor load, as well as for the theater personnel. It remains to be investigated whether the theoretical advantages of the proposed technique will also lead to better long-term results.

Malignant melanoma of the penis.

A case of malignant melanoma of the penis is herein reported. Malignant melanoma of the penis is rare and accounts for a small percentage of malignant melanomas and of malignant penile lesions. The diagnosis is often delayed by the patient's reluctance to consult a physician and by the intrinsic difficulty in clinical diagnosis of such a rare neoplasm. The surgical treatment is not standardized and is shortly discussed. In general, prognosis is poor and most patients die within a few years due to distant metastasis.

Bilateral angiosarcoma of the breast after conservative treatment of bilateral invasive carcinoma: genetic predisposition?

AIMS: In view of the increasing application of breast-conserving therapy (BCT) for early breast cancer during the last decades, the number of BCT-associated angiosarcomas is likely to increase. Their aetiology is not completely clear. The aim of this study was to examine the potential role of genetic predisposition for development of this rare tumour. METHODS: The authors report on a case of consecutive bilateral development of angiosarcoma of the breast 6 and 12 years after BCT for bilateral invasive breast carcinoma. The literature was reviewed and the potential role of genetic predisposition was examined. RESULTS: Such a case of bilateral BCT-induced breast angiosarcoma has not been previously reported in the international literature. The change on development of such a tumour bilaterally is 0.25-2.6 per million women who underwent bilaterally BCT with radiotherapy for invasive carcinoma. The case history and the literature review suggest that gene mutations are likely to play a role in development of post-radiation angiosarcoma of the breast. CONCLUSIONS: It is assumed that genetic predisposition may play a role in the development of angiosarcoma after BCT. When such a predisposition is known, one might decide to avoid BCT in favour of mastectomy.

Axillary lymphadenectomy for breast cancer - the influence of shoulder mobilisation on lymphatic drainage.

AIM: The purpose of the present study was to study the influence of external axillary compression dressing with immobilisation of the ipsilateral shoulder after axillary lymph node dissection (ALND) on postoperative axillary drainage. METHODS: One hundred consecutive women with breast cancer undergoing ALND were enrolled in this study. They were allowed free shoulder movement and were compared with a matched historical control group of 60 patients, in whom the ipsilateral arm was immobilised for four days. For all patients the amount of drainage was recorded each postoperative day until drain removal. Prognostic data on drainage amounts and duration were gathered from all patients. Complications were recorded. RESULTS: Hospital stay was the only statistically significant difference between the two groups, it was prolonged for patients with immobilisation of the arm. The parameters found to influence the drain production with a statistically significant difference were body mass index and the removal of more than 10 lymph nodes. Postoperative complications were similar in both groups. CONCLUSIONS: External compression dressing of the axillary cavity with immobilisation of the ipsilateral arm has no impact on the postoperative drainage volume and duration. It is associated with adverse effects, such as discomfort, prolonged hospital stay and shoulder stiffness.

Contribution of 99mTc-anti-carcinoembryonic antigen antibody and 99mTc-sestamibi scintimammography in the evaluation of high risk palpable breast lesions.

Mammography is the screening test of choice for breast cancer. Its low specificity leads to a large number of unnecessary biopsies. Scintimammography, with either Tc-sestamibi (MIBI) or Tc-anti-carcinoembryonic antigen (CEA) Fab', has been proposed as a non-invasive test to lower the high false positive rate of mammography in certain patients. The two agents have not been compared, nor has their combined application been evaluated. We performed a prospective, non-randomized, open-label, single-centre study of 32 women with clinically and mammographically suspected breast cancer [Breast Imaging Reporting and Data System (BI-RADS, American College of Radiology) 4 or 5]. All patients underwent Tc-MIBI and Tc-anti-CEA Fab' scintimammography, and the results were correlated with histopathology. Overall, the accuracies for MIBI and CEA scans were 90.3% (28/31) and 77.4% (24/31), respectively. The probability of disease after mammography was 0.939+/-0.081 (95% confidence interval, CI). The post-mammography probabilities after positive MIBI or CEA scan were 0.965 and 0.960, respectively, and after negative MIBI or CEA scan 0.750 and 0.875, respectively. None of the above differences is significant. The post-test probability when both scans were positive (irrespective of which was performed first) was 0.977. It can be concluded that there are indications that scintimammography with Tc-MIBI is superior to that with Tc-anti-CEA Fab' when these tests are used as screening tests for breast cancer. However, mammography remains the screening test of choice for highly suspicious clinically palpable breast lesions. In this group of patients, the application of scintimammography with either Tc-MIBI or Tc-anti-CEA Fab' (alone or in combination) offers no additional advantage.

Cysts of the adrenal gland: diagnosis and management.

OBJECTIVE: Cysts of the adrenal gland are rare, but with the wider application of sonography and computed tomography more adrenal cysts are detected incidentally. To gain more insight into this entity, five such cases are reported and their diagnostic approach and management are discussed. PATIENTS AND METHODS: The records of five patients with six cysts of the adrenal glands seen at our department from 1987 till 1995 are reviewed. There were four males and one female and their age ranged from 24 to 72 years, with a mean age of 43 years. One patient had a primary hydatid cyst of the right adrenal gland, which was preoperatively thought to arise from the liver or the right kidney. A second patient had a very large pseudocyst of the left adrenal gland, which is the largest ever reported in the literature. The other four cysts in three patients were found incidentally during sonography or computed tomography. RESULTS: The hydatid cyst with a rim of normal adrenal tissue was excised. The large pseudocyst was removed together with the adrenal gland. In the cases of the incidentally found cysts, observation of the patient with regular follow-up was decided upon. All patients are in good condition and without symptoms 2 to 10 years after the initial diagnosis. CONCLUSIONS: Adrenal cysts are rare and their diagnosis may pose problems. Symptomatic adrenal cysts should be operated, but small, asymptomatic, non-functional cysts with benign characteristics may be treated conservatively with regular follow-up by sonography or computed tomography and hormonal evaluation.

Experience with benign splenic disease.

PURPOSE: In the ongoing effort to improve patient treatment, a deeper understanding of the symptomatology, physical signs and management options of rare splenic, non-traumatic, benign diseases is extremely important. PATIENTS AND METHODS: The records of eight consecutive patients with benign splenic conditions, other than injury and abscess, were reviewed retrospectively in order to analyse the clinical presentation, diagnostic methodology and therapeutic procedures applied in these rare conditions. Of the eight patients, three were diagnosed with splenic hydatid cyst, two with pseudocysts, one with splenic epidermoid cyst, one with wandering spleen and one with infraction of an ectopic spleen with situs inversus of other intra-abdominal organs. RESULTS: Upper abdominal pain was the most common presenting symptom and a tender palpable mass in the left upper abdominal quadrant, the predominant clinical finding. Pre-operative CT scanning confirmed the diagnosis in six patients, but failed to reveal the splenic pathology in the remaining two cases. Seven patients underwent splenectomy while saving splenic parenchyma was feasible in only one patient (12,5%). CONCLUSIONS: Splenic, non-traumatic, benign diseases have vague clinical presentation and may create diagnostic difficulties. Although spleen saving intervention can be applied in selected cases, splenectomy would be required in most patients.

Pylorus-preserving pancreaticoduodenectomy with external pancreatic remnant drainage.

BACKGROUND: Pancreaticoduodenectomy is the mainstay of surgical treatment for various benign and malignant diseases of the head of the pancreas and the periampullar region. The incidence of postoperative morbidity remains significantly high. Various modifications have been advocated for the restoration of the digestive continuity and drainage of bile and pancreatic ducts in order to diminish this high morbidity rate. METHODS: A new modification with the combination of an end-to-end duodenojejunal anastomosis and creation of an external pancreatic fistula following pylorus-preserving pancreaticoduodenectomy is described. Our initial experience with this modification in seven patients is reported and its advantages are discussed. RESULTS: There was no mortality, while morbidity was 29%, including postoperative pneumonia and psychosis in one patient, and intra-abdominal abscess in another patient. No significantly delayed gastric emptying was observed and no patient developed diabetes, anastomotic ulcer or reflux cholangitis postoperatively. CONCLUSIONS: The reported technique seems to be a safe modification of restoration after pancreaticoduodenectomy, with maintenance of anatomical gastrointestinal continuity, avoidance of complications from anastomosis with the pancreatic remnant, as well as maintenance of endocrine pancreatic function. However, long-term follow-up and larger comparative studies are needed to evaluate the impact of this modification on morbidity and mortality, including long-term nutritional complications.

Splenic abscess: a diagnostic and therapeutic challenge.

The records of five patients treated in our department for splenic abscess are analysed and the literature is reviewed. Computed tomography revealed the correct diagnosis in all patients, while clinical presentation was often nonspecific. Spleen-preserving management was possible in two patients (40%). Outcome was uneventful for four patients. One patient with a splenic abscess caused by Mycobacterium tuberculosis and acquired immunodeficiency syndrome, died 4 months after splenectomy from sepsis. We discuss the clinical presentation of splenic abscess, its diagnostic approach, and treatment. Additionally, we studied whether spleen-preserving management is feasible or not.

Primary psoas abscess. Report of three cases.

BACKGROUND: Primary psoas abscesses are a rare clinical entity with subtle and non specific symptoms, most commonly seen in patients predisposed to infections. Early diagnosis and appropriate management are therefore challenging aspects for physicians. PATIENTS AND METHODS: We present three patients with primary pyogenic psoas abscess, treated at the Heraklion University Hospital, during a 5-year period. The two male and one female patient, aged 36-51 years were admitted with fever, abdominal pain and a palpable tender mass. RESULTS: The classical sign of limping was absent in all cases. Positive psoas symptoms were detected in only two patients. CT scan accurately confirmed the diagnosis in all cases. The patients were successfully treated with antibiotics and prolonged surgical drainage. Staphylococcus aureus was the causative microorganism in the first two and Bacteroides fragilis in the third patient. This is the first reported case resulting from this specific bacteria. None of our patients had any predisposing risk factor. CONCLUSIONS: A high index of suspicion is mandatory to enable early recognition of this rare clinical disease. CT scan is the standard diagnostic tool to confirm diagnosis. Prolonged drainage and appropriate antibiotics are essential for the successful treatment of primary psoas abscesses.

Assessment of the effect of surgery on the kinetics of circulating tumour cells in patients with operable breast cancer based on cytokeratin-19 mRNA detection.

AIMS: The aim of this study was to evaluate the effect of surgery on the kinetics of CTCs in breast cancer patients. METHODS: The detection of CK-19 mRNA-positive CTCs in the blood by RT-PCR was analysed in 104 stage 0-IIIA patients at 4 time-points: prior to surgery, upon completion, 24 h after surgery and 15 days after surgery. Furthermore, a late sample was assessed prior to initiation of adjuvant chemotherapy in a subgroup of 53 patients. As negative controls, peripheral blood was obtained from 50 female patients undergoing excision of benign breast lesions and from 11 female patients receiving surgery for early-stage colorectal cancer. RESULTS: A significant percentage of blood samples from breast cancer patients (14.4%) were negative for CK-19 preoperatively but turned transiently positive early postoperatively. However, no significant difference in CK-19 mRNA detection was noted among the first 4 examined time-points. There was no significant correlation between CK-19 mRNA-positive cells and classic prognostic factors. A significant increase in CK-19 mRNA-positivity (32.1%) was observed in a late sample of the subgroup of 53 patients before adjuvant chemotherapy after a median of 54 days, postoperatively. CONCLUSIONS: Surgery may result in CTC detection in a small proportion of early breast cancer patients. There is no clear correlation to indicate which patients are expected to have detectable CTCs. Although CTCs are detected in a small proportion of patients during the perioperative period, the detection rate may increase over time and with longer follow-up.