Characterization of early recurrences following liver resection by ALPPS and two stage hepatectomy in patients with colorectal liver-metastases and small future liver remnants; a translational substudy of the LIGRO-RCT.

BACKGROUND: Associated liver partition and portal vein ligation in staged hepatectomy (ALPPS) is an alternative resection method to portal vein embolization (PVE) in patients with small future liver remnants (FLR) but has been associated with early tumor recurrences. METHODS: Twenty-four patients with colorectal liver metastases (CRLM) patients from the randomized multicenter LIGRO trial comparing outcome of ALPPS (n = 13) vs PVE (n = 11) were included in the study. Mutational analyses of the KRAS, NRAS, BRAF, PIC3CA and TP53 genes of the metastases were performed in 21 patients and correlated to early tumor recurrence. RESULTS: Within 12 months, 13 patients experienced recurrences (6 in TSH group and 7 in ALPPS group). Nine of 13 patients with recurrences had mutations in the TP53 gene, while 3 of 8 patients without recurrence carried the same mutation. Only sporadic cases of the other mutations studied were identified. CONCLUSIONS: ALPPS did not appear to be associated with higher rate of rapid recurrences than PVE following radical resection of colorectal liver metastases. Mutations in genes associated with negative oncologic outcome after surgical resection most likely play a role for tumor recurrences in these patients.

Resection of synchronous liver metastases between radiotherapy and definitive surgery for locally advanced rectal cancer: short-term surgical outcomes, overall survival and recurrence-free survival.

AIM: There is debate as to the correct treatment algorithm sequence for patients with locally advanced rectal cancer with liver metastases. The aim of the study was to assess safety, resectability and survival after a modified 'liver-first' approach. METHOD: This was a retrospective study of patients undergoing preoperative radiotherapy for the primary rectal tumour, followed by liver resection and, finally, resection of the primary tumour. Short-term surgical outcome, overall survival and recurrence-free survival are reported. RESULTS: Between 2009 and 2013, 45 patients underwent liver resection after preoperative radiotherapy. Thirty-four patients (76%) received neoadjuvant chemotherapy, 24 (53%) concomitant chemotherapy during radiotherapy and 17 (43%) adjuvant chemotherapy. The median time interval from the last fraction of radiotherapy to liver resection and rectal surgery was 21 (range 7-116) and 60 (range 31-156) days, respectively. Rectal resection was performed in 42 patients but was not performed in one patient with complete response and two with progressive metastatic disease. After rectal surgery three patients did not proceed to a planned second stage liver (n = 2) or lung (n = 1) resection due to progressive disease. Clavien-Dindo ≥Grade III complications developed in 6.7% after liver resection and 19% after rectal resection. The median overall survival and recurrence-free survival in the patients who completed the treatment sequence (n = 40) were 49.7 and 13.0 months, respectively. Twenty of the 30 patients who developed recurrence underwent further treatment with curative intent. CONCLUSION: The modified liver-first approach is safe and efficient in patients with locally advanced rectal cancer and allows initial control of both the primary tumour and the liver metastases.

[Laparoscopic resection of primary and metastatic malignant tumors of the adrenals].

An analysis was made of experience with treatment of 24 patients who underwent laparoscopic adrenalectomy for adrenocortical carcinomas (in 7 patients) and metastases in adrenals (in 17 cases). Laparoscopic adrenalectomy was shown to be a safe and effective method of treatment of primary and metastatic tumors of the adrenals. The method can replace open operative intervention in the majority of patients with metastases to adrenals and primary cancer of the adrenals.

[Laparoscopic resection of malignant liver tumors: immediate and long-term results].

The study was concerned with laparoscopic liver resection for cancer (140) (1998-2009). Faulty intraoperative performance and postoperative complications were evaluated according to Clavien and Satava. 188 resections were performed in the course of 154 operations. Median operation duration and blood loss were 180 min and 300 ml, respectively. Most patients started taking water on the same day and eating the next day. There were 16 incidents including 6 (3.9%) cases involving change of surgical strategy. Surgical complications were reported in 22 (14.3%) cases including one death from multiple organ failure. Median postoperative intensive care duration and inpatient stay were zero and 3 days, respectively; median follow-up--24-105 months; 3-5 year survival--(68 +/- 6%) and (46 +/- 8%), respectively. 3-year survival in patients with colorectal metastasis to liver, metastasis of neuroendocrine tumors of the gastrointestinal tract and those of hepatocellular carcinoma was 71, 50 and 47%, respectively. Laparoscopic liver resection is a safe and effective method of tumor treatment. It is least invasive and followed by good end results.

Single-centre experience of laparoscopic pancreatic surgery.

BACKGROUND: Laparoscopic resection is regarded as safe and feasible in selected patients with benign pancreatic tumours. Few data exist on laparoscopic surgery for malignant lesions and larger neoplasms in unselected patients. METHODS: The study included all patients admitted to Oslo University Hospital, Rikshospitalet, from March 1997 to March 2009 for surgery of lesions in the body and tail of the pancreas, and selected patients with lesions in the pancreatic head, who underwent surgery by a laparoscopic approach with curative intent. RESULTS: A total of 166 patients had 170 operations, including 138 pancreatic resections, 18 explorations, nine resections of peripancreatic tissue and five other therapeutic procedures. Four patients had repeat procedures. There were 53 endocrine tumours (31.0 per cent), 28 pancreatic carcinomas (16.4 per cent), five cases of metastases (2.9 per cent), 48 cystic tumours (28.1 per cent) and 37 other lesions (21.6 per cent). The total morbidity rate was 16.5 per cent. Fistula was the most common complication (10.0 per cent). Three patients needed reoperation for complications. There were three hospital deaths (1.8 per cent). Median hospital stay following surgery was 4 days. CONCLUSION: Laparoscopic resection of lesions in the body and tail of the pancreas in an unselected patient series was safe and feasible, and should be the method of choice for this patient group in specialized centres.

The Fas/FasL system and T cell apoptosis in HIV-1-infected lymphoid tissue during highly active antiretroviral therapy.

Apoptosis has been proposed as a mechanism responsible for T cell depletion in HIV-1 infection. In the present study we have phenotyped apoptotic T cells in tonsillar lymphoid tissue from 11 HIV-1-infected patients by flow cytometry light-scatter characteristics during 48 weeks of highly active antiretroviral therapy (HAART). We found that the decline in tonsillar viral load was associated with a decrease in the proportion of apoptotic CD4+ and CD8+ T cells. CD4 cell apoptosis was predominantly seen within the memory CD28+ Fas+ FasL+ population. The increased level of apoptotic CD8+ T cells was found among activated Fas+ memory cells irrespective of CD28 and FasL expression. These T cell subsets were expanded in untreated infection, but normalized with therapy. We conclude that HIV-1 triggers FasL-mediated apoptosis of uninfected CD4+ T cells, whereas CD8+ T cell apoptosis is driven by chronic immune activation. Virus suppression reverses both of these mechanisms, contributing to immune reconstitution during HAART.

Normalization of CD4+ cell numbers and reduced levels of memory CD8+ cells in blood and tonsillar tissue after highly active antiretroviral therapy in early HIV type-1 infection.

Antiretroviral therapy increases the number of both CD4+ and CD8+ T cells in the blood of HIV-1-positive patients with advanced disease. In the present study, we have examined the kinetics of CD4+ and CD8+ T cell restoration in blood and lymphoid tissue in asymptomatic HIV-1-positive individuals with high CD4+ cell counts during highly active antiretroviral treatment. Tonsillar biopsies and blood samples were collected at baseline and at regular intervals during the following 48 weeks and from HIV-1-negative controls. Mononuclear cells from blood and tonsils were phenotyped and quantified by three-color flow cytometry. After 48 weeks of therapy, blood CD4+ cell counts in the HIV-1-infected group were comparable to those found in uninfected controls. Naive CD4+ T cells in blood increased during the initial 2 weeks in parallel with reduced plasma viremia. Both naive and memory CD4+ T cells in blood reached normal numbers by week 48, whereas the CD4+ naive/memory cell ratio in tonsils was within normal range throughout the study. The level of memory CD8+ T cells in blood declined during the first 8 weeks in parallel with a reduction in the tonsillar memory CD8+ T cells. Naive CD8+ T cells in the blood increased after 4 weeks, while the level of naive CD8+ T cells in tonsils remained unaltered. Our data indicate that in the early stages of HIV-1 infection antiretroviral therapy normalizes CD4+ cell counts and causes a decrease in the level of memory CD8+ cells in blood and lymphoid tissue, suggesting reduced CD8+ cell turnover in response to reduced viral replication.

Early changes in peripheral blood T cell subsets induced by antiretroviral treatment of human immunodeficiency virus-1 positive individuals.

Human immunodeficiency virus (HIV)-1 infection causes a gradual decline in peripheral blood CD4+ T cells. Shortly after the primary infection, an expansion of the activated memory CD8+ T-cell pool is also observed paralleling increased levels of plasma viraemia. In the present study we investigated the immediate effects of zidovudine therapy on peripheral blood T-cell subsets during the first 3 weeks of therapy in a group of HIV-1 positive individuals receiving influenza vaccine. HIV-1 positive individuals who received vaccine, but no treatment, were included as controls. Both the number of CD4+ and CD8+ T cells increased during the first week of therapy in parallel with a decline in plasma viraemia. The majority of CD4+ T cells contributing to this expansion expressed CD28, CD45RO and Fas, whereas the expanded CD8+ T cells were predominantly CD28-, CD45RO+, CD38+, Fas+ and Fas+ (CD95). We propose that the increase in the number of activated memory T cells observed in peripheral blood immediately after the onset of antiretroviral treatment is most likely caused by the redistribution of cells from various lymphoid organs in response to decreased levels of viral load in these compartments. The degree of T-cell redistribution is probably dependent on the magnitude of virus suppression.

Changes in tonsillar tissue in early HIV-1 infection and during 3 years of antiretroviral therapy.

Tonsillar tissue from individuals in the early stages of HIV-1 infection was studied during the natural course of infection and during antiretroviral therapy with and without a protease inhibitor in order to investigate markers of clinical progression and evaluate the effects of therapy. Tonsillar biopsies and blood samples were collected at regular intervals during 3 years and clinical observations were noted. Tonsillar morphology was evaluated and the fragmentation of the follicular dendritic cell network was quantified by standardised follicular fragmentation rate (FR) analysis. Lymphocyte subsets were phenotyped by flow cytometry, and viral load was calculated by limiting dilution assay. The FRs were higher in the HIV-1-infected individuals than in the uninfected controls, although tonsillar tissue from both groups contained follicular fragmentation. During HIV-1 infection, the FR increased and the tonsillar CD4/CD8 ratio declined. During maximum viral suppression, FR approached that of controls while tonsillar T cell subsets and blood CD4 cell counts normalised. Even when virus suppression was incomplete, tonsillar improvements were observed in parallel with a resolution of the HIV-1-related dermatological disorders. However, persistent viral replication paralleled distortion of the tonsillar architecture. We suggest that a normalisation of the lymphoid tissue may have important functional and clinical implications in HIV-1 infection.

Correlates of apoptosis of CD4+ and CD8+ T cells in tonsillar tissue in HIV type 1 infection.

The immunopathogenesis of human immunodeficiency virus type 1 (HIV-1) infection has been associated with increased death by apoptosis of T cell subsets. In the present study, we have examined correlates of apoptosis of CD4+, CD8S+CD28+, and CD8+CD28- T cells in tonsillar lymphoid tissue in persons with HIV-1. Single-cell suspensions of tonsillar lymphocytes were analyzed by flow cytometry to determine the fraction of cells showing typical characteristics of apoptosis as well as the expression of activation markers within the live and the apoptotic cell populations. The proportion of cells carrying infectious provirus was quantified by limiting dilution analysis. Compared with uninfected controls, apoptosis of both CD4+ and CD8+ T cells was enhanced in HIV-1 infection and was higher among CD8+ than among CD4+ T cells. Apoptosis of CD28-cells was more prevalent than apoptosis of CD28+ cells for both CD4+ and CD8+ T cells. Occurrence of apoptosis of CD4+ T cells correlated with provirus levels and proportional expression of the activation marker HLA-DR. Apoptosis of CD8+CD28+ cells correlated with expression of the activation markers CD69 and HLA-DR while apoptosis within CD8+CD28- cells did not correlate with any of the studied parameters. Although apoptosis was much more prevalent among CD8+ than CD4+ T cells, CD8+ T cells still accumulated in tonsillar lymphoid tissue in persons with HIV-1. Our data may be interpreted to suggest that apoptosis of CD4+, CD8+CD28+, and CD8+CD28- cells in tonsillar tissue is regulated by different mechanisms and the results are of importance to our understanding of the immunopathogenesis of HIV-1 infection.

Activation and proliferation of CD8+ T cells in lymphoid tissues of HIV-1-infected individuals in the absence of the high-affinity IL-2 receptor.

Activation of CD8+ T cells may have important pathogenic implications in HIV-1 infection. Studies of this process have so far been confined to cells from the peripheral blood. In the present study, we have examined molecules involved in activation and proliferation of CD8+ T cells in lymphoid tissues from HIV-1-infected patients. Tonsillar tissue and blood samples from 13 HIV-1-infected patients and 6 seronegative controls were examined for cell surface expression and the presence of mRNA for CD69, CD25, and HLA-DR. Intonsillar tissue, the number of CD8+ T cells was increased several fold in HIV-1-infected patients compared with controls. The majority of these cells expressed CD69 and HLA-DR, but virtually no tonsillar CD8+ T cells were found to express CD25 on the cell surface or at the mRNA level. Following in vitro activation, however, almost all activated CD8+ T cells were found to express CD25. Tonsillar CD4+ T cell numbers were maintained or reduced compared with controls, and a considerable proportion expressed CD25. The data suggest that CD8+, but not CD4+ T cells proliferate extensively in lymphoid tissues in HIV-1-infected patients in the absence of the high-affinity interleukin-2 (IL-2) receptor.

Reduced CD4 cell counts in blood do not reflect CD4 cell depletion in tonsillar tissue in asymptomatic HIV-1 infection.

OBJECTIVE: To investigate whether the loss of CD4 cells seen in peripheral circulation of HIV-1-positive individuals reflects a similar depletion of CD4 cells from lymphoid tissue. DESIGN: CD4 and CD8 cells in tonsillar mononuclear cell suspensions were quantified relative to tonsillar B cells, as these were thought to remain numerically unchanged in the course of HIV infection. Results were related to the CD4 cell counts in blood and to the clinical status of the patients. METHODS: Blood samples and tonsillar tissue were obtained from 13 HIV-1-seropositive individuals and six seronegative controls. B cells and T-cell subsets in mononuclear cells were quantified using a three-colour flow cytometry protocol. Histological sections were morphologically classified and B-cell areas were quantified by morphometry. RESULTS: The B-cell fraction was confirmed to be relatively unchanged in asymptomatic HIV-1-seropositive individuals compared with controls. The tonsillar CD4 : B-cell ratios in asymptomatic individuals was similar to those seen in controls, whereas the CD4 : B-cell ratios in symptomatic HIV-1-infected individuals were greatly reduced. The tonsillar CD4 : CD8 cell ratios in HIV-1-infected individuals were much lower than those seen in controls, in the asymptomatic group due to a considerable expansion of the tonsillar CD8 cell subset, and in the symptomatic group also due to a loss of CD4 cells. CONCLUSIONS: We found no evidence of CD4 cell depletion in tonsillar tissue in asymptomatic HIV-1-infected individuals despite low CD4 cell counts in blood. Loss of CD4 cells from this lymphoid tissue seems to occur as a late-stage phenomenon correlated with the onset of clinical symptoms.