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Pseudomyxoma peritonei (PMP) is a rare cancer commonly originating from appendiceal neoplasms that presents with mucinous tumor spread in the peritoneal cavity. Patients with PMP are treated with curative intent by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The value of adding HIPEC to CRS has not been proven in randomized trials, and the objective of this study was to investigate the efficacy of intraperitoneal mitomycin C (MMC) and regional hyperthermia as components of this complex treatment. Xenograft tissue established from a patient with histologically high-grade PMP with signet ring cell differentiation was implanted intraperitoneally in 65 athymic nude male rats and the animals were stratified into three treatment groups; the cytoreductive surgery group (CRSG, CRS only), the normothermic group (NG, CRS and intraperitoneal chemotherapy perfusion (IPEC) with MMC at 35 ºC), and the hyperthermic group (HG, CRS and IPEC at 41 ºC). The main endpoints were survival and tumor weight at autopsy. Adequate imitation of the clinical setting and treatment approach was achieved. The median survival was 31 days in the CRSG, 60 days in NG and 67 days in HG. The median tumor weights at autopsy were 34 g in CRSG, 23 g NG and 20 g in HG. In conclusion, the addition of IPEC with MMC after CRS doubled the survival time and reduced tumor growth compared to CRS alone. Adding regional hyperthermia resulted in a modest improvement of treatment outcome.

Background In locally advanced rectal cancer (LARC), beyond total mesorectal excision (bTME) is often necessary to obtain complete resection (R0). The aim of this study was to identify prognostic determinants and compare morbidity and survival in LARC cases requiring bTME or TME surgery. Method Single centre cohort study of LARC cases where all patients received neoadjuvant radiotherapy (n = 332). Data was registered prospectively in an institutional database linked to the National Registry. Results bTME surgery was performed in 224 patients, 171 with resections of adjacent organs (bTME-o group) and 53 with pelvic side-wall resections (bTME-pw group). TME surgery was performed in 108 patients. Six deaths occurred within 100 days and severe morbidity was registered in 23.8% of the whole cohort and in 25.4% of the bTME groups. The R0 rates were 93.5%, 84.2%, and 75.5% in the TME, bTME-o, and bTME-pw groups, respectively. Five-year disease free survival (DFS) was 67.3% (TME group), 54.5% (bTME-o group) and 48.7% (bTME-pw group), and five-year overall survival (OS) 78.7%, 69.0% and 60.4% respectively. Patients with involved resection margins (R1), high pT-stage, pN-positivity or poor response to neoadjuvant therapy were associated with inferior DFS and OS. Conclusion In organ-threatening or infiltrating LARC, bTME surgery can be performed with low mortality and acceptable morbidity to obtain a good long-term outcome. Patients with pelvic side-wall infiltration were identified as a subgroup with increased risk of R1 resection and inferior long-term outcome.

MOC31PE immunotoxin was developed to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule, which is highly expressed in colorectal cancer. Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer long-term survival to patients with peritoneal metastasis from colorectal cancer (PM-CRC), most patients experience disease relapse and novel therapeutic options are needed. On this basis, MOC31PE is being developed as a novel therapeutic principle to target PM-CRC.This was a dose-escalating phase I trial to evaluate the safety and toxicity (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon intraperitoneal administration of MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with Mitomycin C. Fifteen patients received the study drug at four dose levels (3+3+3+6), administered intraperitoneally as a single dose the day after CRS-HIPEC.No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. There was negligible systemic absorption of the study drug. Drug concentrations in peritoneal fluid samples were in the cytotoxic range and increased in a dose-dependent manner. MOC31PE recovered from peritoneal cavity retained its cytotoxic activity in cell-based assays. All patients developed neutralizing antibodies.Intraperitoneal administration of MOC31PE was safe and well tolerated, and combined with low systemic uptake, MOC31PE seems ideal for local intraperitoneal treatment. The drug will be further evaluated in an ongoing phase II expansion cohort.

Pseudomyxoma peritonei (PMP) is a rare cancer commonly originating from appendiceal neoplasms that presents with mucinous tumor spread in the peritoneal cavity. Patients with PMP are treated with curative intent by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The value of adding HIPEC to CRS has not been proven in randomized trials, and the objective of this study was to investigate the efficacy of intraperitoneal mitomycin C (MMC) and regional hyperthermia as components of this complex treatment. Xenograft tissue established from a patient with histologically high-grade PMP with signet ring cell differentiation was implanted intraperitoneally in 65 athymic nude male rats and the animals were stratified into three treatment groups; the cytoreductive surgery group (CRSG, CRS only), the normothermic group (NG, CRS and intraperitoneal chemotherapy perfusion (IPEC) with MMC at 35 ºC), and the hyperthermic group (HG, CRS and IPEC at 41 ºC). The main endpoints were survival and tumor weight at autopsy. Adequate imitation of the clinical setting and treatment approach was achieved. The median survival was 31 days in the CRSG, 60 days in NG and 67 days in HG. The median tumor weights at autopsy were 34 g in CRSG, 23 g NG and 20 g in HG. In conclusion, the addition of IPEC with MMC after CRS doubled the survival time and reduced tumor growth compared to CRS alone. Adding regional hyperthermia resulted in a modest improvement of treatment outcome.

To bypass possible nuclear contamination and to exclusively amplify DNA from the mitochondrion, a set of 23 primers was selected. On the mitochondrial DNA selection fragments, a second set of fragments was used to amplify and identify mutant fractions with a detection limit of 1% . This mutation scanning method analyzed 76% of the mitochondrial genome and was used to examine 94 tumours from different tissues of origin. In all, 87 tumours had one or more mutations, leaving seven samples without observed mutations. Sanger sequencing verified samples carrying mutations with a mutant fraction exceeding 30%. The generated data validate that several regions of the mitochondrial DNA have more mutations than others.

Zinc finger E-box-binding homeobox 1 (ZEB1) is a transcriptional factor known to repress E-cadherin promoter and thus induce EMT. Expression of ZEB-1 has in numerous cancers been associated with aggressive disease and poor clinical outcome. Our aim was to investigate the expression of ZEB1 in esophageal squamous- and small-cell carcinomas. Immunohistochemical staining was performed on tissue sections obtained from 151 patients with esophageal squamous cell carcinoma (ESCC) and 25 patients with primary small-cell carcinoma of the esophagus (PSCCE). Semi-quantitative analysis, and thus statistical analysis, has been accomplished on the samples. Immunohistochemistry revealed ZEB1 expression in the cytoplasm (64.9% of cases), in nuclei (11.3% of cases) and in tumor stroma (80.1% of cases) of ESCC. In PSCCE only nuclear staining (88.0% of cases) was observed. Weak cytoplasmic expression of ZEB1 in ESCC was associated with longer survival. Immunohistochemical evaluation of ZEB1 cytoplasmic expression in ESCC may have clinical prognostic value, but further studies are needed to fully understand the function as well as potential clinical and therapeutic implications of ZEB1 expression in cancers.

Background The prognostic significance of free cancer cells detected in peritoneal fluid at the time of rectal surgery remains unclear. A substantial number of patients will develop metastatic disease even with successful local treatment. This prospective non-randomized study investigated the prognostic value of intraperitoneal free cancer cells harvested in peritoneal lavage after surgery for rectal cancer. Mutational hotspots in mitochondrial DNA were examined as potential molecular signatures to detect circulating intraperitoneal free cancer cells when present in primary tumor and in lavage. Methods Point mutations in mitochondrial DNA amplifications were determined in primary tumors and corresponding exfoliated intraperitoneal free cancer cells in lavage from 191 patients with locally advanced rectal cancer scheduled for radical treatment. Mitochondrial DNA target sequences were amplified by polymerase chain reaction and base substitutions were detected by denaturant, cycling temperature capillary electrophoresis. Detection of intraperitoneal free cancer cells was correlated to survival. Results Of 191patients analyzed, 138 (72%) were identified with somatic mitochondrial point mutations in rectal cancer tumors. From this fraction, 45 patients (33%) had positive lavage fluid with corresponding somatic mtDNA point mutations in lavage representing circulating intraperitoneal free cancer cells. There was no significant survival difference between patients identified with or without somatic mitochondrial DNA point mutations in the corresponding lavage. Conclusion Somatic mitochondrial DNA point mutations identified in primary rectal tumors enable detection of circulating intraperitoneal free cancer cells in lavage fluid. Intraperitoneal free cancer cells harvested from lavage immediately after surgery for rectal cancer does not represent an independent prognostic factor on survival.

Background and Objectives Patients with peritoneal surface malignancies are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, commonly using mitomycin C (MMC). The purpose of this study was to investigate impact of hyperthermia on pharmacokinetics of intraperitoneal MMC. Methods In 14 athymic nude male rats, microdialysis (MD) probes were implanted in jugular vein (V), hind leg muscle (M) and extraperitoneal space (XP). Probes were calibrated by retrodialysis. Intraperitonal chemotherapy perfusion (IPEC) was administered over 90 min with MMC 5 mg/kg and saline 0.9% 500 ml/kg at 35 and 41°C, defining the normothermic (NG) and hyperthermic groups (HG), respectively. MD and peritoneal perfusion fluid (PPF) samples were collected at 10 min intervals to determine MMC concentration. Results Time–concentration curves were virtually parallel between temperature groups, with equal peak concentrations (µM) of 0.3 (V), 0.7 (XP) and 0.3 (M). The following area under time–concentration curve (AUC) ratios were calculated: AUC PPF/AUC V were 69 in NG and 79 in HG (P = 0.54); AUC XP/AUC V were 2.7 in NG and 2.6 in HG (P = 0.90). Conclusions IPEC provides high intraperitoneal MMC concentration and increased bioavailability in extraperitoneal tissue, combined with low systemic absorption. Hyperthermia at 41°C did not modify MMC pharmacokinetics. J. Surg. Oncol. 2014 109:521–526. © 2013 Wiley Periodicals, Inc.

Background and purpose The novel procedure of magnetic resonance-(MR) guided histopathology was applied to determine the false-negative rate of conventional histopathologic tumor response evaluation of neoadjuvant radiation/chemoradiation therapy (RT/CRT) in organ-infiltrating rectal cancer. Materials and methods Ninety-two consecutive patients that had received RT/CRT and proceeded to extended total mesorectal excision for organ-infiltrating rectal cancer were identified from the institutional database. For each patient, the study radiologist and pathologist separately interpreted preoperative MR images and histologic preparations from the surgical specimen, to determine whether tumor down-staging had resulted. In cases of discrepancy (52 patients), histologic sections were jointly reassessed for residual tumor in areas outside the mesorectal fascial compartment, using MR images as guidance for where to inspect. Results Following RT/CRT, 67.5% of cases were found to remain ypT4, even though half of the study population had complete (ypT0; 7.6%) or near-complete (sparsely remaining tumor; 43.5%) histomorphologic tumor regression. After MR-guided histologic reassessment of surgical specimens, the false-negative rate of conventional histopathology for detection of ypT4 was determined to be 41.1%. Five-year estimate for locally recurrent disease was 12.7%. Conclusion This response data to neoadjuvant RT/CRT in organ-infiltrating rectal cancer indicate that tumor down-staging is over-estimated by conventional evaluation.

Cytoreductive surgery and intraperitoneal (i.p.) chemotherapy constitute a curative treatment option in mucinous peritoneal surface malignancies of intestinal origin, but treatment outcome is highly variable and the search for novel therapies is warranted. Immunotoxins are attractive candidates for targeted therapy in the peritoneal cavity because of direct cytotoxicity, distinct mechanisms of action and tumor cell selectivity. The MOC31PE immunotoxin targets the tumor-associated adhesion protein EpCAM (Epithelial Cell Adhesion Molecule), and has been administered safely in early clinical trials. In our work, the efficacy of i.p. administration of MOC31PE alone and together with mitomycin C (MMC) was investigated in unique animal models of human mucinous peritoneal surface malignancies. In initial model validation experiments, clear differences in efficacy were demonstrated between MMC and oxaliplatin, favoring MMC in five investigated tumor models. Subsequently, MOC31PE and MMC were given as single i.p. injections alone and in combination. In the PMCA-2 model, moderate growth inhibition was obtained with both drugs, while the combination resulted in at least additive effects; whereas the PMP-2 model was highly sensitive to both drugs separately and in combination and intermediate sensitivity was found for the PMCA-3 model. Furthermore, results from ex vivo experiments on freshly obtained mucinous tumor tissue from animals and patients suggested that classic mechanisms of immunotoxin activity were involved, i.e., inhibition of protein synthesis and induction of apoptosis. The present results suggest that adding MOC31PE to MMC-based i.p. chemotherapy should be further explored for EpCAM-expressing peritoneal surface malignancies, and a phase I trial is in preparation.

Aims To investigate the aberrant expression of CD117 in oesophageal squamous cell carcinoma (SCC) and its prognostic significance. Methods and results Immunohistochemical staining for CD117 was performed on tissue microarray and routine tissue sections from 157 oesophageal SCC patients and 10 normal oesophageal epithelia adjacent to tumour. The positive rate of CD117 expression was 29.9% in oesophageal SCC tissues, whereas no CD117 expression was detected in the 10 normal oesophageal epithelia. CD117 expression was significantly associated with T stage (P

Detection of disseminated tumour cells (DTCs) in bone marrow by immunocytochemistry (ICC) includes morphological evaluation of cytokeratin immunopositive cells. The aim of this study was to disclose the prognostic significance of different morphological categories of ICC-positive cells according to treatment status and tumour subtype. Bone marrow samples (at surgery) were analysed for the presence of cytokeratin-positive DTCs by a standard immunocytochemical method. The immunopositive cells were classified into the following categories, prior to any analysis of the association between DTCs and clinical outcome: tumour cells (TC), uninterpretable cells (UIC), hematopoietic cells (HC), and questionable HC (QHC). The analysis included 747 early breast cancer patients. Median follow-up was 84 months for relapse, and 99 months for death. The categorisation of the ICC positive cells revealed TC in 13.3 % of the patients, whereas 13.1, 17.8, and 21.4 % of the cases were positive for UIC, QHC, and HC, respectively. Analysing all patients, only TC and UIC predicted systemic relapse. Separate analysis of all patients not receiving adjuvant systemic treatment (No-Adj; n = 389) showed that only QHC were associated with reduced survival (DDFS: p = 0.008; BCSS: p = 0.004, log rank) and the presence of QHC also remained significant in multivariate analysis. Primary tumour subgroup analysis (of all patients) by hormone receptors (HR) and HER2, demonstrated that only TC/UIC had prognostic impact in the HR+/HER2- patients, whereas presence of QHC was associated with unfavourable outcome only in triple negative patients (DDFS: p = 0.004; BCSS: p = 0.024). Patients with ≥3HC had improved outcome compared to those with fewer/no HC (DDFS: p = 0.005; BCSS: p = 0.009). Hence, morphological DTC subgroups may differ in clinical significance according to primary tumour subtype and treatment status. This emphasises the importance of DTC characterisation, and separate analyses of DTC categories according to tumour subtype. Hematopoietic ("false positive") cells might predict an immune-related favorable clinical outcome.

Over-treatment of low-risk early breast cancer patients with adjuvant systemic therapies is an important clinical challenge. Better techniques are required which can be used to distinguish between the large group of patients with no residual disease after surgery and consequently no benefit of adjuvant treatment, from the smaller group with high relapse risk. A better integration of available prognostic factors might contribute to improved prediction of clinical outcome.The current study included 346 unselected pT1pN0 patients who did not receive adjuvant systemic treatment. In Norway, no patients with this stage were recommended systemic treatment at the time of the study (1995-1998). Histological type, tumour size, grade, vascular invasion (VI), hormone receptor (HR) status, HER2 and Ki67 (cut-off 10%) were analysed. Median follow-up was 86 months for relapse and 101 months for death.Thirty-eight patients experienced relapse, 31 with distant metastasis. Twenty-one patients died of breast cancer. In univariate analysis grade, HER2, HR, VI and Ki67 had impact on clinical outcome (p0.005, log rank). In multivariate analysis, only grade 1-2 vs. grade 3, HER2, VI, and Ki67 status were significant for disease free survival, distant disease free survival, and/or breast cancer specific survival. These factors were used in combination, to separate patients into groups based on the number of unfavourable factors present [combined prognostic score (CPS) 0-4]. Close to 2/3 of the patients (61.4%) had no unfavourable factor (CPS0), whilst 18.4% had CPS ≥ 2. Only 3.6% of those with CPS0 developed metastasis (p0.001). The outcome was clearly worse for patients with CPS ≥ 2 (p0.001), systemic relapse was detected in approximately 40%.This study indicates that the combined use of grade, VI, HER2 and Ki67 identifies a subgroup of breast cancer patients with a relapse risk that may question the benefit of adjuvant systemic therapy.

Aims Vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR-1) and VEGF receptor 2 (VEGFR-2) play a role in breast cancer growth and angiogenesis. We examined the expression and relationship with clinical outcome and other prognostic factors. Methods and results Tumour sections from 468 breast cancer patients were immunostained for VEGF, VEGFR-1, and VEGFR-2, and their relationships with tumour vascularity, disseminated tumour cells (DTCs) in bone marrow and other clinicopathological parameters were evaluated. VEGF, VEGFR-1 and VEGFR-2 immunoreactivities were observed in invasive breast carcinoma cells. VEGF expression was significantly associated with VEGFR-1 and VEGFR-2 expression (P Conclusions High-level expression of VEGFR-1 indicates reduced survival. Higher-level expression of VEGFR-1 or VEGFR-2 in primary breast carcinomas combined with the presence of DTC selects a prognostically unfavourable patient group.

Objectives: To assess the expression of the cell surface protein B7-H3 in prostate cancer, and its association to clinically relevant parameters after radical prostatectomy and to the proliferation marker Ki-67. Methods: Radical prostatectomy specimens from a cohort of 130 patients with a median clinical follow up of 8 years were used for the analysis. The expression of B7-H3 and the proliferation marker Ki-67, as well as other standard clinicopathological parameters, were evaluated. Results: A high expression of B7-H3 was associated with pathological stage T3a and T3b, high Gleason score, extraprostatic extension, seminal vesicle invasion and high proliferative activity. Univariable analysis showed that a high expression level of B7-H3 was also correlated with biochemical failure and clinical relapse, and with the expression of Ki-67. A high expression level of Ki-67 was associated with clinical progression and a tendency towards higher rates of prostate-specific antigen relapse in multivariate analyses. Conclusions: Our findings show that a high expression level of B7-H3 in prostate cancer correlates with the expression of the proliferation marker Ki-67, biochemical failure and clinical relapse. Thus, expression of the cell surface molecule B7-H3 adds to the malignant phenotype of prostate cancer cells expressing high levels of Ki-67. The impact of B7-H3 function on prostate cancer and its potential role in immunotherapy should be explored further.

Aim This study investigated whether total mesorectal excision (TME), when carried out at the original operation for rectal cancer, influenced the effectiveness of subsequent salvage treatment for pelvic recurrence. Method Between September 1990 and January 2006, 124 patients underwent radiotherapy and salvage surgery at the Norwegian Radium Hospital for locally recurrent rectal cancer without known distant metastases. Most of the primary operations had been performed at other hospitals: 62 patients had undergone a non-TME procedure (most operations in this group of patients were carried out before 1994); and 62 patients had undergone a TME procedure (all operations in this group of patients were carried out after 1992). In the TME group, 17 patients also received radiosensitizing chemotherapy. Results A lower proportion of primary abdominoperineal resection and more sensitizing chemotherapy seemed to be to the advantage of the TME group, while a higher frequency of intra-operative radiotherapy might be beneficial in the non-TME group. The 5-year survival and R0 stage achievement were 30/24% and 44/40% for non-TME/TME groups. The local re-recurrence rates were nearly identical, at around 50%, for both groups. There was no change in R stage over time. Conclusion A primary operation which includes TME does not reduce the effectiveness of subsequent salvage treatment for locally recurrent rectal cancer.

Background and purpose Radiotherapy (RT) remains the cornerstone of management of spine metastases (SM), even though surgery is a well-established treatment for selected patients. We compared the use of RT and surgery in a population-based cohort of patients with SM, investigated pre-treatment factors that were associated with use of these treatment modalities, and examined survival. Patients and methods 903 patients in the south-eastern Norway who were admitted for RT or surgery for SM for the first time during an 18-month period in 2007–2008 were identified and their medical records were reviewed. Results The primary treatment was surgery in 58 patients and RT in 845 patients, including 704 multiple-fraction (MF) and 141 single-fraction (SF) RT schedules. 11 of 607 patients without motor impairment (2%) and 47 of 274 patients with motor impairment (17%) underwent primary operations. 11 of 58 operated patients and 244 of 845 irradiated patients died within 2 months after the start of treatment. 26% of th...

Purpose Tumor response of rectal cancer to preoperative chemoradiotherapy (CRT) varies considerably. In experimental tumor models and clinical radiotherapy, activity of particular subsets of kinase signaling pathways seems to predict radiation response. This study aimed to determine whether tumor kinase activity profiles might predict tumor response to preoperative CRT in locally advanced rectal cancer (LARC). Methods and Materials Sixty-seven LARC patients were treated with a CRT regimen consisting of radiotherapy, fluorouracil, and, where possible, oxaliplatin. Pretreatment tumor biopsy specimens were analyzed using microarrays with kinase substrates, and the resulting substrate phosphorylation patterns were correlated with tumor response to preoperative treatment as assessed by histomorphologic tumor regression grade (TRG). A predictive model for TRG scores from phosphosubstrate signatures was obtained by partial-least-squares discriminant analysis. Prediction performance was evaluated by leave-one-out cross-validation and use of an independent test set. Results In the patient population, 73% and 15% were scored as good responders (TRG 1–2) or intermediate responders (TRG 3), whereas 12% were assessed as poor responders (TRG 4–5). In a subset of 7 poor responders and 12 good responders, treatment outcome was correctly predicted for 95%. Application of the prediction model on the remaining patient samples resulted in correct prediction for 85%. Phosphosubstrate signatures generated by poor-responding tumors indicated high kinase activity, which was inhibited by the kinase inhibitor sunitinib, and several discriminating phosphosubstrates represented proteins derived from signaling pathways implicated in radioresistance. Conclusions Multiplex kinase activity profiling may identify functional biomarkers predictive of tumor response to preoperative CRT in LARC.

Background. Peritoneal metastasis (PM) from colorectal cancer (CRC) is associated with poor outcome, but in patients with resectable disease long-term survival through cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can be achieved. The dual rationale for applying intraperitoneal therapy in PM-CRC is dose intensification because of the peritoneal-plasma barrier and the conception of PM as a localized disease within the peritoneal cavity. Outcome following CRS-HIPEC is however highly variable and most patients will experience disease recurrence, illustrating the need for improved treatment. MOC31PE immunotoxin, composed of the monoclonal antibody MOC31 and pseudomonas exotoxin A (PE), was developed by researchers at the Norwegian Radium Hospital to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule (EpCAM), which is highly expressed in CRC. In the ImmunoPeCa trial we investigated the use of intraperitoneal MOC31PE as a novel therapeutic principle to target PM-CRC. Methods. The ImmunoPeCa trial was a dose-escalating phase I trial to evaluate the safety and tolerability (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon a single dose of intraperitoneal MOC31PE in patients with PM-CRC undergoing CRS-HIPEC. Overall survival (OS) and disease-free survival (DFS) were also examined (secondary endpoints). Fifteen patients received the study drug at four dose levels (2.5 (n=3), 5.0 (n=3), 7.5 (n=3) and 10 (n=6) µg kg). Additional 6 patients, constituting an expansion cohort, were treated on dose level 4 (10 µg/kg). Results. There was no major toxicity, and the maximum tolerated dose was not reached. The systemic drug exposure was low, and MOC31PE in peritoneal fluid samples retained cytotoxic capacity, suggesting that the drug is very stable under physiological conditions. With a median follow-up of 29 months (95% CI 22-35 months), the median OS was not reached and the estimated 3-year OS was 85%. Estimated median DFS was 20 months (95% CI 8-33 months) and the estimated 3-year DFS was 36%, with a median follow-up of 25 months (95% CI 19-31 months). Although very encouraging, the results may reflect the selection of the cohort, and investigation in a larger cohort would be necessary to study efficacy. Conclusions. Intraperitoneal, perioperative administration of MOC31PE was safe and well tolerated. The promising long-term outcome combined with the low systemic uptake and retained cytotoxic activity in peritoneal fluid samples support further clinical testing. Citation Format: Ida S. Froysnes, Yvonne Andersson, Stein Larsen, Ben Davidson, Janne-Merete T. Oien, Kari H. Olsen, Karl-Erik Giercksky, Lars Julsrud, Oystein Fodstad, Svein Dueland, Kjersti Flatmark. Novel treatment with intraperitoneal MOC31PE immunotoxin in colorectal peritoneal metastasis: Long-term outcome from the ImmunoPeCa phase I/II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT094.

Background and Aims: A significant change in the occurrence of oesophageal squamous cell carcinomas (SCCs) in relation to adenocarcinomas (ACs) has been observed in the Norwegian population during the last 20 years (1988–2007). The AC incidence has increased from 5–10% to more than 50% nowadays, while the incidence of SCCs has decreased. Our goal was to evaluate if the change from SCC to AC and the increased effort to control reflux could be reflected in tumour stage, patient demographics and treatment results. Material and Methods: We analysed clinical and pathological data from 347 patients with oesophageal AC (n = 189) and SCC (n = 158) treated at The Norwegian Radium Hospital during said period for patient- and tumour characteristics, treatment modalities and survival. Results: An oesophageal resection was performed in 169 of 347 patients. The median survival rate for all patients was 15 months, with a 5-year survival rate of 10%. The median survival time for operated and non-operated patients was 25 and 12 months respectively, with the corresponding 5-year survival rate of 13% and 2%. Patients with N0M0 disease operated with free resection margins presented a 5-year survival rate of 28%. Conclusions: The change from SCC to AC and the ensuing considerable efforts made in surveillance and treatment of AC did not lead to improved long time survival for our patients.

Objective To compare the clinical ability of MRl taken before and after neo-adjuvant treatment in locally advanced rectal cancer (LARC) to predict the necessary extension of TME (ETME) and the possibility to achieve a R0 resection. Method Prospective registration of 92 MRI evaluated T4a cancers undergoing elective surgery between 2002 and 2007 in a tertiary referral centre for multimodal treatment of rectal cancer. Results MRI identified patients in need of neo-adjuvant treatment and predicted T-downstaging in 10% and N-downstaging in 59%. Seventy-nine percent R0 resections, 18% R1 and 3% R2 were obtained after ETME in 95% of the patients and TME in the rest. Higher tumour regression grade (TRG) was achieved in higher ypT-stage (P

A total of 32 Wistar rats were given 1, 10, 100 and 1000 mg glove powder (Biosorb) intraperitoneally for 4, 11, 18 or 25 days. Four control rats received physiological saline. Examination of the abdominal cavity displayed granulomatous inflammation which was clearly dose-dependent in the experimental animal, but not in the controls. A biphasic time-sequence of the granulomatous reaction was observed in those rats receiving 100 and 1000 mg Biosorb with a minimum at day 18. The mean size of the granules (8.1 microns) within the inflammatory tissue was almost identical with the size of powder granules found on the external surface of the gloves (8.8 microns). X-ray microanalysis demonstrated maize-starch additives of magnesium and aluminium. The study indicates a foreign body reaction to maize-starch. In addition, immunological factors may play a role later in the development of the disease.

Twenty-one young, splenectomized, healthy individuals (S group) and ten healthy individuals (K group) were vaccinated with a 14-valent pneumococcal polysaccharide vaccine. All individuals in the S group were splenectomized due to abdominal trauma. IgM and IgG antibodies against each of the 14 pneumococcal serotypes were determined by enzyme-linked immunosorbent assay. Serum concentrations of IgM and IgG were measured by radial immunodiffusion. The mean prevaccination IgM pneumococcal antibody level was lower in the S group than in the K group for most of the serotypes. The mean total serum IgM was considerably reduced in the S group. Vaccination induced a significant IgM pneumococcal antibody response in both groups, but the response tended to be smaller in the S than in the K group. These findings may appear compatible with suboptimal immune regulation in the splenectomized individuals. There were small variations between the total serum IgG and the prevaccination IgG pneumococcal antibody level in the two groups. Both groups obtained a significant IgG pneumococcal antibody response after vaccination to most of the serotypes.

Introduction Laparoscopic adrenalectomy for metastases is considered controversial. Multicenter retrospective study was performed to gain new knowledge in this issue. Materials and Methods From January 1997 till November 2008, 41 adrenalectomies were performed during follow-up of the patients operated for malignant tumors. The median age was 64 (52–77) years. Metastases were confirmed in 31/41 cases. Metastatic lesions were further studied and to define factors influencing on survival, patients were divided to sub-groups of metachronous/synchronous, tumor origin and tumor size. Results The median operative time was 104 (50–230) min, the median blood loss was 100 (0–500) ml. One procedure (3.2%) was converted. There were 3 (10.7%) intraoperative and 2 (7.4%) postoperative complications. The median tumor size was 6 (1.5–16) cm. Pathohistological analysis revealed 12 colorectal, 9 renal cell carcinoma, 5 lung carcinoma, 4 melanoma, and 1 hepatocellular metastases. The resection margin was not free in one case (3.7%). The median hospital stay was 2 (1–21) days. The median length of survival was 29 ± 2.1 months for all patients. Conclusion Laparoscopic adrenalectomy for metastases is feasible regardless of their sizes. However these procedures should be performed by highly skilled laparoscopic surgeon in a fully equipped operating room and with a coordinated operation team. J. Surg. Oncol. 2009;100:43–47. © 2009 Wiley-Liss, Inc.

Homogenates of several rat and human adipose tissues contain procoagulant activity mainly due to the presence of tissue thromboplastin. Intravenous injections in rats of the active fraction from such homogenates cause the accumulation of 51Cr-labelled platelets and 125I-labelled fibrin in the lungs. The effect of phospholipase C and of specific antibodies against tissue thromboplastin on this procoagulant activity of adipose tissue has been studied in vitro and in vivo.

Rat blood platelets were treated with phospholipase C in vitro or phospholipase C was injected i.v. to rats. In both cases its effect on the functions of the platelets in vivo has been studied. No change was found in primary bleeding time or in platelet survival. Treatment with phospholipase C gave a moderate reduction of ADP-induced platelet aggregation in the pulmonary circulation whereas the aggregation induced by thrombin was unchanged. I.v. injection of phospholipase C caused a rapid, very moderate and transient increase of 51Cr-activity in the lungs without concomitant overt respiratory distress. A moderate increase in 51Cr-activity was noted in liver and kidney 24 and 48 h after injection of phospholipase C. This may be caused by a slightly increased leakage of 51Cr-labelled material from the platelets during exposure to phospholipase C.

Objective: Seprase, dipeptidyl peptidase IV (DPPIV) and urokinase-type plasminogen activator (uPA) play a crucial role in the degradation of the extracellular matrix and in the progression of various human tumors. However, their pathophysiologic significance in esophageal carcinoma has not yet been fully elucidated. Methods: The expression of seprase, DPPIV and uPA in esophageal dysplasia, squamous cell carcinoma (SCC) and normal epithelium was examined by immunohistochemistry. Results: Seprase, DPPIV and uPA immunoreactivity was found in dysplastic and cancer cells as well as in stromal cells adjacent to dysplasia and cancer sites, but not in normal epithelium. We found a significant association between uPA expression and sex, tumor size and histological classification in carcinomas. High expression of DPPIV in cancer cells correlated with longer survival of the patients. No significant associations between seprase and clinicopathological features either in dysplasia or in carcinomas were found. Finally, we demonstrated higher levels of seprase, DPPIV and uPA in SCC cell lines than in normal esophageal epithelial cell lines. Conclusions: Our results showed that seprase, DPPIV and uPA are expressed in both premalignant and malignant forms of SCC, but are lacking in normal esophageal epithelia, suggesting that they are involved in SCC neoplastic progression.

Aims This non-randomised study was undertaken to examine oxaliplatin as possibly an intensifying component of sequential neoadjuvant therapy in locally advanced rectal cancer for improved local and metastatic outcome. Materials and methods Ninety-seven patients (57 T2–3 cases, 40 T4 cases) received two cycles of the Nordic FLOX regimen (oxaliplatin 85 mg/m 2 day 1 and bolus 5-fluorouracil 500 mg/m 2 and folinic acid 100 mg days 1 and 2) before long-course chemoradiotherapy with concomitant oxaliplatin and capecitabine, followed by pelvic surgery. Treatment toxicity, local tumour response and long-term outcome were recorded. Results Good histologic tumour regression was obtained in 72% of patients. Implementing protocol-specific dose adjustments, tolerance was acceptable and 95% of patients received the total prescribed radiation dose. Estimated 5 year progression-free and overall survival were 61% and 83%, respectively. T4 stage was associated with an inferior local response rate, which again was highly associated with impaired long-term outcome. Conclusions In this cohort of rectal cancer patients dominated by T4 and advanced T3 cases given sequential oxaliplatin-containing preoperative therapy with acceptable toxicity, high tumour response rates and overall survival were obtained, consistent with both local and systemic effects. However, tumour response and long-term outcome remained inferior for a significant number of T4 cases, suggesting that the T4 entity is biologically heterogeneous with subgroups of patients eligible for further individualisation of therapy.

Despite advanced diagnostics and multimodal treatments, the overall 5-year survival rate for patients with esophageal cancer remains low. In the past, several specific antibodies, including tyrosine kinase inhibitors, targeting different steps of carcinogenesis were investigated. We examined two receptor tyrosine kinases, platelet-derived growth factor receptor (PDGFR-α) and mast/stem cell growth factor receptor (CD117) in esophageal carcinomas.Tissue samples of 52 Norwegian patients who underwent esophagectomy were examined using immunohistochemistry.PDGFR-α and CD117 expression was observed in cancer cells in all samples of both carcinoma types. A higher PDGFR-α immunoreactivity was detected in the squamous cell carcinoma group (p=0.032). Surprisingly, a higher number of PDGFR-α-positive cells in the analyzed samples for the entire population was associated with longer survival (p=0.05).The findings of our study need to be further validated as we examined a low number of patients. Both PDGFR-α and CD117 probably play an important role in the progression of esophageal carcinoma, and they may possibly be targets for biological anticancer therapy in the future.

Objective Reports of multimodal treatment regimens especially focusing on locally advanced or recurrent rectal cancer in the elderly, aged > 75 years, are unavailable. We have tried to identify and evaluate pre- and peri-operative risk factors for morbidity and mortality and outcome after irradiation/surgery regimens in such patients. Patients and methods Prospective registration of 86 consecutive patients aged > 75 years undergoing elective surgery after irradiation 46–50 Gy for either primary locally advanced rectal cancer (n = 51) or recurrent rectal cancer (n = 35) from January 1991 to August 2003, 51 men and 35 women, median age 78 years (range 75–85 years) in a national cancer hospital. Results Multivisceral resections were needed in 63% of patients and 70% R0 resections were obtained in locally advanced cases and 46% in recurrent ones. Both in-hospital- and 30-day-mortality was 3.5%. Sixty-two postoperative complications occurred in 38 patients, three of them fatal. Both operation times over 5 h and transfusion of more than 3 SAG were prognostic factors regarding infections. Estimated five-year survival in R0 patients was 46%. Estimated five-year survival for patients with nonmetastatic tumours with locally advanced primary cancer was 29% and for locally recurrent rectal cancer 32%. Old males had a higher mortality rate the first year after surgery than females with only 65% relative survival compared to a matched normal population. The estimated five-year local recurrence rates were 24% for R0 resections and 54% for R1 resections (P = 0.434 ns) and 24% and 45% for locally advanced and recurrent rectal cancer (P = 0.248 ns), respectively. Conclusion Thorough pre-operative evaluation and preparation and judicious surgery are important for achieving potentially curative treatment with acceptable morbidity in locally advanced and recurrent rectal cancer in patients over 75 years of age. We suggest that these patients should be evaluated and considered for treatment by multidisciplinary teams as younger patients.

To optimize the indication for sentinel lymph node (SLN) biopsy according to tumour size in penile carcinoma.This was a retrospective analysis of 23 consecutive patients (median age 65 years; range 49-85 years) with primary penile carcinoma classified according to the TNM classification as stage T1-T3 who were identified as having SLNs in the groins. SLNs were detected by means of preoperative injection of a 99mTc nanocolloid around the tumour and peroperative use of a gamma detector probe. The average tumour size was 2.9+/-1.3 cm.In 7/25 patients with penile carcinoma examined with the SLN method, metastases to inguinal lymph nodes could be demonstrated. Two out of three patients with primary penile carcinomas classified as T1 according to the TNM classification and tumours3 cm in diameter had inguinal lymph node metastases. One of the patients had a micrometastasis, which was detected by means of immunohistochemical analysis. Seven out of eight patients with penile carcinomas3 cm in diameter had lymph node metastases. We did not observe any major surgical complications associated with the SLN procedure.These data indicate that penile carcinomas with a diameter of3 cm should be investigated with SLN biopsy regardless of stage. However, multicentre studies are needed in order to obtain the appropriate number of patients.

Background After multimodal treatment estimated 5-year survival of locally recurrent rectal cancer is about 25%. Hydronephrosis secondary to pelvic recurrence of colorectal cancer is a condition claimed to represent a contraindication to surgery due to a dismal prognosis. Methods Prospective registration of 193 consecutive patients operated for pelvic recurrence in rectal or colon cancer from January 1991 until March 2002 at a tertiary referral hospital, 121 men and 72 women, median age 67 years, all given irradiation preoperatively. Twenty-three of 193 had hydronephrosis prior to preoperative irradiation for recurrent disease. Results R-0 stage resection was obtained in 22% of patients with hydronephrosis and in 41% without. The median survival times in patients without metastasis were 27 and 32 months, respectively, and 5-year survival rates were 11% and 25%. Conclusions An aggressive surgical approach offers patients with pelvic recurrence from rectal and colon cancer the best potential for survival. The presence of hydronephrosis probably indicates a lower chance for complete surgical resection of the recurrence, but local control and improved survival may still be achieved, and about two thirds of patients may benefit from the operation.

A large number of DNA single-nucleotide polymorphisms (SNPs) have been discovered following the Human Genome Project. Several projects have been launched to find associations between SNPs and various disease cohorts. This study examined the possible association between the reported SNPs and sporadic rectal cancer. It has been proposed that SNPs in the ataxi-telangiectasia mutated (ATM) gene modulate the penetrance of some cancers. The investigated target sequence harbors three polymorphisms (IVS38-8 T/C in intron 38, 5557 G/A and 5558 A/T in exon 39), resulting in eight possible microhaplotypes at the DNA level. Furthermore, the two exonic SNPs are sited next to each other, allowing four possible amino acids in the same codon. We report on a new method analyzing SNPs and microhaplotypes based on theoretical thermodynamics and migration of variant fragments by cycling temperature capillary electrophoresis. Fluorophore-labeled PCR products were analyzed without any post-PCR steps on a standard 96 capillary-sequencing instrument under denaturing conditions. More than 7000 alleles were microhaplotyped based on peak migration patterns of individual samples and sequencing results. The ATM polymorphisms and microhaplotypes examined did not significantly differ between sporadic rectal cancer and normal population. No associations were found between the IVS38-8 T/C, 5557 G/A and 5558 A/T polymorphisms and microhaplotypes in the ATM gene with respect to sporadic rectal cancer.

Aim: Three papers including five patients have described en bloc radical prostatectomy for locally advanced rectal cancer. Methods: Six patients (median age 63 years) underwent en bloc radical prostatectomy for locally advanced (3) or recurrent (3) rectal cancer involving the prostate. Quality of life questionnaires were answered postoperatively and the data prospectively entered in a database. Results: One primary case had low anterior resection (LAR), the others abdominoperineal resections (APR) of R0 stage. Two recurrent cases had APRs and one tumour resection—all R1 stage. Anastomotic leakage led to construction of an ileal conduit in one patient and in two healed on conservative treatment. Follow up was 10–50 months. One patient died from distant metastases at 29 months postoperatively, one was operated for a single lung metastasis and one has disseminated lung metastases. None has developed local recurrence. Four of the five with anastomoses had good quality of life and none wanted an ileal conduit. Conclusion: In spite of a relatively high urinary leak rate the total complication rate seems to be lower than after pelvic exenteration. En bloc radical prostatectomy seems an option in selected patients otherwise needing pelvic exenteration for locally advanced or recurrent rectal cancer.

Over the past few decades, advances in genetics and molecular biology have revolutionized our understanding of cancer initiation and progression. Molecular progression models outlining genetic events have been developed for many solid tumors, including colon cancer. Previous reports in the literature have shown a relationship between different KRAS mutations and prognosis and response to medical treatment in colon cancer patients. Furthermore, the presence of a mutated KRAS has been correlated with different clinicopathological variables including age and gender of patients and tumor location. To our knowledge, few institutions screen for KRAS mutations on regular basis in colon cancer patients despite such evidence that knowledge of KRAS exon 1 status is informative. Here, we report on a mutation analysis method adapted to a 96-capillary electrophoresis instrument that allows identification of all 12 oncogenic mutations in KRAS exon 1 under denaturing conditions. To determine the optimal parameters, a series of DNA constructs generated by site-directed mutagenesis was analyzed and the migration times of all mutant peaks were measured. A classification tree was then made based on the differences in migration time between the mutants and an internal standard. A randomized series of 500 samples constructed with mutagenesis as well as 60 blind samples from sporadic colon carcinomas was analyzed to test the method. No wild-type samples were scored as mutants and all mutants were correctly identified. Post polymerase chain reaction (PCR) analysis time of 96 samples was performed within 40 min.

The authors describe a method in which the population frequency of single-nucleotide polymorphisms (SNPs) can be efficiently detected and their allele frequencies accurately measured. Selected SNPs in TNFbeta, IL-4, and CTLA-4 were used to demonstrate the method. Blood from 4000 individuals was pooled, DNA was extracted, and target sequences were PCR amplified and analyzed by denaturant capillary electrophoresis. Alleles were separated into peaks based on melting properties of the double DNA helix. Frequencies of the different alleles were determined by calculating the area under the peaks. Allele frequencies and Hardy-Weinberg equilibrium estimated from the pooled data were verified by analyzing 7.5% of the samples randomly selected from the blood donor series. The method herein is equally suitable for single-samples and/or pooled-samples analysis of SNPs, in which sample treatment is kept to a minimum. The potential throughput of the method is beyond obtainable numbers of samples.

Objective Determine the significance of recovering yeasts from intraoperative specimens from the abdominal cavity and to evaluate the effect of a single intraoperative dose of fluconazole on clinical outcome in patients with intra-abdominal perforations. Design Prospective, randomized, double-blind study. Setting Multicenter study from 13 hospitals in Norway. Patients One hundred nine patients with intra-abdominal perforations. Interventions Patients were randomized to receive either a single 400-mg fluconazole dose or placebo during the operation. Measurements and main results An intra-abdominal specimen for microbiological culture was obtained at the time of the operation. The primary response variable in the study was death. Secondary response variables were three parameters indicating a complicated postoperative period: mechanical ventilation for > or = 5 days, intensive care treatment for > or = 10 days, and use of a central venous catheter for > or = 10 days. Yeasts were recovered from a intraoperative intra-abdominal specimen from only 1 (3.5%) of 28 patients with perforated appendicitis and from 32 (39.5%) of 81 nonappendicitis patients. Excluding the appendicitis patients, the yeast recovery rate was high both for patients hospitalized at the time of the perforation (45%) and for nonhospitalized patients (32%). The overall mortality was 11% (12 patients). Single-dose intraoperative fluconazole prophylaxis did not reach a statistically significant effect on mortality (4 of 53 patients in the fluconazole group and 8 of 56 patients in the placebo group died [p = .059]). The only two explanatory variables significantly related to death were a intraoperative finding of yeast from an intra-abdominal specimen and the occurrence of a spontaneous perforation in a patient already hospitalized for nonsurgical cancer treatment. Detection of yeast was also a significant explanatory variable for a prolonged period of mechanical ventilation, intensive care treatment, and prolonged use of a central venous catheter. Conclusions Single-dose intraoperative fluconazole prophylaxis did not have a statistically significant effect on overall mortality (odds ratio = 0.21; 95% confidence interval, 0.04-1.06; p = .059) in patients with intra-abdominal perforation. The recovery rate of yeast from intraoperative specimens from the abdominal cavity was high (>30%) and was associated with death and a complicated postoperative course.

Background : The therapeutic gain of surgery for recurrent rectal cancer is not clear, particularly with regard to the addition of intraoperative radiotherapy (IORT). Methods : Patients (107) with isolated pelvic recurrence of rectal cancer received preoperative external radiotherapy of 46–50 in 2 Gy fractions. At surgery 59 patients had IORT 12–18 Gy. Survival and local recurrence was analysed with regard to surgical resection stages and IORT. Results : Patients (44) had R0- and 39 R1-resections, 24 R2-resections or exploratory laparotomy. IORT was given most often after R1-resections, least in R0-patients. Estimated 5-year survival was overall around 30%, around 60% in the R0-, around 25% for R1- and 0% in R2-patients. Local recurrence was around 30% in the R0- and around 65% in R1-stage patients. R0-/R1-stage patients survived statistically significantly longer than the R2-group otherwise there was no statistical significant difference between IORT and non-IORT groups in any R-stages regarding overall survival or local recurrence. Conclusions : Macroscopic removal of the recurrence improves survival. Whether R0- is better than R1-resections is not clear. The effect of IORT is not a major one. IORT need be evaluated in randomised controlled trials.

Intraoperative radiotherapy (IORT) has been given for primary and locally recurrent rectal cancer for 30 years. Still, its effect is not clear.PubMed and EMBASE search for papers after 1989 on surgical treatment and external beam radiotherapy (EBRT) for primary advanced and locally recurrent rectal cancer, with and without IORT. From each center the most recent paper was generally selected. Survival and local recurrence at five years was tabulated for the total groups and separate R-stages. Also, the technique for IORT, use of EBRT and chemotherapy as well as surgical approach was registered.In primary cancer 18 papers from 14 centers were tabulated, including one randomized and five internally comparing studies, as well as seven studies without IORT. In locally recurrent cancer 18 papers from 13 centers were tabulated, including four internally comparing studies and also five without IORT. Overall survival (OS) and local recurrence rate (LRR) were higher for primary cancer compared to recurrent cancer. Patients with R0 resections had better outcome than patients with R1 or R2 resections. For primary cancer OS and LR rate of the total groups and R0 stages was not influenced by IORT. An effect on R1/R2 stages cannot be excluded. The only randomized study (primary cancer) did not show any effect of IORT.IORT does not convincingly improve OS and LR rate for primary and locally recurrent rectal cancer. If there is an effect of IORT, it is small and cannot be shown outside randomized studies analyzing the separate R stages.

The potential for cyclo-oxygenase inhibition in cancer prevention and treatment is founded on epidemiology (reduction of colorectal cancer in aspirin users), animal experiments and molecular genetics. Trials using the NSAID sulindac also reduced the number of polyps in patients with familial adenomatous polyposis, but the well-known gastrointestinal toxic effects of aspirin and NSAIDs have discouraged the exploitation of their antineoplastic potential. The advent of specific COX-2 inhibitors, which do not interfere with the cytoprotective constitutive COX-1 enzyme, and the demonstration of increased COX-2 expression in many common malignancies beside colorectal cancer, has opened up new therapeutic possibilities. Recently a non-cyclo-oxygenase effect of COX-2 inhibitors, which combines the PPARdelta and the APC tumour suppressor activity, was also demonstrated. The selective COX-2 inhibitor celecoxib has been approved by the FDA for adjuvant treatment of familial adenomatous polyposis, and a large number of prevention and treatment trials of colorectal and other common cancers (prostate and breast cancer) have been started.

Topical photodynamic therapy (PDT) of superficial basal cell carcinoma (BCC) with 5-aminolevulinic acid (ALA) has achieved promising clinical results. However, the efficacy of this therapy for thick BCC is dramatically decreased by a limited diffusion of hydrophilic ALA into the tumor. Lipophilic esters of ALA may enhance their penetration into the lesion. In this randomized, open clinical study, microscopic fluorescence photometry incorporating a light-sensitive thermo-electrically cooled charge-coupled device (CCD) camera was employed to investigate the penetration of methyl 5-aminolevulinate-induced porphyrin fluorescence in thick BCC lesions. Both the distribution pattern and the amount of porphyrins in 32 lesions of 16 patients were studied after topical application of 16, 80 or 160 mg/g of methyl 5-aminolevulinate for 3 or 18 h. A highly selective and homogeneous distribution of methyl 5-aminolevulinate-induced porphyrin fluorescence was seen in all lesions studied, with much less fluorescence in the adjacent normal skin tissues. In lesions of up to 2 mm thickness the application of 160 mg/g methyl 5-aminolevulinate for 3 h showed the highest ratio of porphyrin fluorescence depth to tumor depth (0.98+/-0.04), thus providing a biologic rationale for a clinical PDT trial with this regimen.

A prospective study was conducted to determine (i) the degree of yeast colonization in surgical patients with intra-abdominal perforations and (ii) whether the frequency of colonization is different in patients with a complicated postoperative course than in patients recovering uneventfully. A total of 1,496 specimens taken per- and post-operatively from the mouth, stomach, feces, urine, trachea, and abdomen of 109 surgical patients with intra-abdominal perforations were examined. Yeast was recovered from 98 (90%) of the patients and from 634 (42%) of the specimens. Approximately 70% of the specimens from the mouth and stomach, 47% of fecal specimens, and 31% of abdominal specimens were positive for yeast. A total of 42 patients had a complicated postoperative course. The majority of these patients were colonized with yeast at multiple body sites: yeast was recovered on one or more occasions from two or more body sites in 90% and from three or more body sites in 71%. Many of the patients with an uncomplicated postoperative course also were colonized: yeast was recovered from two or more body sites in 69% and from three or more body sites in 34%. The results of this study indicate that treatment recommendations based on yeast colonization will expose a large number of patients to unnecessary or even harmful antifungal treatment. This does not mean that yeast colonization is insignificant; however, more accurate criteria and methods based on prospective clinical studies are needed to detect patients at risk of developing severe Candida infection.

OBJECTIVES To study the relation between nitrite, nitrate, nitrotyrosine, and nitrosothiols as NO indices in human septic shock. DESIGN A prospective clinical study. SETTING Intensive care units in a university hospital and a central county hospital. PATIENTS Sixteen patients admitted for septic shock. Nine healthy volunteers served as controls. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS Patients with septic shock had a hyperdynamic circulatory response and required infusion of at least two vasopressors to maintain systemic blood pressure. Four episodes of recurrent shock occurred in two patients. Heparinized plasma was collected once daily for analysis of NO indices. Peak plasma concentrations of nitrite + nitrate (NOx) were elevated in first episodes of septic shock; 144+/-39 microM vs. controls, 20+/-3 microM (p < .05). Peak plasma NOx concentrations in recurrent shocks were; 160+/-19 microM. Peak plasma concentrations of 3-nitrotyrosine (NT) were elevated in primary septic shock 102+/-19 pmol x mL(-1) vs. controls 14+/-6 pmol x mL(-1) (p < .05). Peak NT concentrations were 117+/-37 pmol x mL(-1) in recurrent septic shock. Peak plasma NT concentrations did not coincide with peak NOx concentrations in half of the episodes of septic shock. Plasma NT was elevated (59+/-15 pmol x mL(-1) vs. controls 14+/-6 pmol x mL(-1), p < .05) in patients with normal plasma NOx concentrations throughout septic shock. Plasma concentrations of nitrosothiols did not change during septic shock. CONCLUSIONS Plasma concentrations of NOx and NT are elevated in primary episodes of septic shock and may also be elevated in secondary septic shock, but too few episodes of recurrent septic shock occurred to allow firm conclusions. Plasma concentrations of NT are elevated in patients with septic shock with normal plasma NOx concentrations, indicating that plasma concentrations of NOx may not always accurately reflect NO production. Reactive nitrogen species may be formed in septic shock, and measuring both NOx and NT may give a better indication of NO production in septic shock than NOx alone. Plasma levels of nitrosothiols did not change during septic shock.

Cancer of the prostate remains poorly characterized cytogenetically. This is due in part to methodological problems and in part to the paucity of radical prostatectomies, until now the main source of material for cytogenetic analyses. We have improved existing techniques for the culturing of prostatic neoplasms removed by radical prostatectomy or sampled by ultrasound-guided needle biopsy. Successful short-term cultures were obtained from all 10 prostatectomy samples and from all 10 ultrasound-guided needle biopsies, always with a pure epithelial morphology. Of the 19 cases yielding a sufficient number of high-quality metaphases for chromosome banding analysis, the single atypical epithelial hyperplasia had a normal karyotype, whereas both prostatic intraepithelial neoplasias and 12 of 16 (75%) invasive carcinomas were shown to have clonal abnormalities. Ten of the 12 (83%) karyotypically abnormal invasive carcinomas presented structural chromosomal rearrangements. A recurrent deletion, del(10)(p13), was seen in three tumors; in one of them the terminal nature of the deletion was confirmed by two-color FISH. A del(17)(p11) was seen in one PIN lesion, but since the analysis of exons 4–8 of the TP53 tumor suppressor gene revealed no mutations, there probably was no inactivation of the second TP53 allele. Our study thus leads to the following main conclusions. First, better culturing methods allow the detection of abnormal karyotypes in a much higher percentage of prostatic neoplasms than has hitherto been possible. Second, ultrasound-guided needle biopsies of prostatic neoplasms are a sufficient source of material for cytogenetic analysis. Third, a terminal deletion of the short arm of chromosome 10, del(10)(p13), seems to identify a subgroup of prostatic cancer. Genes Chromosomes Cancer 28:211–219, 2000. © 2000 Wiley-Liss, Inc.

The aim of this study was to determine the impact of intra-operative irradiation (IORT) combined with pre-operative external beam irradiation (EBRT) and surgical resection in patients with locally advanced primary or recurrent rectal cancer. 64 patients with locally advanced primary cancer and 104 with recurrence had EBRT (46-50 Gy) before surgery. 80 patients received IORT (median dose 15 Gy energy 12 MeV). 80 patients had R0 resections, 47 R1 and 41 R2 resections. More R1 resections were performed in the IORT group, more R0 and R2 resections in the non-IORT group. Median follow-up was around 22 months. 146 patients were resected, 22 had exploratory laparotomy. The cumulative overall survival was similar for both the IORT and non-IORT groups. 5-year survival for primary cancers was 48% versus 28% for recurrences. No R2 resections survived 3.5 years. 5-year-survival for R0 resections was nearly 60% and around 30% for R1 resections. The survival curves of the patients given and not given IORT treatment was not statistically different when R0, R1 and R2 resections were analysed separately. IORT did not seem to influence the local recurrence rate when R0 and R1 resections were analysed separately or in a multivariate analysis. The IORT and non-IORT groups were not identical with regard to type of cancer and R-stage. Still the lack of an identifiable impact of IORT suggests that there is a need for randomised studies of the IORT effect.