Neoadjuvant chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: a feasibility and safety study.

BACKGROUND: Standard treatment for colorectal peritoneal carcinomatosis typically involves cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and if possible, postoperative adjuvant chemotherapy. However, a substantial percentage of patients never receive adjuvant chemotherapy because of postoperative complications. Neoadjuvant chemotherapy could be beneficial in this setting, so we assessed its feasibility and safety when used before cytoreductive surgery and HIPEC. METHODS: In this non-randomized, single-center, observational feasibility study, patients were scheduled to receive six cycles of capecitabine and oxaliplatin before cytoreductive surgery and HIPEC. Computed tomography was performed after the third and sixth chemotherapy cycles to evaluate tumor response, and patients underwent cytoreductive surgery and HIPEC if there were no pulmonary and/or hepatic metastases. Postoperative complications, graded according to the Clavien-Dindo classification, were compared with those of a historic control group that received postoperative adjuvant chemotherapy. RESULTS: Of the 14 patients included in the study, 4 and 3 had to terminate neoadjuvant chemotherapy early because of toxicity and tumor progression, respectively. Cytoreductive surgery and HIPEC were performed in eight patients, and the timing and severity of complications were comparable to those of patients in the historic control group treated without neoadjuvant chemotherapy. CONCLUSION: Patients with peritoneal metastases due to colorectal carcinoma can be treated safely with neoadjuvant chemotherapy before definitive therapy with cytoreductive surgery and HIPEC. TRIAL REGISTRATION NUMBER: NTR 3905, registered on 20th march, 2013, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3905.

Deep lymph node metastases in the groin significantly affects prognosis, particularly in sentinel node-positive melanoma patients.

BACKGROUND: In order to define patients eligible for only a superficial groin dissection or a combined superficial and deep groin dissection, this study aimed to determine the incidence of deep lymph node metastases (LNM) in patients with melanoma metastasized to the groin, to identify patient and melanoma factors that predict deep nodal involvement, and to analyze the impact of deep nodal involvement on survival and recurrence. METHODS: Patients who underwent a combined superficial (inguinal) and deep (iliac and obturator) complete (CLND) or therapeutic lymph node dissection (TLND) of the groin between 1994 and 2012 were analyzed. RESULTS: QueryDeep LNM were found in 8 of 62 CLND patients (13 %) and in 21 of 67 TLND patients (31 %). More than three superficial LNM was the only independent predictor for deep LNM in both CLND and TLND patients. The 5-year melanoma-specific survival (MSS) for CLND and TLND patients with deep LNM was 14.3 and 16.6 %, respectively, and was significantly worse (hazard ratio [HR] 3.39, 95 % CI 1.34-8.58, p = 0.010; and HR 2.01, 95 % CI 1.04-3.88, p = 0.039) compared with CLND and TLND patients without deep LNM (5-year MSS: 54.1 and 37.2 %, respectively). Distant recurrence was significantly associated with deep LNM in CLND patients (p = 0.032). CONCLUSIONS: The present study showed that LNM in the deep area of the groin are fairly common in both CLND and TLND patients and significantly affect prognosis, especially in CLND patients. The number of superficial LNM is the only factor that was found to predict a finding of deep nodal metastases.

The oncological outcomes of isolated limb perfusion and neo-adjuvant radiotherapy in soft tissue sarcoma patients - A nationwide multicenter study.

INTRODUCTION: Patients with locally extensive high-grade extremity soft tissue sarcomas (eSTS) are often presented in multidisciplinary teams to decide between ablative surgery (amputation) or limb-salvage surgery supplemented with either neo-adjuvant radiotherapy (RT) or induction isolated limb perfusion (ILP). In The Netherlands, ILP typically aims to reduce the size of tumors that would otherwise be considered irresectable, whereas neo-adjuvant RT aims mainly at improving local control and reducing morbidity of required marginal margins. This study presents a 15-year nationwide cohort to describe the oncological outcomes of both pre-operative treatment strategies. METHODS: All consecutive patients with locally extensive primary high-grade eSTS surgically treated between 2000 and 2015 at five tertiary sarcoma centers that received neo-adjuvant ILP or RT were included. 169 patients met the inclusion criteria (89 ILP, 80 RT). Median follow-up was 7.3 years. RESULTS: Limb salvage was achieved in 84% of cases in the ILP group (80% for patients with amputation indication) and 96% of cases in the RT group. 5-Year overall survival was 47% in the ILP group, 69% in the RT group. 5-Year local recurrence rate was 14% in the ILP group, 10% in the RT group. Distant metastasis rate was 55% in the ILP group, 36% in the RT group. CONCLUSION: We find oncological outcomes and limb salvage rates in line with existing literature for both treatment modalities. Whether the tumor was locally advanced with an indication for induction therapy to prevent amputation or morbid surgery appeared to be the main determinant in choosing between neo-adjuvant ILP or RT.

Therapeutic lymph node dissection in melanoma: different prognosis for different macrometastasis sites?

BACKGROUND: The prognostic significance of primary tumor location, especially the poor prognosis for melanomas in the scalp and neck region, is well established. However, the prognosis for different sites of nodal macrometastasis has never been studied. This study investigated the prognostic value of the location of macrometastasis in terms of recurrence and survival rates after therapeutic lymph node dissection (TLND). METHODS: All consecutive FDG-PET-staged melanoma patients with palpable and cytologically proven lymph node metastases operated at our clinic between 2003 and 2011 were included. Disease-free survival and disease-specific survival (DSS) were compared for nodal metastases in the groin, axilla, and neck regions by multivariable analysis. RESULTS: A total of 149 patients underwent TLND; there were 70 groin (47 %), 57 axillary (38 %), and 22 neck (15 %) dissections. During a median follow-up of 18 (range 1-98) months, 102 patients (68 %) developed recurrent disease. Distant recurrence was the first sign of progressive disease in 78, 76, and 55 % of the groin, axilla, and neck groups, respectively (p = 0.26). Low involved/total lymph nodes (L/N) ratio (p < 0.001) and absence of extranodal growth pattern (p = 0.05) were independent predictors of a longer disease-free survival. For DSS, neck site of nodal metastasis (p = 0.02) and low L/N ratio (p < 0.001) were independent predictors of long survival. The estimated 5-year DSS for the groin, axilla, and neck sites was 28, 34, and 66 %, respectively. CONCLUSIONS: There seems significantly longer DSS after TLND for nodal macrometastases in the neck compared to axillary and groin sites, although larger series should confirm this finding.

Impact of extent of disease on 1-year healthcare costs in patients who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: retrospective observational cohort study.

BACKGROUND: The goal of this retrospective observational study was to determine the impact of the extent of peritoneal disease on 1-year healthcare costs in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). The extent of peritoneal disease, expressed by the Peritoneal Cancer Index (PCI), directly affects the complexity of CRS + HIPEC and ultimately survival outcomes. The impact of the PCI on treatment-related healthcare costs remains unknown. METHODS: Data from patients with colorectal PM who underwent CRS + HIPEC between January 2012 and November 2017 were extracted retrospectively from an institutional database. Patients were divided into four subgroups with PCI scores ranging from 0 to 20. Treatment-related costs up to 1 year after CRS + HIPEC were obtained from the financial department. Differences in costs and survival outcomes were compared using the χ2 test and Kruskal-Wallis H test. RESULTS: Seventy-three patients were included (PCI 0-5, 22 patients; PCI 6-10, 19 patients; PCI 11-15, 17 patients; PCI 16-20, 15 patients). Median (i.q.r.) costs were significantly increased for the PCI 11-15 and PCI 16-20 groups (€51 029 (42 500-58 575) and €46 548 (35 194-60 533) respectively) compared with those for the PCI 0-5 and PCI 6-10 groups (€33 856 (25 293-42 235) and €39 013 (30 519-51 334) respectively) (P = 0·009). CONCLUSION: Treatment-related healthcare costs are significantly increased among patients with extensive tumour burden (PCI score 10 or above) who undergo CRS + HIPEC for the treatment of colorectal PM.

ANTECEDENTES: El objetivo de este estudio observacional retrospectivo fue determinar el impacto de la extensión de la enfermedad peritoneal sobre los costes de atención médica al año en pacientes con metástasis peritoneales (peritoneal metastases, PM) de origen colorrectal que se someten a cirugía citorreductora con quimioterapia intraperitoneal hipertérmica (cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, CRS + HIPEC). La extensión de la enfermedad peritoneal, expresada por el índice de carcinomatosis peritoneal (peritoneal cancer index, PCI), afecta directamente a la complejidad de la CRS + HIPEC y, en última instancia, a los resultados de supervivencia. El impacto de la PCI en los costes de la atención médica relacionados con el tratamiento sigue siendo desconocido. MÉTODOS: Los datos de pacientes con PM de origen colorrectal que se sometieron a CRS + HIPEC entre enero de 2012 y noviembre de 2017 se extrajeron retrospectivamente de una base de datos institucional. Los pacientes se dividieron en cuatro subgrupos con PCI que variaron de 0 a 20. Los costes relacionados con el tratamiento hasta un año después de la CRS + HIPEC se obtuvieron del departamento financiero. Las diferencias en los costes y los resultados de supervivencia se compararon mediante los tests χ2 y de Kruskal-Wallis H. RESULTADOS: Se incluyeron 73 pacientes (PCI 0-5, 22 pacientes; PCI 6-10, 19 pacientes; PCI 11-15, 17 pacientes y PCI 16-20, 15 pacientes). Los costes medios aumentaron significativamente para los grupos PCI 11−15 y PCI 16−20 (51.029€ (rango intercuartílico, RIQ) 42.500€−58575€)) y 46.548€ (RIQ 35.194€-60.533€), respectivamente)) en comparación con los de los grupos PCI 0−5 y PCI 6-10 (33.856€ (RIQ 25.293€−42.23€) y 39.013€ (RIQ 30.519€-51.334€), respectivamente, P = 0,009). CONCLUSIÓN: Los costes de la atención médica relacionados con el tratamiento aumentan significativamente entre los pacientes con una carga tumoral extensa (es decir, PCI ≥ 10) que se someten a CRS + HIPEC para el tratamiento de PM de origen colorrectal.

S-100B concentrations predict disease-free survival in stage III melanoma patients.

BACKGROUND: Elevation of the tumor marker S-100B in melanoma patients is a highly specific indicator of recurrence. MATERIALS AND METHODS: The role of S-100B in disease-free survival (DFS) was evaluated in stage III melanoma patients (staged with fluorodeoxyglucose positron emission tomography [FDG-PET] and computed tomography [CT]) with palpable lymph node metastases who underwent therapeutic lymph node dissection. S-100B and LDH were measured on the day before surgery (d = -1) and on days 1, 2, and 7 postoperatively. Multivariate logistic regression was used to study factors associated with preoperative elevation of S-100B. Univariate (log-rank test) and multivariate (Cox regression) survival analyses were performed to identify factors associated with DFS. RESULTS: Between 2004 and 2008, 56 patients (median age 57, range 24-93) years, 27 males (48%) and 29 females (52%) entered the study. Preoperative S-100B elevation was found in 27 patients (48%) and elevated LDH in 20 patients (36%). No association was found between these two markers at any time. Multivariate analysis showed that elevated S-100B preoperatively (hazard ratio [HR] 2.7, P = .03) was associated with DFS. S-100B elevation was associated with increased tumor size (odds ratio [OR] 3.40; P = .03). CONCLUSION: Elevated S-100B preoperatively in patients with optimally staged clinical stage III melanoma is associated with decreased disease-free survival. S100-B could be used as a prognostic marker in the stratification of new adjuvant trials to select stage III melanoma patients for adjuvant systematic treatment.

Role of diagnostic laparoscopy in patients with suspicion of colorectal peritoneal metastases to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

Background: The aim of the present study was to determine the feasibility and safety of performing diagnostic laparoscopy (DLS) routinely in patients with suspicion of colorectal peritoneal metastases (PM) to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Methods: Data for consecutive patients who underwent DLS between 2012 and 2018 were extracted retrospectively from an institutional database. The primary outcome was the degree of visibility of the abdominal cavity during DLS. Good laparoscopic evaluation of the abdominal cavity was defined as visibility of at least the regions of the diaphragm, pelvis and small bowel. Secondary outcomes were reasons for perioperative exclusion for CRS + HIPEC, major postoperative complications (Clavien-Dindo grade III or above) and difference in overall survival (OS) between patients deemed suitable or unsuitable for CRS + HIPEC. Kaplan-Meier analyses were performed. Results: Some 184 patients were analysed. Good laparoscopic evaluation was possible in 138 patients (75·0 per cent), and 24 (13·0 per cent) had conversion to an open procedure. Ninety-three patients (50·5 per cent) were excluded for CRS + HIPEC, most commonly because of absence of colorectal PM (34 patients, 37 per cent) or extensive disease (Peritoneal Cancer Index 20 or above) (33 patients, 35 per cent). Major complications occurred in five patients (2·7 per cent), with no postoperative deaths. Median OS was significantly decreased in patients who were excluded due to extensive disease (14 (95 per cent c.i. 10 to 18) months) compared with patients suitable for CRS + HIPEC (36 (27 to 45) months) (P < 0·001). Conclusion: Routinely performing DLS in patients with suspicion of colorectal PM to evaluate suitability for CRS + HIPEC is feasible and safe, avoiding the morbidity of an unnecessary laparotomy in patients with extensive disease.

Antecedentes: El objetivo del presente estudio fue determinar la viabilidad y seguridad de realizar una laparoscopia diagnóstica (diagnostic laparoscopy, DLS) de rutina en pacientes con sospecha de metástasis peritoneal (peritoneal metastasis, PM) de origen colorrectal para evaluar la idoneidad para la cirugía citorreductora con quimioterapia intraperitoneal hipertérmica (cytoreductive surgery + hyperthermic intraperitoneal chemotherapy, CRS+HIPEC). Métodos: Los datos de los pacientes consecutivos que fueron sometidos a DLS entre 2012 y 2018 se obtuvieron retrospectivamente de una base de datos institucional. La visualización de al menos las regiones de los diafragmas, pelvis e intestino delgado se definió como una correcta evaluación laparoscópica de la cavidad abdominal. Los resultados secundarios fueron las complicaciones postoperatorias mayores (Clavien­Dindo grado ≥ III), razones para la exclusión perioperatoria para CRS+HIPEC y diferencia en supervivencia global (overall survival, OS) entre pacientes que se consideraron apropiados y no apropiados para CRS+HIPEC. Se realizaron análisis de Kaplan­Meier y análisis de riesgos proporcionales. Resultados: Se analizaron 181 pacientes. En 138 pacientes (75,0%) fue posible una adecuada evaluación laparoscópica, mientras que 24 casos (13%) fueron convertidos a un procedimiento abierto. Se excluyeron 93 (50,5%) pacientes para CRS+HIPEC, más comúnmente por la ausencia de PM colorrectales (36,6%) o enfermedad extensa (37,6%). En cinco pacientes aparecieron complicaciones mayores (2,7%), sin mortalidad postoperatoria. La mediana de la OS disminuyó de forma significativa en pacientes que fueron excluidos debido a enfermedad extensa (14 meses, i.c. del 95% 10­18) en comparación con pacientes idóneos para CRS+HIPEC (35 meses, i.c. del 95% 30­40, P < 0,0001). Conclusión: La realización rutinaria de DLS en pacientes con sospecha de PM de origen colorrectal para evaluar la idoneidad de la CRS+HIPEC es viable y segura. La morbilidad de una laparotomía innecesaria puede prevenirse en pacientes con enfermedad extensa o ausencia de PM colorrectales.

Insulin-like factor 3, luteinizing hormone and testosterone in testicular cancer patients: effects of ß-hCG and cancer treatment.

BACKGROUND: Primary hypogonadism (low testosterone and high luteinizing hormone, LH) is present in approximately 20% of testicular cancer (TC) survivors after orchidectomy with or without chemotherapy. OBJECTIVES: We investigated insulin-like factor 3 (INSL3), a novel marker of Leydig cell function, in TC patients. MATERIALS AND METHODS: We analyzed: (I) a cross-sectional cohort of TC patients after orchidectomy with or without chemotherapy (1988-1999) at long-term follow-up (median 36 and 35 years of age at follow-up, respectively) and healthy men of similar age; (II) a longitudinal cohort of chemotherapy-treated TC patients (2000-2008), analyzed before and 1 year after chemotherapy (median 29 years of age at chemotherapy). INSL3, testosterone, and LH were compared between groups and over time and related to pre-chemotherapy ß-hCG levels. RESULTS: In the cross-sectional cohort, TC patients at median 7 years after orchidectomy and chemotherapy (n = 79) had higher LH (p < 0.001), lower testosterone (p = 0.001), but similar INSL3 as controls (n = 40). After orchidectomy only (n = 25), higher LH (p = 0.02), but no differences in testosterone or INSL3 were observed compared to controls. In the longitudinal cohort, patients with normal pre-chemotherapy ß-hCG (≤5 mU/L, n = 35) had increased LH 1 year after chemotherapy compared to pre-chemotherapy (p = 0.001), and no change in testosterone or INSL3. In contrast, patients with high ß-hCG pre-chemotherapy (n = 42) had suppressed LH, markedly elevated testosterone, and low INSL3 at start of chemotherapy, with increased LH, decreased testosterone, and increased INSL3 1 year later (all p < 0.001). DISCUSSION: Changes in LH show that gonadal endocrine function is disturbed before chemotherapy, 1 year later, and at long-term follow-up in chemotherapy-treated TC patients. CONCLUSION: Pre-chemotherapy, ß-hCG-producing tumors affect the gonadal endocrine axis, demonstrated by increased testosterone and decreased LH. INSL3 did not uniformly follow the pattern of testosterone.

Pelvic lymph node dissection in metastatic melanoma to the groin should not be abandoned yet.

BACKGROUND: In recent years there has been a plea to abandon the pelvic lymph node dissection in the treatment of patients with metastatic melanoma to the groin. A trend towards a conservative surgical treatment is already evolving in several European countries. The purpose of this study is to identify factors associated with pelvic nodal involvement, in order to improve selection of patients whom might benefit from a pelvic nodal dissection. METHODS: A retrospective analysis was performed on prospectively collected data concerning patients who underwent an inguinal lymph node dissection (ILND) with pelvic lymph node dissection for metastatic melanoma at the University Medical Center Groningen. Multivariable logistic regression analysis was performed to determine factors associated with pelvic nodal involvement. Diagnostic accuracy was calculated for 18F-FDG PET + contrast enhanced CT-scan and 18F-FDG PET + low dose CT-scan. RESULTS: Two-hundred-and-twenty-six ILND's were performed in 223 patients. The most common histologic subtype was superficial spreading melanoma (42.6%). In patients with micrometastatic disease, 15.7% had pelvic nodal involvement vs 28.2% in patients with macrometastatic disease (p: 0.030). None of the characteristics known prior to the ILND, were associated with pelvic nodal involvement. Imaging methods were unable to accurately predict pelvic nodal involvement. Negative predictive value was 78% for 18F-FDG PET + low dose CT-scan and 86% for an 18F-FDG PET + contrast enhanced CT-scan. CONCLUSION: There are no patient- or tumor characteristics available that can predict pelvic nodal involvement in patients with melanoma metastasis to the groin. As no imaging technique is able to predict pelvic nodal involvement it seems unjust to abandon the pelvic lymph node dissection.

Image guided surgery: new technology for surgery of soft tissue and bone sarcomas.

AIM: Providing the surgical oncologist with a new means of performing safe and radical sarcoma surgery with the help of image guidance technology. METHOD: Two patients with pelvic sarcomas were operated upon with the help of an intra-operative navigation system. The technology of image guided surgery is described in one patient with a retroperitoneal sarcoma invading the bony pelvis and another patient with a chondrosarcoma of the iliac crest. RESULTS: We show that this new procedure enables optimal radical surgical resection with minimal treatment related morbidity or loss of function. CONCLUSION: Image guided surgery is a new technical tool in sarcoma surgery.

Morbidity after inguinal sentinel lymph node biopsy and completion lymph node dissection in patients with cutaneous melanoma.

BACKGROUND: Aim of the study was to assess the short-term and long-term morbidity after inguinal sentinel lymph node biopsy (SLNB) with or without completion groin dissection (GD) in patients with cutaneous melanoma. METHODS: Between 1995 and 2003, 127 inguinal SLNBs were performed for cutaneous melanoma. Sixty-six patients, median age 50 (18-77) years, met the inclusion criteria and were studied. Short-term complications were analysed retrospectively, while long-term complications were evaluated using volume measurement and range of motion measurement of the lower extremities. RESULTS: Fifty-two patients underwent SLNB alone (SLNB group) and 14 patients underwent completion groin dissection after tumour-positive SLNB (SLNB/GD group). Morbidity after SLNB alone: wound infections (n=1), seroma (n=1), postoperative bleeding (n=1), erysipelas (n=1), and slight lymphedema 6% (n=3). Morbidity after SLNB/GD: wound infections (n=4), seroma (n=1), wound necrosis (n=1), postoperative bleeding (n=1), and slight lymphedema 64% (n=9). There were differences between the two groups in the total number of short-term complications (p<0.001), volume difference (p<0.001), flexion (p=0.009), and abduction (p=0.011) limitation of the hip joint. CONCLUSION: Inguinal SLNB is accompanied with a low complication rate. However, SLNB followed by groin dissection is associated with an increased risk of wound infection and slight lymphedema.

Effects of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha and melphalan on the human fibrinolytic system.

This study was undertaken to determine the effects on systemic fibrinolysis of hyperthermic isolated limb perfusion with recombinant tumor necrosis factor alpha (r-TNF-alpha) and melphalan, with or without pretreatment with recombinant IFN-gamma (r-IFN-gamma). Twenty patients were treated with r-TNF-alpha and melphalan; four patients, treated with melphalan only, served as controls. Of the twenty patients treated with both r-TNF-alpha and melphalan, eight received r-IFN-gamma for two days before the perfusion and as a bolus into the perfusion circuit. A significant leak of r-TNF-alpha from the perfusion circuit to the systemic circulation was observed in all r-TNF-alpha-treated patients (mean maximum TNF-alpha, 87,227 ng/liter versus 31 ng/liter in controls; P < 0.002). In these patients, but not in controls, there was an almost instantaneous rise in systemic tissue plasminogen activator activity (from 0.26 to 5.28 IU/ml in 90 min), causing activation of fibrinolysis. After a delay of 90 min, plasminogen activator inhibitor-1 (PAI-1) antigen rose to high levels in the r-TNF-alpha-treated group (mean maximum PAI-1, 1652 ng/ml versus 211 ng/ml in controls; P < 0.02), associated with a sharp decrease of tissue plasminogen activator activity and a slower decrease of plasminogen-antiplasminogen complexes (from 5.28 to 0.02 IU/ml in 2 h and from 1573 to 347 micrograms/liter in 22 h, respectively). No additional effect of IFN-gamma pretreatment on fibrinolysis could be demonstrated. These results suggest that in isolated limb perfusion with r-TNF-alpha and melphalan an initial activation of systemic fibrinolysis, induced by leakage of r-TNF-alpha from the perfusion circuit, is set off by a subsequent inhibition of the fibrinolytic system by PAI-1. This large increase in PAI-1 could place the patient at risk for deposition of microthrombi in the systemic circulation.

Cytoreduction and hyperthermic intraperitoneal chemotherapy: The learning curve reassessed.

BACKGROUND: CytoReductive Surgery and Hyperthermic IntraPEritoneal Chemotherapy (CRS-HIPEC) is now the preferred treatment of many peritoneal surface malignancies. In this retrospective study we aimed to analyze how several performance indicators changed during the first 100 CRS-HIPEC procedures in hospitals which recently introduced this treatment, and compare those with an experienced institution. METHODS: The first consecutive 100 CRS-HIPEC procedures of three institutions were compared to those of the pioneer hospital. The training provided by the pioneer hospital consisted of hands-on training during the first ten procedures; hereafter guidance was available on consult basis. Operation characteristics, morbidity and completeness of cytoreduction were evaluated by case sequence. Locally-estimated-scatter-plot smoothing was used to evaluate the learning curve. RESULTS: From four institutions 372 cases were included. A macroscopic complete cytoreduction was reached in 66% of the cases in the pioneer hospital and in 86% in the new hospitals (p < 0.001). Complete cytoreduction rates were higher at start off in the new institutions compared with the experienced institution and increased significantly in the first 100 procedures. The new hospitals started with lower morbidity than the experienced hospital, which did not significantly decrease during the study period. CONCLUSION: New institutions that were trained and mentored by an experienced CRS-HIPEC hospital performed better from the beginning with regard to complete cytoreduction and morbidity rate with than the experienced center. An improvement in complete cytoreduction rate during the first 100 procedures was observed in the new institutions.

Morbidity after axillary sentinel lymph node biopsy in patients with cutaneous melanoma.

AIM: In this study, the short-term and long-term morbidity was assesed after axillary sentinel lymph node biopsy (SLNB) with or without completion axillary lymph node dissection (SLNB/ALND) in patients with cutaneous melanoma. METHODS: Between 1995 and 2003, 119 axillary SLNBs were performed for cutaneous melanoma. Fifty-eight patients met the inclusion criteria and entered the study. RESULTS: Forty-four patients underwent SLNB alone and 14 patients underwent axillary lymph node dissection after positive SLNB. Complications after SLNB alone: post-operative bleeding (n=2), seroma (n=1) and slight lymphedema 11%. Complications after SLNB/ALND: wound infections (n=2), seroma (n=5) and slight lymphedema 7%. There were differences between the two groups in short-term complications (p<.001) and functional limitations of the shoulder (p=.011). CONCLUSION: Axillary SLNB alone had a low complication rate. However, SLNB followed by completion ALND was associated with an increased risk of short- and long-term complications.

[Sentinel lymph node biopsy for melanoma: prognostic value and disadvantages in 300 patients]. / Schildwachtklierbiopsie bij het melanoom: prognostische betekenis en nadelen bij 300 patiënten.

OBJECTIVE: The aim of this study was to evaluate the advantages and disadvantages of sentinel lymph node biopsy (SLNB) in patients with cutaneous melanoma. DESIGN: Descriptive follow-up study. METHOD: In the period 1995-2004, 300 patients with cutaneous melanoma (Breslow thickness: > or = 1.0 mm) underwent SLNB and, in case of a tumour-positive result, regional lymph node dissection. Results of the SLNB procedure, postoperative complications, follow-up, recurrences, disease-free survival and disease-specific survival were evaluated. RESULTS: The SLNB detection rate was 99%. 85 patients had a tumour-positive SLNB (28%) and underwent completion regional lymph node dissection; 215 patients underwent SLNB alone. The rate of postoperative complications after SLNB was 7%. With a median follow up of 51 months, the false-negative rate was 11%. The recurrence rate was 23% (SLNB negative: 19%; SLNB positive 34%; p = 0.005). In-transit metastases were found in 4% of the SLNB-negative group and in 20% of the SLNB-positive group (p < 0.001). The 5-year disease-free survival and disease-specific survival rates were 79% and 86%, respectively, in SLNB-negative patients and 57% and 71%, respectively, in SLNB-positive patients. Multivariate analysis showed that the independent prognostic factors for disease-free survival were presence of ulceration (p < 0.001) and SLNB positivity (p < 0.01). Prognostic factors for overall survival were presence of ulceration (p < 0.001) and male sex (p < 0.05), but not the SLNB results. Multivariate analysis also showed that SLNB positivity (p < 0.001) and presence of ulceration (p < 0.01) were independent prognostic factors for developing in-transit metastases. CONCLUSION: SLNB in patients with cutaneous melanoma is still only of prognostic value since survival benefit is not proven. Disadvantages of SLNB were the false-negative rate, the possibility of an increased risk of in-transit metastases in SLNB-positive patients, and postoperative complications. These must be kept in mind when offering patients SLNB.

Feasibility and efficacy of external beam radiotherapy after hyperthermic isolated limb perfusion with TNF-alpha and melphalan for limb-saving treatment in locally advanced extremity soft-tissue sarcoma.

PURPOSE: Hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and melphalan is associated with a dramatic antitumor effect in locally advanced extremity soft-tissue sarcomas (STS). The aim of this study was to demonstrate the feasibility and efficacy of adjuvant radiotherapy after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed surgical resection. METHODS AND MATERIALS: Between 1991 and 1995, 34 patients--16 males and 18 females, median age 50 (range 18-80) years--underwent HILP for locally advanced extremity STS. Resection of the residual tumor mass was performed in most patients after 6-8 weeks. Fifteen patients with histopathological viable tumor after resection received adjuvant 60-70 Gy external beam radiotherapy (EBRT) (44%, HILP + EBRT group). Nineteen patients received HILP without adjuvant EBRT (56%, HILP-only group). Five patients in the HILP-only group had also distant metastases (15%) and received HILP as a palliative treatment. Treatment morbidity, local recurrences, and regional and distant metastases were scored. RESULTS: During a median follow-up of 34 months (range 8-54), limb salvage was achieved in 29 patients (85%): 14 patients after HILP + EBRT and 15 patients after HILP only. None of the patients from the HILP + EBRT group developed local recurrences; however, five patients from the HILP-only did (26%) (p < 0.05). Regional metastases were observed in one patient from the HILP + EBRT group (7%) and in two patients from the HILP-only group who were treated with curative intent (14%). Distant metastases occurred in four patients after HILP + EBRT (27%) and in four patients after HILP only with curative intent (29%). The mean morbidity (subjective, objective, medical management, and analytical evaluation) score in both groups was, respectively, 0.33 for skin and subcutaneous tissue and for muscle and soft tissue, 0.34 (HILP + EBRT group) and 0.33 (HILP-only group). CONCLUSION: Adjuvant EBRT after HILP with TNF-alpha, IFN-gamma, and melphalan and delayed tumor resection of locally advanced extremity STS is feasible and may increase local tumor control without increasing treatment morbidity.

PET with L-[1-carbon-11]-tyrosine to visualize tumors and measure protein synthesis rates.

UNLABELLED: We studied the potential of PET with L-[1-11C]-tyrosine (TYR) to visualize tumors outside the central nervous system and to quantify their protein synthesis rates (PSRs). METHODS: Twenty-two patients suspected of having a malignant tumor underwent a PET study with TYR before biopsy. The PSR in nanomoles per milliliter tumor tissue per minute as well as the PSR in contralateral normal tissue, standardized uptake values (SUVs) and tumor-to-nontumor-ratios (T/N ratios) were calculated. RESULTS: Fifteen of the 16 malignancies (94%) were correctly visualized as a hot spot. A chondrosarcoma of the sacrum was not visualized. Of the six patients with benign lesions, cold spots were correctly identified in four (67%). A benign schwannoma and an intramuscular hemangioma of the forearm were visualized as hot spots. PSR in tumor tissue was higher than in the corresponding contralateral normal tissues. PSR and SUV in malignant tumors were higher than in benign tumors. CONCLUSION: TYR appears to be a good tracer for imaging malignancies. The PSR, which was higher in malignant tumors than in normal tissue and the studied benign lesions, could be quantified and correlated with the SUV.

Fluorine-18-fluorodeoxyglucose PET imaging of soft-tissue sarcoma.

UNLABELLED: PET with 18F-fluoro-2-deoxy-D-glucose (FDG) was used to study soft-tissue lesions. The goals of the study were to establish FDG uptake in soft-tissue sarcoma, to determine the sensitivity of this technique, to investigate the correlation between histologic grade and glucose consumption and to determine whether FDG-PET can discriminate between benign and malignant lesions. METHODS: PET imaging was performed in 18 patients with soft-tissue sarcoma and 4 patients with a benign soft-tissue lesion. Glucose consumption in the tumors was calculated using Patlak's graphical analysis with an assumption made for the lumped constant. Standardized uptake values also were calculated. RESULTS: All soft-tissue sarcomas were clearly depicted. The median glucose consumption was 13.0 mumole/100 g/min (range 2.9-41.8 mumole/100 g/min). A correlation was found between glucose metabolism and the histopathologic malignancy grade. Such a correlation was not demonstrated for the standardized uptake values. One benign lesion was also visualized. Benign lesions were not visualized in two patients and in the remaining patient an equivocal scan was obtained. Benign lesions could be distinguished from high-grade malignant lesions but not consistently from lesions with low or intermediate malignancy grades. CONCLUSION: PET with FDG is an effective technique to visualize soft-tissue sarcomas. We found a sensitivity of 100%. There is a correlation between glucose metabolic rate and tumor malignancy grade. FDG appears to be unsuitable for discriminating benign lesions from soft-tissue sarcomas with low or intermediate malignancy grades.

L-[1-11C]-tyrosine PET to evaluate response to hyperthermic isolated limb perfusion for locally advanced soft-tissue sarcoma and skin cancer.

UNLABELLED: PET with L-[1-11C]-tyrosine (TYR) was investigated in patients undergoing hyperthermic isolated limb perfusion (HILP) with recombinant tumor necrosis factor alpha (rTNF-alpha) and melphalan for locally advanced soft-tissue sarcoma and skin cancer of the lower limb. METHODS: Seventeen patients (5 women, 12 men; age range 24-75 y; mean age 52 y) were studied. TYR PET studies were performed before HILP and 2 and 8 wk afterwards. The protein synthesis rates (PSRs) in nanomoles per milliliter per minute were calculated. After final PET studies, tumors were resected and pathologically examined. Patients with pathologically complete responses (pCR) showed no viable tumors after treatment. Those with pathologically partial responses (pPR) showed various amounts of viable tumors in the resected tumor specimens. RESULTS: Six patients (35%) showed a pCR and 11 patients (65%) showed a pPR. All tumors were depicted as hot spots on PET studies before HILP. The PSR in the pCR group at 2 and 8 wk after perfusion had decreased significantly (P < 0.05) in comparison to the PSR before HILP. A significant difference was found in PSR between the pCR and pPR groups at 2 and at 8 wk (P < 0.05). Median PSR in nonviable tumor tissue was 0.62 and ranged from 0.22 to 0.91. With a threshold PSR of 0.91, sensitivity and specificity of TYR PET were 82% and 100%, respectively. The predictive value of a PSR > 0.91 for having viable tumor after HILP was 100%, whereas the predictive value of a PSR < or = 0.91 for having nonviable tumor tissue after HILP was 75%. The 2 patients in the pPR groups with a PSR < 0.91 showed microscopic islets of tumor cells surrounded by extensive necrosis on pathological examination. CONCLUSION: Based on the calculated PSR after HILP, TYR PET gave a good indication of the pathological outcome. Inflammatory tissue after treatment did not interfere with viable tumor on the images, suggesting that it may be worthwhile to pursue TYR PET in other therapy evaluation settings.

FDG-PET to evaluate response to hyperthermic isolated limb perfusion for locally advanced soft-tissue sarcoma.

UNLABELLED: We investigated FDG-PET in patients undergoing hyperthermic isolated limb perfusion (HILP) with rTNF-alpha, rIFN-gamma and melphalan for locally advanced soft-tissue sarcoma of the extremities. METHODS: Twenty patients (11 women, 9 men; aged 18-80 yr, mean age 49 yr) were studied. FDG-PET studies were performed before, 2 and 8 wk after HILP. After the final PET study, the tumor was resected and pathologically graded. Patients with pathologically complete response (pCR) showed no viable tumor after treatment. Those with pathologically partial response (pPR) showed various amounts of viable tumor in the resected specimens. RESULTS: Seven patients showed a pCR (35%) and 12 patients showed a pPR (60%). In one patient, pathological examination was not performed (5%). The pre-perfusion glucose consumption in the pCR group was significantly higher than in the pPR group (p<0.05). Visual analysis of the PET images after perfusion showed a rim of increased FDG uptake around the core of absent FDG uptake in 12 patients. The rim signal contained a fibrous pseudocapsule with inflammatory tissue in the pCR group, viable tumor was seen in the pPR group. The glucose consumption in the pCR group at 2 and 8 wk after perfusion had decreased significantly (p<0.05) in comparison to the glucose consumption in the pPR. CONCLUSION: Based on the pretreatment glucose consumption in soft-tissue sarcomas, one could predict the probability of a patient achieving complete pathological response after HILP. FDG-PET indicated the pathological tumor response to HILP, although the lack of specificity of FDG, in terms of differentiation between an inflammatory response and viable tumor tissue, hampered the discrimination between pCR and pPR.