Intraperitoneal heated chemotherapy affects healing of experimental colonic anastomosis: an animal study.

BACKGROUND: The peritoneal spread of cancer is a well-known entity carrying a dismal prognosis. A new therapeutic approach is the combination of cytoreduction with heated intraperitoneal chemotherapy (HIPC). The risk of an intra-abdominal anastomosis in the presence of such chemotherapy is recognized clinically but the experimental data on the subject are lacking. The aim of this study is to examine the influence of chemotherapy and hyperthermia on the healing of colonic anastomosis. MATERIALS AND METHODS: Colonic anastomosis were performed in four groups of male Wistar rats: (1) control (operation only), (2) HIPC with saline, (3) with mitomycin C (MMC), and (4) with cisplatinum. HIPC was performed using a closed circulation system at 40 degrees C over 20 min. Anastomotic strength was tested on day 4, 7, 10, and 21. RESULTS: The bursting pressure of anastomoses in rats treated by HIPC was significantly lower than in controls. On day 4, it was 54.8 mm Hg, 38 mm Hg, 18 mm Hg, and 14.8 mm Hg in groups 1-4, respectively, while on day 7 it was 170 mm Hg, 188 mm Hg, 83 mm Hg, and 19 mm Hg, respectively (P < 0.01). The difference decreased on day 10 and almost vanished on day 21. HIPC with cisplatinum had the worst effect on anastomotic healing during the early postoperative period. CONCLUSIONS: Cytoreduction and HIPC are gaining popularity. However, the use of heated chemotherapy has a detrimental effect on the strength of colonic anastomosis, especially during the early postoperative period (until day 10). This may cause anastomotic failure and postoperative morbidity. Therefore, careful selection and avoidance of unnecessary anastomoses are mandatory.

Hydronephrosis associated with colorectal carcinoma: treatment and outcome.

AIM: Obstruction of the upper urinary tract, hydronephrosis, is not uncommon in the context of primary or recurrent colorectal cancer (CRC). Its presence poses a therapeutic dilemma. This study focuses on the significance of hydronephrosis as a prognostic marker for CRC by analysing the resectability and survival rates of patients affected. PATIENTS AND METHODS: Retrospective data of 52 patients with hydronephrosis were analysed. Ten had primary CRC at different sites and 42 developed hydronephrosis 1-84 months following resection of a primary CRC. Twenty eight had unilateral and 24 bilateral hydronephrosis. RESULTS: In 10 patients with primary CRC and in 38 of those with a history of CRC, hydronephrosis was secondary to malignant obstruction. In four it was related to iatrogenic injury to the urinary tract. Complete surgical resection was possible in five patients (10%) with malignant obstruction. The remaining 90% underwent palliative or no surgical treatment due to diffuse metastasis or extensive local disease. No difference in survival was found between these two groups (6 vs 8 months) nor when comparing CEA levels, Duke's staging, or unilateral vs bilateral hydronephrosis. Patients with benign obstruction were treated by a ureteric stent, leading to resolution of hydronephrosis. All four are alive. CONCLUSIONS: Malignant hydronephrosis, secondary to primary or recurrent CRC, represents local manifestation of a disseminated disease with almost no probability of long-term survival and cure. It would seem that patients with such disease do not benefit from aggressive operations.

Multiple primary malignancies in association with soft tissue sarcomas.

BACKGROUND: Modern cancer treatment has increased the survival of patients with various malignancies substantially. One of the late sequelae of successful treatment is the development of a second malignant tumor. However, in many cases of second primary tumors, exposure to chemotherapy or radiation therapy is not evident, and it should be postulated that the putative mechanism for the development of the second tumor is different. In the current series, the association between soft tissue sarcoma (STS) in adults and the development of other primary malignancies was studied. METHODS: A retrospective search of the data files of 610 patients with STS or bone sarcomas who were treated at the study institution between January 1995 and December 1999 was performed. All files regarding patients with STS who developed a second malignant tumor were retrieved for analysis. RESULTS: Of 375 patients with STS, 28 (7.5%) developed other malignant neoplasms either before or after the diagnosis of STS. STS as the first tumor occurred in 14 patients (ages 16-72 years). Only three patients were treated with chemotherapy for their sarcoma. Radiation therapy was administered to five patients as an adjuvant to surgery for the first tumor. The second tumor types mainly included STS and renal cell carcinoma. The time interval between the diagnosis of the STS and the second malignancy was 0 (for synchronous tumors) to 21 years. Three patients developed a third primary tumor within 3 years after the diagnosis of the second tumor. The median overall survival was > 78 months. Fourteen patients (ages 35-87 years) had a first primary tumor other than STS (mainly breast carcinoma and genitourinary malignancies). The second tumors (mainly STS) appeared within 0 (for synchronous tumors) to 27 years. The median overall survival for the 14 patients in this group from the time of diagnosis of the first tumor was > 102 months. CONCLUSIONS: The phenomenon of two or three primary neoplasms developing in patients in whom one of the tumors was STS occurs at a rate of 7.5%, a significantly higher rate than that reported for the occurrence of STS among the general cancer population (1%). The majority of cases occur incidentally. The clinical implication includes the need to search for an occult second primary tumor in patients with STS as an integral part of their follow-up. This is especially true in patients with primary malignant fibrous histiocytoma who demonstrate a risk for developing a renal cell carcinoma.

[Diagnostic laparoscopy--a useful tool in abdominal lymphoma].

Imaging-guided (CT/US) percutaneous biopsy has significantly improved diagnosis of intra-abdominal lymphoma. However, in many cases the tissue retrieved may be inadequate for specialized studies such as immunophenotyping or cytogenetic analysis that may be required for a complete analysis of lymphoma or determination of therapy. The success of diagnostic laparoscopy in the diagnosis and staging of gastrointestinal malignancies suggests that it could be used for intra-abdominal lymphomas as well. We describe our experience in 15 patients with suspected lymphoma who underwent diagnostic laparoscopy during 1995-98. Preoperative investigation performed in all included percutaneous FNA in 9 without conclusive diagnosis. Laparoscopy was diagnostic for lymphoma in 14 (93%) while in 1 there was a false negative result due to sampling error and the lymphoma was only diagnosed at a second laparoscopy. There was no mortality nor any major complication. Average hospital stay was 2 days and patients were then referred for further oncological treatment. Our experience shows that diagnostic laparoscopy is a safe and efficient tool and without major complications in diagnosing abdominal lymphoma.

Is forequarter amputation justified for palliation of intractable cancer symptoms?

BACKGROUND: Limb-sparing surgery has replaced the radical surgical approach for treating limb sarcomas in most cases. Amputation has been advocated as a palliative procedure for symptomatic locally advanced disease that has already failed to respond to radiation therapy, chemotherapy and limited surgery. METHODS: Twelve patients with advanced malignant tumors involving the shoulder girdle or the proximal humerus underwent forequarter amputation (FQA) for palliative purposes. The tumor-related local problems were severe pain, limb dysfunction, tumor fungation, bleeding (requiring emergency FQA in one case) and infection. The preoperative Karnofsky performance status (KPS) in our series ranged from 30 to 70%. RESULTS: No perioperative mortality was observed. The morbidity was well tolerated by the patients. The KPS improved in most of the patients, and was assessed as 90-100% in 9 of the 12 patients. Overall, quality of life was reported to be at least moderately improved by 2 out of 3 patients. Survival was measured in months (3-24 months), but ultimately had no meaning since the procedure was palliative. Lung metastases were the dominant cause of death in our patients. CONCLUSIONS: The results of FQA in our series point to its feasibility and the gain in quality of life and performance status in severely ill patients with advanced malignancies. Local symptoms and signs were controlled, and quality of life was restored.

Transanal endoscopic microsurgery: experience with 75 rectal neoplasms.

PURPOSE: The aim of this study was to describe a single institution's experience with transanal endoscopic microsurgery in patients with benign and malignant rectal tumors. PATIENTS: Between January 1992 and April 1998, 75 patients with a mean follow up of 38 months, underwent transanal endoscopic microsurgery excision of benign (46) or malignant (29) rectal tumors, located 3 to 18 cm from the dentate line. RESULTS: A total of 3 of 46 (6.5 percent) patients with benign tumors underwent conversion to radical surgery owing to tumor size. During the follow-up period, benign tumor recurrence was observed in four (9 percent) patients, three of whom were managed by repeat transanal endoscopic microsurgery, whereas one required radical surgery. Histologic staging of malignant tumors was T1 (10), T2 (10), and T3 (9). Seven patients with either inadequate resection margins or T3 tumors were complimented with radical surgery. Of the remaining 22 patients, 11 received adjuvant radiation therapy whereas 11 had no further treatment. Four (18 percent) had recurrent disease, which was managed by repeat transanal endoscopic microsurgery in two, radical surgery in one, and laser ablation in one. No cancer-related deaths were observed during the follow-up period. There was one operative mortality in a cardiac-crippled patient. Postoperative complications were mainly of a minor character and included fever, urinary retention, and bleeding; none of which required reintervention. Rectourethral fistula developed in one patient who underwent repeat transanal endoscopic microsurgery excision for a T3 malignancy. Fecal soiling was transient in three patients and persisted in two. CONCLUSION: Transanal endoscopic microsurgery excision is a safe and precise technique that is well tolerated even in high operative risk patients. Transanal endoscopic microsurgery may become a procedure of choice for benign rectal tumors and selected early malignant neoplasms.

Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan in advanced soft-tissue sarcomas: histopathological considerations.

BACKGROUND: Hyperthermic isolated limb perfusion with tumor necrosis factor-alpha and melphalan was used as induction treatment in locally advanced extremity soft-tissue sarcomas for limb sparing surgery. The typical histopathological changes that occur in these tumoral masses are described in a series of 30 patients. METHODS: Fresh tumor specimens of 27 high grade extensive soft-tissue sarcomas and 3 recurrent desmoid tumors of the extremities were collected 6 to 8 weeks after hyperthermic isolated limb perfusion with tumor necrosis factor-alpha plus melphalan. The specimens were studied for surgical margins, extent and type of tumor necrosis, lymph node involvement, perineural and vascular invasion, and the effects on adjacent normal tissues such as nerves, muscles, and blood vessels. RESULTS: The typical histological changes were central cystic hemorrhagic necrosis with pericystic extensive fibrosis. Some nonspecific changes were noted in the soft tissues around the mass. In eight cases, more than 90% necrosis was found. In 17 cases, the extent of necrosis ranged between 60% and 90% (80%-90% in 4 of 17 cases). In five cases, less than 60% necrosis was noted. The best responses (>90% necrosis) were observed in distally located tumors. The responsive types were malignant fibrous histiocytoma, followed by myxoid liposarcoma and synovial sarcoma. Desmoid tumors showed less necrosis than high grade sarcomas. Vascular invasion was observed in two cases and intralesional venous thrombosis in one case. No perineural invasion or lymph nodes involvement were observed. The soft tissues adjacent to the tumor bed did not show major morphological changes. No correlation was found between the histological changes and each of the following: the anatomical (upper vs. lower limb) or compartmental location of the tumor; whether the tumor was primary or recurrent; and the types of previous treatment (systemic chemotherapy or radiotherapy) and tumor size. CONCLUSIONS: This is the first serial histological description of the effects of tumor necrosis factor-alpha and melphalan administered via hyperthermic isolated limb perfusion on the tumoral masses of limb soft-tissue sarcomas. The small number of specimens and, especially, the variability of tumors preclude definite conclusions. Larger numbers and more homogeneity are needed in future studies.

Metastases to the retroperitoneum in patients with extremity soft tissue sarcoma: an unusual metastatic pattern.

BACKGROUND: Extremity soft tissue sarcoma (STS) metastasizes preferentially to the lungs via the hematogenous route. Metastases in extrapulmonary sites such as bone, brain, and subcutaneous tissues are observed less frequently. To the authors' knowledge, limb STS primarily metastasizing to the retroperitoneum has not been described to date. The current study reviews the clinical course, management, and patient prognosis in such a pattern of metastasis. METHODS: Records of patients with retroperitoneal metastases originating from an extremity STS between 1994-1998 were reviewed. Patient demographics, primary tumor site, other tumor sites, local recurrence, distant metastasis, treatment, and survival were analyzed. RESULTS: Ten patients were included in the study. All had primary STS of different histologic types and high histologic grade confined to a lower limb. The retroperitoneal metastases were diagnosed between 6-120 months (mean, 45 months) after diagnosis of the primary sarcoma. At that time, one patient had evidence of local recurrence of the primary tumor site, two patients had lung metastases, and one patient had diffuse bone metastases. Eight patients were eligible for surgery. In six of these patients the metastases were excised completely. The median follow up was 12 months. Of the six patients who underwent complete resection, 3 were alive at last follow-up with no evidence of disease after 12 months, 14 months, and 24 months, respectively. Two patients with recurrent retroperitoneal disease and one patient with retroperitoneal and lung metastases died despite systemic chemotherapy. CONCLUSIONS: Extremity STS can metastasize hematogenously to the retroperitoneum, a fact that mandates a high index of suspicion and abdominal imaging studies during the follow-up of such patients. Retroperitoneal metastases necessitate aggressive surgical resection to enable prolongation of survival.

Limb desmoid tumors: a possible role for isolated limb perfusion with tumor necrosis factor-alpha and melphalan.

BACKGROUND: The management of extensive, recurrent limb desmoid tumors is extremely difficult. The failure of multimodality treatments, such as repeated resections, radiotherapy, systemic chemotherapy, or endocrine manipulations, can end up with multilating surgery or even amputation, similar problems sometimes encountered in soft tissue sarcoma of the limbs. The high rate of limb salvage achieved by isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan for extensive, high-grade soft tissue sarcoma led us to implement this modality in difficult cases of limb desmoids. METHODS: During a 4-year period, 6 patients aged 14 to 52 years were treated. All were significantly symptomatic and candidates for amputation or mutilating surgery. Five had lower and one had upper limb lesions. Two had multifocal disease. At ILP, 3 to 4 mg TNF and 1 to 1.5 mg/kg melphalan were delivered during a 90-minute period. One patient had a double perfusion. All patients underwent definitive resective operation 6 to 8 weeks after perfusion. RESULTS: No systemic complications were observed, and local complications included reversible skin redness and blisters. Response rate was 83% with 33% (2 of 6) complete response and 50% (3 of 6) partial response. In 1 patient less than 50% regression was observed. Limb salvage rate was 100%; even the patient with stabilization of disease could be locally resected. Local recurrence during a follow-up period of 7 to 55 months (median 45 months) occurred in 2 patients at 8 and 24 months, respectively; the first underwent amputation, whereas for the second a wide excision was possible. CONCLUSIONS: ILP with TNF and melphalan can be used as a limb preservation modality in patients with recurrent desmoids and significant symptoms who would otherwise require multilating surgery to control their neoplasm.

Adriamycin-ifosfamide induction chemotherapy for extremity soft tissue sarcoma: comparison of two non-randomized protocols.

Chemotherapeutic cytoreduction of soft tissue sarcomas may permit less radical operation. In cases of large or multi-compartmental masses, deeply seated tumors or involvement of a neurovascular bundle, down-sizing of the mass is required before limb sparing surgery can be considered. We have applied a combination chemotherapy consisting of intravenous adriamycin and ifosfamide with intra-arterial cisplatin for patients with soft tissue sarcomas of the extremity as induction treatment, and switched to an intravenous-only protocol due to toxicity and management difficulties. Adjuvant chemotherapy and radiation therapy were given after limb-sparing surgery in both regimens. Fresh tumor specimens were obtained and were examined for tumor size, surgical margins, percent of necrosis, evidence of vascular or perineural invasion, and the presence of Pgp, Ki-67, p53, PCNA and bcl-2-oncoprotein. Our results in terms of percentage of tumor necrosis were comparable and even better in favor of the second regimen [38% good histological response with intravenous (i.v.)-only versus 12.5% for combined i.v. + intra-arterial (i.a.]. The clinical and radiological responses were also better for the second (i.v. only) regimen (45%) than for the first (i.v. + i.a.) regimen (12.5%). The toxicity and the inconvenience to the patients and to the treating staff were greater in the first regimen that combined intra-arterial and intravenous infusions. In the first group the failure rate is 75% within 32 months of follow-up, while it is 33% within 12 months follow-up in the second group. The immunohistochemical markers did not correlate with disease control nor with the patient outcome. Intravenous administration of ADR-IFX induction chemotherapy was more feasible than combined i.v. ADR-IFX plus i.a. cisplatin and achieved better results.

Multifocal soft tissue sarcoma: limb salvage following hyperthermic isolated limb perfusion with high-dose tumor necrosis factor and melphalan.

BACKGROUND AND OBJECTIVES: The prognosis for recurrent multifocal limb soft tissue sarcoma (STS) is dismal due to systemic spread. However, many of these patients undergo amputation due to ineffective local control. The purpose of the present study was to determine whether isolated limb perfusion (ILP) with tumor necrosis factor (TNF) and melphalan permits limb salvage and palliation for such patients. METHODS: Of 53 STS patients treated with hyperthermic ILP with TNF (3-4 mg) and melphalan (1-1.5 mg/kg), 13 (25%) had multifocal STS and were candidates for amputation. RESULTS: The overall response rate was 92% (12/13) with 38% complete response and 54% partial response. Two patients died during the early postoperative period. Limb salvage was achieved in 85% of patients. One patient (8%) had only stable disease and underwent amputation. Local recurrence occurred in 38% but did not result in amputation. CONCLUSIONS: Although the number of patients in this study is too small to allow definitive conclusions, it seems that ILP/TNF offer limb salvage and palliation for recurrent multifocal STS patients.

Isolated limb perfusion with high-dose tumor necrosis factor alpha and melphalan for Kaposi sarcoma.

BACKGROUND: Although the classic form of Kaposi sarcoma is considered indolent and benign, at times its evolution is more severe, with an acute onset and debilitating complications necessitating aggressive treatment and even amputation. OBJECTIVE: To evaluate the efficacy of hyperthermic isolated limb perfusion (ILP) with tumor necrosis factor alpha and melphalan as a limb-sparing modality for extensive regional Kaposi sarcoma. SETTING: University hospital and national referral center. PATIENTS: Five patients, aged 60 to 82 years, with extensive, symptomatic, classic Kaposi sarcoma of the lower limb were operated on. All were candidates for amputation owing to debilitating symptoms. INTERVENTIONS: Patients underwent ILP through the iliac (n = 2), femoral (n = 2), and popliteal (n = 1) vessels. Tumor necrosis factor alpha, 4 mg, and melphalan, 1.5 mg/kg body weight, were perfused for an overall time of 90 minutes. The limb was heated to 40 degrees C. Clinical and pathological responses were recorded for all patients after 6 to 8 weeks. RESULTS: The overall response rate was 100%: 1 of 5 patients had complete response and 4 of 5 had partial response. Two patients had progression of disease 2 months after ILP but one of them was asymptomatic and did not require any further treatment. The second patient underwent amputation. Thus, limb preservation was achieved in 80% (4 of 5 patients). Median follow-up was 24 months. There were no deaths associated with treatment or major system complications. Local complications were all reversible. CONCLUSION: These findings suggest that hyperthermic ILP with tumor necrosis factor alpha and melphalan can be considered an effective palliative and limb-sparing treatment modality for extensive Kaposi sarcoma.

Morgagni hernia: unique presentations in elderly patients.

We present case reports of 2 patients who were admitted to our ward for complications of Morgagni hernias. Both patients were elderly. Morgagni hernia is a rare condition. Its unique and late presentation are presented and discussed.

[Retroperitoneal sarcoma. Treatment of 51 patients].

Soft tissue sarcomas are exceedingly rare, making up less than 1% of all solid malignancies. In the retroperitoneum, they tend to be large when diagnosed and are a therapeutic challenge to the surgical oncologist. Our experience with 51 patients with retroperitoneal sarcomas operated on during the past 4 years is presented. 37 were primary and 26 presented as recurrent tumors. The group included many different histological subtypes, the majority being high grade tumors. Complete resection was achieved in 84%, necessitating extensive surgery, but was not possible in 8 patients (16%) who underwent partial resection or biopsy only. There was 1 perioperative fatality (2%). 18 (35%) suffered complications, all of which were reversible. The estimated 5-year survival in the complete resection group is 40%, while none of those who underwent partial resection survived more than 2 years. There was significantly better survival in patients with primary, low grade sarcomas which were smaller than 8 cm, compared to those with high-grade, recurrent sarcomas larger than 8 cm. Local recurrence developed in 8 patients of the complete resection group (18%), 2 months to 3 years after surgery. These data show that despite the concept of retroperitoneal sarcomas as being aggressive, invasive tumors with a poor prognosis, the prognosis is not unusually bad. With proper surgical technique, resectability may be high, with improved overall survival.

Synergism of tumor necrosis factor-alpha and melphalan in systemic and regional administration: animal study.

Tumor necrosis factor (TNF) is a highly cytotoxic cytokine. However, due to its severe side effects, the only clinical situation allowing its administration in humans is isolated limb perfusion (ILP). Early studies have shown that TNF alone is of limited efficacy even at high doses via ILP, and that a chemotherapeutic agent needs to be added. The most commonly used drug in this setting is melphalan which is considered to be synergistic with TNF. However, since melphalan has not been commonly used in sarcoma, we believed that confirmation of its synergistic effect with TNF in an experimental sarcoma model could prove valuable for future drug choice. B16F10 melanoma and CT26 colon carcinoma cells were injected subcutaneously (s.c.) into mice, while GF fibrosarcoma cells were injected s.c. into the hindleg of Wistar rats. The animals were then divided into four treatment groups: TNF alone, melphalan alone, TNF and melphalan, and 0.9% NaCl controls. Mice were treated with intraperitoneal injections and rats by ILP. TNF dosage was 20 microgram for mice and 200 microgram for rats. Melphalan was given at 5-10 mg/kg for both mice and rats. Results showed synergism of TNF and melphalan in both modes of therapy. In the systemic administration groups (mice carrying B16F10 and CT26 tumors), tumors increased in size in all but the combined TNF-melphalan group. In the regional delivery groups (rats carrying GF sarcoma cells treated via ILP), there was a 16% decrease in tumor volume in rats treated with TNF alone, a 29% decrease in rats treated with melphalan, and a 75% decrease in the combined TNF-melphalan group. In conclusion, TNF and melphalan proved to be highly synergistic in both systemic and regional delivery. This fact makes melphalan an adequate choice for TNF perfusion in advanced limb malignancies.