Significant Factors For Poor Prognosis Research Articles

Case report: role of multidisciplinary approach in a case of spine osteosarcoma with oligometastatic heart disease

Introduction. Primary spinal osteosarcoma and rare metastatic heart lesion are considered significant factors for poor prognosis. The available work indicates that combined treatment, including the radical surgery of heart solitary metastatic lesion, probably provides the best outcome.Case report. Man, 27-year-old, with Th8 spinal osteosarcoma and solitary left atrial metastasis. From October 2019 to February 2020 5 cycles of chemotherapy (high doses of platinum and doxorubicin) were carried out with positive effect. Next steps were surgery: March 2020 – spondylectomy of the Th8 vertebra with combined stabilization; September 2020 – subtotal resection with plasty of the right atrium, tricuspid valve and prosthesis of the right coronary artery. Between the first and second surgery, 4 more same chemotherapy cycles were carried out. Currently, 24 months after completion of treatment, there are no signs of the disease.Conclusion. The article presents a unique case of treatment of primary osteosarcoma and metastatic lesion of rare location. Multidisciplinary approach and combination treatment in specialized centers increase the probability of favorable outcome in such cases.

Single-cell RNA sequencing of a poorly metastatic melanoma cell line and its subclones with high lung and brain metastasis potential reveals gene expression signature of metastasis with prognostic implication.

The molecular mechanisms underlying melanoma metastasis remain poorly understood. In this study, we aimed to delineate the mechanisms underlying gene expression alterations during metastatic potential acquisition and characterize the metastatic subclones within primary cell lines. We performed single-cell RNA sequencing of a poorly metastatic melanoma cell line (WM239A) and its subclones with high metastatic potential to the lung (113/6-4L) and the brain (131/4-5B1 and 131/4-5B2). Unsupervised clustering of 8173 melanoma cells identified three distinct clusters according to cell type ('Primary', 'Lung' and 'Brain' clusters) with differential expression of MITF and AXL pathways and putative cancer and cell cycle drivers, with the lung cluster expressing intermediate but distinct gene profiles between primary and brain clusters. Principal component (PC) analysis revealed that PC2 (the second PC), which was positively associated with MITF expression and negatively with AXL pathways, primarily segregated cell types, in addition to PC1 of the cell cycle pathway. Pseudotime trajectory and RNA velocity analyses suggested the existence of cellular subsets with metastatic potential in the Primary cluster and an association between PC2 signature alteration and metastasis potential acquisition. Analysis of The Cancer Genome Atlas melanoma samples by clustering into PC2-high and -low clusters by quartiles of PC2 signature expression revealed that the PC2-high cluster was an independent significant factor for poor prognosis (p-value = 0.003) with distinct genomic and transcriptomic characteristics, compared to the PC2-low cluster. In conclusion, we identified signatures of melanoma metastasis with prognostic significance and putative pro-metastatic subclones within a primary cell line.

Prognostic impacts of soluble immune checkpoint regulators and cytokines in patients with SARS-CoV-2 infection.

Coronavirus disease 2019 (COVID-19) has been a pandemic for the past two years. Predicting patient prognosis is critical. Although immune checkpoints (ICs) were shown to be involved in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, quantitative studies of ICs in clinical practice are limited. In this study, various soluble ICs (sICs) and cytokine levels in patients with SARS-CoV-2 infection at different time points were compared between survivors and deaths; we also examined whether sICs are useful for predicting prognosis. sICs and cytokines were measured in serum samples from 38 patients diagnosed with COVID-19 in the first and second week post-diagnosis. All assays were performed by bead-based multiplexed immunoassay system using Luminex Bio-Plex 200 system. The correlation of sICs and cytokines with laboratory markers was evaluated, and the levels of sICs in survivors were compared with those in deaths. Among the sICs, the second-week levels of soluble cluster of differentiation (sCD27, p = 0.012), sCD40 (p< 0.001), cytotoxic T-lymphocyte-associated protein 4 (sCTLA-4, p< 0.001), herpes virus entry mediator (sHVEM, p = 0.026), and T-cell immunoglobulin and mucin-domain containing-3 (sTIM-3, p = 0.002) were significantly higher in deaths than in survivors. The levels of nine cytokines assessed in the second week of deaths were significantly higher than those in survivors. The sICs sCD27, sCD40, sCTLA-4, and sTIM-3 and cytokines chemokine CC motif ligand 2 (CCL2), GM-CSF, IL-10, and IL-8 showed significant positive correlations with the levels of C-reactive protein (CRP) and procalcitonin and were negatively correlated with the absolute lymphocyte count and platelet values. Increased levels of sICs including sCD27, sCD40, sCTLA-4, and sTIM-3 and cytokines were significant factors for poor prognosis. sICs, together with cytokines and inflammatory markers, may be useful as prognostic stratification markers in SARS-CoV-2-infected patients.

P1586: IN-HOSPITAL MORTALITY AND POOR PROGNOSIS FACTORS ASSESSMENT IN PATIENTS WITH ACUTE LYMPHOBLASTIC LEUKEMIA AND COVID-19.

Background: Acute lymphoblastic leukemia (ALL) belongs to a heterogeneous, highly aggressive group of hematologic malignancies. In the context of the epidemic of a new coronavirus infection (COVID-19), patients with hemoblastoses have a more severe course of the viral infection and high mortality rate due to COVID-19. The management protocols of patients with ALL in the context of the COVID-19 pandemic has not been developed, and approaches to both the treatment of a new coronavirus infection and the antitumor treatment of ALL in patients with COVID-19 have not been defined. Aims: To analyze in-hospital overall survival of patients with acute lymphoblastic leukemia and coronavirus infection, to assess the impact of poor prognostic factors on the outcome of the disease, and to determine the therapeutic tactics for ALL and COVID-19. Methods: From April 21, 2020 to November 30, 2021 46 patients with ALL (24 men, 22 women) with a median age of 44.5 (18-74) years were observed on the basis of the hematological service of the City Clinical Hospital No. 52 (Moscow). According to the immunophenotypic variant of ALL, 27 (59%) were patients with B-ALL, of which Ph-positive ALL was diagnosed in 8 (30%), Ph-negative - in 19 (70%); T-ALL - 16 (35%), biphenotypic - 2 (4%). Patients with newly diagnosed ALL (20%) underwent induction antitumor therapy, 67% - convalescents and PCR positive for SARS-CoV-2 infection. To determine the factors of hospital mortality, a statistical analysis was performed, including: age, hematological disease status, degree of lung tissue damage according to computer tomography (CT), stay in the intensive care unit due to severe respiratory failure requiring mechanical ventilation (ALV), the presence of neutropenia of the IV degree, transfer from another hospital, the formation of an antiviral immune response after a coronavirus infection. Results: Hospital mortality in ALL patients was 30%. Statistically significant factors for poor prognosis were: age (>40 years), p=0.033, hematological disease status (newly diagnosed ALL, progression/relapse), p=0.004, high (≥50%) degree of lung tissue damage according to CT (p =0.003), neutropenia IV degree (p=0.004), their transfer to another hospital, stay in the intensive care unit and mechanical ventilation (p=0.004). Summary/Conclusion: The main adverse factors affecting hospital mortality were the absence of ALL remission and the presence of severe infectious complications. Carrying out antitumor therapy allows to stabilize the status of ALL and is an important aspect in the simultaneous course of coronavirus infection. In patients with ALL and confirmed coronavirus infection, the decision to conduct induction therapy should be discussed on an individual basis, depending on ALL status, the activity of coronavirus infection and comorbidity status.

A risk-stratified therapy for infants with acute lymphoblastic leukemia: a report from the JPLSG MLL-10 trial

AbstractThe prognosis for infants with acute lymphoblastic leukemia (ALL), particularly those with KMT2A gene rearrangement (KMT2A-r), is dismal. Continuous efforts have been made in Japan to investigate the role of hematopoietic stem cell transplantation (HSCT) for infants with KMT2A-r ALL, but improvement in outcome was modest. In the Japanese Pediatric Leukemia/Lymphoma Study Group MLL-10 trial, infants with ALL were stratified into 3 risk groups (low risk [LR], intermediate risk [IR], and high risk [HR]) according to KMT2A status, age, and presence of central nervous system leukemia. Children's Oncology Group AALL0631 modified chemotherapy with the addition of high-dose cytarabine in early intensification was introduced to KMT2A-r patients, and the option of HSCT was restricted to HR patients only. The role of minimal residual disease (MRD) was also evaluated. Ninety eligible infants were stratified into LR (n = 15), IR (n = 19), or HR (n = 56) risk groups. The 3-year event-free survival (EFS) rate for patients with KMT2A-r ALL (IR + HR) was 66.2% (standard error [SE], 5.6%), and for those with germline KMT2A (KMT2A-g) ALL (LR), the 3-year EFS rate was 93.3% (SE, 6.4%). The 3-year EFS rate was 94.4% (SE, 5.4%) for IR patients and 56.6% (SE, 6.8%) for HR patients. In multivariable analysis, female sex and MRD ≥0.01% at the end of early consolidation were significant factors for poor prognosis. Risk stratification and introduction of intensive chemotherapy in this study were effective and were able to eliminate HSCT for a subset of infants with KMT2A-r ALL. Early clearance of MRD seems to have translated into favorable outcomes and should be incorporated into risk stratifications in future trials. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) as #UMIN000004801.

Expression of Cripto-1 predicts poor prognosis in stage I non-small cell lung cancer.

Cripto‐1 (CR‐1) is related to the biological behaviour and prognosis of carcinomas. The purpose of this study was to investigate the significance of CR‐1 expression in surgically resected stage I non‐small cell lung cancer (NSCLC). One hundred and forty‐eight patients with completely resected stage I NSCLC and available clinical follow‐up data were assessed. The protein expression of CR‐1 in the tumours was detected by immunohistochemistry. CR‐1 was highly expressed in 64 of 148 tumours. Among patients with high CR‐1 expression, progression‐free survival and overall survival rate were significantly lower than those of patients with low CR‐1 levels (P = .013 and P = .019, respectively). The incidence of distant metastasis in patients with high CR‐1 expression was significantly higher than that of in patients with low CR‐1 expression (57.13% vs 21.43%, P = .001). The results of the multivariate analysis confirmed that a high CR‐1 was a significant factor for poor prognosis. In conclusion, CR‐1 could be a useful prognostic factor in patients with stage I NSCLC, likely as an indicator of the metastatic propensity of the tumour.

Prognosis of Differentiated Thyroid Carcinoma with Initial Distant Metastasis: A Multicenter Study in Korea.

BackgroundMost patients with differentiated thyroid cancer (DTC) have a favorable prognosis. However, patients with DTC and initial distant metastasis have not been commonly found, and their clinical characteristics have seldom been reported. In this study, we analyzed the clinical features and prognosis of patients with DTC and initial distant metastasis in Korea.MethodsWe retrospectively reviewed the clinical data of 242 patients with DTC and initial distant metastasis treated from 1994 to 2013, collected from five tertiary hospitals in Korea.ResultsThe patients' median age was 51 years, and 65% were women. They were followed for a median of 7 years. Lung was the most common site of distant metastasis: only lung 149 patients (62%), only bone 49 (20%), other single site one (pleura), and combined sites 43 (40 were lung and bone, two were bone and other site, and one was lung and other site). At the time of diagnosis, 50 patients (21%) had non-radioactive iodine (RAI) avidity. Five-year disease-specific survival (DSS) was 85% and 10-year DSS was 68%, which were better than those in previous studies. After multivariate analysis, old age, male sex, metastatic site, and histologic type (follicular type) were significant factors for poor prognosis. However, negative RAI avidity status was not a significant prognostic factor after adjusting for other variables.ConclusionThe prognosis of Korean patients with DTC and initial distant metastasis was better than in previous studies. Old age, male sex, metastasis site, and histologic type were significant prognostic factors.

Ephrin-B2 reverse signaling regulates progression and lymph node metastasis of oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is a common malignant tumor of the head and neck and frequently metastasizes to cervical lymph nodes. Aggressive local invasion and metastasis of OSCC are significant factors for poor prognosis. In this study, we investigated whether ephrin-B2 expressed in OSCC contributed to tumor progression and lymph node metastasis. Clinical specimens from patients with OSCC had robust ephrin-B2-positive tumor cells and ephrin-B2 protein level was associated with clinical stage, lymph node metastasis, and poor survival outcomes. We also determined that ephrin-B2 protein level was increased in OSCC cell lines compared to normal human oral keratinocytes and that its levels were associated with the migratory and invasive potential of OSCC cell lines. Transfection of an EFNB2–specific small interfering RNA (siRNA) into SAS-L1 cells significantly reduced proliferation, attachment, migration, and invasion through phosphorylation of the epidermal growth factor receptor, FAK, ERK1/2, p38, AKT, and JNK1/2 pathways. Furthermore, knockdown of EFNB2 significantly suppressed adhesion and transmigration of SAS-L1 cells toward human lymphatic endothelial cells. In addition, the growth rate of tumor xenografts and cervical lymph node metastases of OSCC were suppressed by local injection of EFNB2 siRNA. These results suggest that ephrin-B2 overexpression and activation of the ephrin-B2 reverse signaling pathway in tumor microenvironment in OSCC facilitates progression and lymph node metastasis via enhancement of malignant potential and interaction with surrounding cells.

Prognostic factors for all-inside meniscal repair. A 87-case series

IntroductionRepair is indicated for tears in non-degenerative menisci. The literature reports a 15% failure rate for all-inside repair. The aim of the present study was to determine prognostic factors for failure of all-inside meniscal repair. The study hypothesis was that epidemiological, clinical and surgical factors affect success. Material and methodsA retrospective study included 87 meniscal repair procedures, with or without anterior cruciate ligament (ACL) tear. Lesions were located in red-red or red-white zones. After freshening, repair comprised an all-inside arthroscopic technique using the FasT-Fix® system (Smith & Nephew), with (70.1%) or without ligament reconstruction; all ACL tears were reconstructed. Preoperative data comprised: age, gender, smoking status, sports activity, trauma-to-surgery time, body mass index (BMI), frontal morphotype, and IKDC score. Intra- and postoperative data comprised: meniscal lesion characteristics, location, number of sutures, type of ACL reconstruction, presence of chondropathy, authorized postoperative ranges of motion, and IKDC score. Failure was defined by secondary meniscectomy. ResultsAt 31 months’ follow-up, there were 13 failures (15%). Mean postoperative IKDC score was 88.19 (range: 64.37–98.95). Bucket-handle lesion (P=0.006) and BMI>25 (P=0.014) emerged as significant factors of poor prognosis. DiscussionThe present failure rate matched those reported in the literature. The more extensive the lesion, the higher the risk of failure. High BMI incurs mechanical stresses that increase the risk of failure. Level of evidenceIV, retrospective cohort study.

Sinonasal mucosal melanoma: A 44-case study and literature analysis

ObjectivesSinonasal mucosal melanoma is a rare disease, representing 4% of nasal cavity and paranasal sinus malignancies. The aim of this study was to assess the clinical characteristics, progression and treatment of this disease and to identify prognostic factors. Material and methodsThis retrospective review presents a cohort of 44 patients treated for a melanoma arising from the nasal cavity and paranasal sinuses, in the ENT Head and Neck Surgery Department of the University Hospital of Nantes (France) between 1988 and 2015. ResultsMean age at diagnosis was 71.2 years. The main signs at diagnosis were epistaxis and unilateral nasal obstruction. 25% of patients were initially classified as T4. Surgical treatment was performed in 42 patients. Postoperative radiotherapy was performed in 19 cases and adjuvant immunotherapy in 14 cases. Mean follow-up was 50 months. Cumulative overall survival was 71.5% at 1 year and 33% at 5 years. Clinically, headache, facial pain and trigeminal V2 nerve anesthesia were significant factors for poor prognosis. Exclusively nasal involvement was a factor for better overall survival than sinus involvement. Adjuvant radiation therapy showed a non-significant trend toward improved local control. ConclusionsMucosal melanoma of the sinonasal cavities has poor prognosis due to high metastatic potential. Surgical resection followed by radiation therapy is the main treatment. There is no consensus regarding new systemic adjuvant treatments in this indication, unlike for primary cutaneous melanoma.

Idiopathic Intracranial Hypertension: Prognostic Factors and Multidisciplinary Management.

Background Idiopathic intracranial hypertension (IIH) mostly affects young obese women and can lead to permanent visual impairment. However, prognostic factors and therapeutic strategy remain unclear. Methods We retrospectively collected data from all patients diagnosed and managed for IIH in our university center from January 2001 to December 2016. Results Seventy-nine patients were diagnosed with IIH. Bilateral transverse sinus stenosis (TSS) was found in 74% of the population. Visual outcome at 6 months was poor for 46% of patients, including all patients presenting weight gain of at least 5% since diagnosis (p < 0.001), whereas mean body mass index at diagnosis was not different between patients with poor versus good outcome (32.9 ± 7.7 versus 34.6 ± 9.4 kg·m−2). Other significant factors of poor prognosis were bilateral TSS (OR = 5.2; 95 CI: 1.24–24.9; p = 0.024). Thirteen patients with poor outcome after 6-month assessment underwent unilateral TSS stenting leading to visual improvement in 11 cases. Conclusion Weight gain, rather than initial weight, emerged as the leading factor of poor visual outcome in patients with IIH, followed by presence of bilateral TSS. Consequently, first-line treatment must include dietary measures to control weight. Unilateral stenting appears to be a safe second-line treatment option for patients with bilateral TSS.

Emerging role of LOXL2 in the promotion of pancreas cancer metastasis.

Lysyl oxidase-like 2 (LOXL2) is associated with invasiveness and metastasis in cancer. We analyzed the prognostic impact of LOXL2 in pancreatic cancer patients and investigated the role of LOXL2 in pancreatic cancer cell lines. Immunohistochemical analysis was performed in samples from 80 patients and showed LOXL2 expression in 81.2% of patients with pancreatic cancer. Regarding recurrence patterns, LOXL2-positive tumors showed a significantly higher rate of distant recurrence. The 1-year and 3-year disease-free survival rates were 84.6% and 0.0%, respectively, for LOXL2-negative patients, and 27.8 % and 0.0 %, respectively, for LOXL2-positive patients. On univariate analysis, combined resection of major vessels, depth of invasion, tumor stage, and LOXL2- positive status were significant factors for poor prognosis. After identification of LOXL2 expression in pancreatic cancer cell lines, LOXL2-silenced and LOXL2-overexpressed cell lines were used to perform transwell invasion and transendothelial migration assays.In vitro studies indicated that LOXL2 silencing in MIA PaCa-2 and PANC-1 cells induced a mesenchymal–epithelial transition (MET)-like process associated with decreased invasive and migratory properties. LOXL2 overexpression in AsPC-1 and BxPC-3 cells enhanced the epithelial-mesenchymal transition (EMT)-like process and increased migratory and invasive activity. These clinical and preclinical data confirm that higher LOXL2 expression is associated with the invasiveness of pancreatic cancer cells and the low survival rate of pancreatic cancer patients. Our results suggest the clinical value of LOXL2 as a therapeutic target in pancreatic cancer.

Characteristics and significance of minimal and maximal extrathyroidal extension in papillary thyroid carcinoma

Maximal extrathyroidal extension (ETE) is known to be an important prognostic factor in papillary thyroid carcinoma (PTC). However, the significance of minimal ETE is controversial. The aim of this study was to investigate the clinicopathologic characteristics and prognostic significance of minimal vs maximal ETE in PTC. A group of 967 patients who underwent thyroidectomy for PTC in a tertiary hospital between January 2000 and December 2011 were studied retrospectively. Patients were classified into three groups: absence of ETE, and minimal and maximal ETE. The minimal ETE group was further categorized into two subgroups according to invasion of strap muscles or no invasion (STI+ and STI-). Gender did not differ between the three groups of patients. The mean age of the patients with maximal ETE was significantly higher than in those belonging to the other groups. Tumor size, bilaterality, lymph node metastasis and stage increased significantly according to the degree of ETE. Recurrence and survival rates did not differ between the absence and minimal ETE groups, or between the STI- and STI+ subgroups of minimal ETE. However, the maximal ETE group had significantly higher recurrence and lower survival rates than the other groups (P<0.001). Maximal ETE is a significant factor for poor prognosis. However, minimal ETE is not associated with increased recurrence or decreased survival in patients with PTC.

Positive peritoneal cytology at interval surgery is a poor prognostic factor in patients with stage T3c advanced ovarian carcinoma: A retrospective study

The purpose of our study is to investigate clinically significant prognostic factors at the time of interval surgery (IS), comprising interval look surgery and interval debulking surgery, for T3c (International Federation of Gynecology and Obstetrics stage IIIc to IV) advanced ovarian cancer (AOC) patients during primary treatment. We reviewed records of patients with T3c AOC who underwent IS following neoadjuvant chemotherapy or up-front primary debulking surgery with adjuvant chemotherapy at our institution between January 1996 and December 2010. For analysis of prognostic factors, cytology of peritoneal exfoliative cells at IS was added to clinicopathological variables. A retrospective analysis was performed on 50 cases. The median age was 61.1 years (range, 38-78), with median follow-up of 45.9 months (range, 12-122). Macroscopic tumors were completely resected in 32 cases (64%) at IS. Univariate analyses of clinicopathological factors for IS identified preoperative serum cancer antigen-125 levels (≥20 IU/mL; P = 0.0539), number of residual lesions at IS (≥20; P = 0.0554), incomplete surgery at IS (P = 0.0171) and positive peritoneal cytology at IS (P = 0.0015) as significant factors for prognosis regarding progression-free survival (PFS). Multivariate analysis identified positive peritoneal cytology (P = 0.0303) as a unique independent predictor of poor prognosis in PFS. Positive peritoneal cytology at IS appears to be a significant factor for poor prognosis in PFS, which may provide useful information for post-IS chemotherapy planning. IS in the treatment of AOC may be useful for not only complete resection, but also for identification of patients with poor prognosis.

In search of the molecular consequences of 8p21 deletion in multiple myeloma: commentary on Gmidéne et al

We have read with great interest but also astonishment, the publication by Gmidene et al. regarding the deletion of chromosomal region 8p21.3 in multiple myeloma (MM) patients [1]. While this study claims to be the first to present the deletion of this region in MM patients, we would like to draw attention to previous work in the field published by us and others. In the January 2009 issue of the British Journal of Haematology, we have presented our observations on the deletion of the 8p21 region and the prognostic significance it presents [2]. Using a commercially available FISH probe located on the 8p21 region, we have identified that 14/58 patients tested (24 %) carried this deletion at the time of diagnosis. In 2010, a larger study by Neben et al. has evaluated 236 MM patients and reported a 19 % frequency for this cytogenetic abnormality [3]. Although using a smaller group of patients, the study by Gmidene et al. describes a similar frequency of the deletion: 21.6 % (8/37 patients) that falls in line with the two previously published observations. Although there are minor differences in the FISH probes used for analysis in these three studies, the similarity of frequencies reported strongly suggests that a similar group of patients are identified with the different approaches. The study by Gmidene et al. confirms our previous report and taken altogether with Neben et al., these data convincingly demonstrate that del(8)(p21) is seen in about 1/5 of MM patients. We have also reported that del(8)(p21) stands out as a significant factor for poor prognosis in MM patients receiving autologous stem cell transplantation [2]. Survival analysis has revealed that loss of8p21 wassignificantlyassociated with poor progression-free survival (PFS: 12 vs. 27 months in patients without the deletion, p \0.05) and overall survival (OS: 24 vs. 67 months in patients without the deletion, p\ 0.005). Moreover, in this group of patients, multivariate analysis of prognostic factors has also identified del(8)(p21) as an independent prognosticfactorforbothPFS(p = 0.033)andOS(p = 0.029). Similarly, Neben et al. have also identified del(8)(p21) as a statistically significant prognostic factor for both PFS (p = 0.011) and OS (p = 0.040), while this significance was lost after p values were adjusted for ISS criteria[3]. In multivariate analysis, del(8)(p21) did not present as an independent factor, possibly due to the use of a larger number of variables compared to our study as well as differences in treatment regimens. Unfortunately, the current study by Gmidene et al. does not present any survival data on the reported patients. Regarding the correlation of the occurrence of different chromosomalaberrations, thehierarchicalclusteringanalysis in our study has presented a very close link between del(8)(p21) and t(4;14), while the correlations with del(17)(p13) and del(13)(q14)weresomewhatweaker.Nebenetal.havereported a significant correlation with del(13)(q14) (p = 0.04) and the absence of correlation with the occurrence of amp1(q)(21) (p = 0.06). Confirming the previous work, Gmidene et al. also suggest a link of del(8)(p21) with del(13)(q14) and t(4;14). In our 2009 paper as well as a review on chromosomal aberrations in MM that was published in 2010 [4], we have drawn attention to the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor gene cluster located in this locus and hypothesized that the downregulation of TRAIL receptor expression due to del(8)(p21) might cause decreased sensitivity of tumor cells to TRAIL-mediated apoptosis [5], providing an advantage for immune escape of the malignant clone [6]. In a similarly structured discussion, Gmidene et al. also speculate about the possibility of such a phenomenon resulting from the deletion of TRAIL receptor T. Sutlu E. Alici G. Gahrton (&) H. Nahi Department of Medicine, M54, Karolinska Institutet, Center for Hematology and Regenerative Medicine, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden e-mail: gosta.gahrton@ki.se

Tumour‐associated macrophages in diffuse large B‐cell lymphoma: a study of the Osaka Lymphoma Study Group

To evaluate the role of tumour-associated macrophages (TAMs) of the M1 and M2 types in the behaviour of diffuse large B-cell lymphoma (DLBCL). Double immunohistochemical staining of HLA-DR/CD68 (M1) or CD163/CD68 (M2) was performed in 101 cases of DLBCL. CD68+ cells represent the total number of TAMs. The average number of double-positive cells was counted, and the cut-off value was set at the mean number of counts, i.e. 30.7 and 27.0 for M1 TAMs and M2 TAMs, respectively. That for total TAMs was set at the 90th percentile number of total counts, i.e. 132.3. Cases were categorized into three pairs: high (34 cases) and low (67 cases) M1 TAM groups, high (39 cases) and low (62 cases) M2 TAM groups, and high (10 cases) and low (91 cases) total TAM groups. The difference in overall survival rates was statistically significant between the high and low M2 TAM groups (P < 0.01) and between the high and low total TAM groups (P < 0.05). Multivariate analysis revealed that the presence of a bulky mass and a higher number of M2 TAMs were significant factors for poor prognosis (P < 0.05). Estimation of specific type of macrophages, of the M1 and M2 types, is superior to the estimation of TAMs as a whole (CD68+ cells) for prediction of the prognosis of DLBCL patients.

Immunohistochemically Detected Expression of p27Kip1 and Skp2 Predicts Survival in Patients with Intrahepatic Cholangiocarcinomas

In intrahepatic cholangiocarcinomas (ICCs), the prognostic significance of p27(Kip1), a cyclin-dependent kinase inhibitor, remains controversial, and there have been no studies of degradation pathway associated proteins, S-phase kinase-interacting protein (Skp2), and Jun activation domain-binding protein-1 (Jab1). In the present study of 74 patients with ICC-mass forming type (ICC-MF) undergoing radical surgery, we determined immunohistochemical expression of p27(Kip1), Skp2, and Jab1 and examined relationships with clinicopathologic findings and patient survival. On the basis of the average of labeling indices, we set cutoff values to define high and low expressors and divided the cases into two groups. A statistically significant correlation was found between low p27(Kip1) expression and lymph node metastasis (P = .009). Patient survival in the low p27(Kip1) expression group (n = 25) was also significantly worse than that in the high p27(Kip1) expression group (n = 49, P = .0007). A significant inverse correlation was found between p27(Kip1) and Skp2 expression (P = .016). High Skp2 expression (n = 36) was significantly associated with poor prognosis (P = .0046). High Jab1 expression was observed in 32 cases, but there was no statistically significant relationship with clinicopathologic findings or patient survival. The multivariate analysis revealed that low p27(Kip1) and high Skp2 expression are independent and significant factors of poor prognosis. The results suggest that low p27(Kip1) and high Skp2 expression are associated with aggressive tumor behavior, and these cell-cycle regulators are useful markers to predict outcome of patients with ICC-MF.

Decreased Expression of Monocyte Chemoattractant Protein-1 Predicts Poor Prognosis Following Curative Resection of Colorectal Cancer

The significance of monocyte chemoattractant protein-1 in colorectal cancer is not well understood. The aim of this study was to investigate the significance of monocyte chemoattractant protein-1 expression in colorectal cancer patients undergoing potentially curative surgery. We studied 101 colorectal cancer patients who underwent potentially curative surgery. The concentration of monocyte chemoattractant protein-1 in the tumor and normal mucosa were measured. The expression of monocyte chemoattractant protein-1 was also evaluated immunohistochemically. The tissue concentration of monocyte chemoattractant protein-1 in the tumor was significantly higher than that in the normal mucosa. The decreased monocyte chemoattractant protein-1 cancer/normal ratio was associated with lymph node involvement and could predict poor prognosis. On univariate analysis, the decreased monocyte chemoattractant protein-1 ratio, carcinoembryonic antigen levels, and serosal invasion were the significant factors for poor prognosis. Multivariate analysis showed that monocyte chemoattractant protein-1 ratio was the only independent risk factor predictive of a poor prognosis. Immunohistochemically, monocyte chemoattractant protein-1 was expressed in the cytoplasm. The decreased monocyte chemoattractant protein-1 ratio was an independent factor predicting poor prognosis in patients undergoing potentially curative surgery. Monocyte chemoattractant protein-1 deficiency may present a new therapeutic approach for colorectal cancer.

Gamma Knife surgery for metastatic brain tumors without prophylactic whole-brain radiotherapy: results in 1000 consecutive cases

The authors analyzed the effectiveness of Gamma Knife surgery (GKS) for metastatic brain tumors without adjuvant prophylactic whole-brain radiotherapy (WBRT). Salvage GKS was performed as the sole treatment for new distant lesions. Among 1127 patients in whom new brain metastases had been diagnosed, 97 who met one or more of the following three criteria were excluded from the study: any surgically inaccessible huge (>/= 35 mm) lesion; tumor number and size requiring an internal skull dose exceeding 10 J; or symptomatic carcinomatous meningitis. Thus, 1030 consecutive patients formed the basis for this study. Huge tumors were totally removed, whereas smaller lesions were treated with GKS. No adjuvant WBRT was given prior to GKS, and new distant lesions were appropriately retreated with GKS. Overall, neurological and new lesion-free survival curves were calculated and the prognostic values of covariates were obtained. In total, 1853 separate GKS sessions were required to treat 10,163 lesions.The patients' median overall survival period was 8.6 months. Neurological survival and new lesion-free rates at 1 year were 89.1 and 49.3%, respectively. In a multivariate analysis, the significant factors for poor prognosis were the development of more than four new brain metastases and active extracranial disease. In meeting the goal of preventing neurological death and maintaining activities of daily living for patients with brain metastases, GKS alone provides excellent palliation without prophylactic WBRT. New distant lesions were quite well controlled with GKS salvage treatment alone.

Prognostic Factors and Surgical Indications of Pulmonary Epithelioid Hemangioendothelioma: A Review of the Literature

Pulmonary epithelioid hemangioendothelioma is a rare vascular tumor of low-grade malignancy, the prognosis of which remains unpredictable. The purpose of this analysis based on 80 patients was to determine prognostic factors and to evaluate results of surgery. We recorded data of 75 patients from reports published in the English and French literature using the terms "intravascular bronchoalveolar tumor" or "pulmonary epithelioid hemangioendothelioma" or a combination of both. We added to this database 5 more cases of pulmonary epithelioid hemangioendothelioma operated on in our thoracic surgery department from 1989 to 2005. Univariate and multivariate analyses of prognostic factors were performed using the log rank test and the Cox model. The factors we tested were age, sex, clinical symptoms, biologic and radiologic findings, and surgical treatment. There were 49 women and 31 men with a mean age of 39.7 years (range, 7 to 72 years). The 5-year survival probability was 60% (range, 47% to 71%). Univariate analysis showed that loss of weight, anemia, pulmonary symptoms, and more particularly pleural hemorrhagic effusions were significant factors of poor prognosis, with a median survival of less than 1 year. Multivariate analysis showed a statistically worse survival in patients with hemorrhagic symptoms (hemoptysis, p < 0.0001; pleural effusion, p < 0.0001). Pulmonary epithelioid hemangioendothelioma typically occurs among young patients. Surgery can be proposed in cases of unilateral single or multiple nodules. There is no single effective treatment in cases of bilateral multiple nodules. Lung transplantation should be evaluated in patients with vascular aggressivity with pleural hemorrhagic effusion and anemia.