Melanoma with benign melanocytic naevus components: reappraisal of clinicopathological features and prognosis

The clinicopathological features and prognosis of primary cutaneous malignant melanoma with benign melanocytic naevus (BMN) components are still under debate. The purpose of this study was to characterize further the clinical and histopathological features of naevus-associated melanomas, with emphasis on the BMN components, and to examine their prognosis based on a large series. Following a histopathological review of 667 consecutive cases of primary cutaneous melanoma, 148 melanomas with BMN components (22.1%) were identified for further study. A control group of 519 melanomas without BMN components seen in a similar period were also studied. Clinically, patients with melanomas containing BMN components (n = 148; age range 25-86 years, mean age 54 +/- 16 years; male to female ratio 1:1.02) presented with tumours located mainly on the trunk (34.5%), followed by the upper extremities (24.3%), lower extremities (20.3%), and head and neck (14.2%). Compared with tumours without BMN components (n = 519; age range 19-89 years, mean age 57 +/- 15 years; male to female ratio 1:1.3), melanomas with BMN components occurred in slightly younger individuals (P = 0.027). Histopathologically, BMN components mainly showed features of acquired naevi (total 87 cases; dysplastic, 80 cases; banal, seven cases) or congenital naevi (total 57 cases; superficial, 56 cases; deep, one case), but a minority of these lesions (four cases) could not be further subcategorized. Generally, melanomas containing BMN components were relatively thinner than melanomas without BMN components (mean Breslow index 0.95 +/- 0.83 mm and 1.3 +/- 1.6 mm, respectively) (P = 0.015). The follow-up data available in 69 patients with naevus-associated melanomas consistently revealed a relatively good outcome (5 year metastasis-free survival rate 93.75%), although no statistical difference in prognosis was observed between this group and a subset of 283 melanomas patients without BMN components stratified by tumour thickness. We conclude that BMN components in naevus-associated melanomas constitute a heterogeneous group morphologically, consisting mainly of dysplastic and superficial congenital naevi. This finding indicates a more important role for superficial congenital naevus as a precursor lesion of naevus-associated melanomas than presently recognized. Patients with naevus-associated melanomas generally show a good clinical outcome, reflecting their small Breslow index.     

Bone marrow necrosis masquerading as interferon toxicity in chronic myeloid leukemia

Bone marrow necrosis (BMN) is a rare pathologic entity associated with a wide variety of diseases. We describe a patient with chronic myeloid leukemia on interferon treatment, who developed BMN with symptoms and signs masquerading as interferon toxicity. This is followed by a literature review of BMN in CML.     

Analysis and Clinical Characteristics of 23 Cases of Bone Marrow Necrosis

BackgroundBone marrow necrosis (BMN) is a rare secondary disorder of many discrepant neoplastic processes. The etiology is diverse, and malignancy is the most common background disease.Patients and MethodsBetween 2005 and 2019, a total of 23 cases of BMN were detected and analyzed at Zhujiang Hospital and Nanfang Hospital.ResultsIn our study, the 40-60-year-old age group was the one with the highest incidence of BMN (n = 12, 52.2%). The background diseases of patients with BMN varied. Eighteen (78.3%) of 23 patients were diagnosed with hematologic diseases at the same time, most of which were acute B lymphocytic leukemia (n = 8, 34.8%). The complete blood count of these 23 patients noted a decrease in hemoglobin (100%), a decrease or increase in white blood cells and neutrophils, and thrombocytopenia (78.3%). The levels of lactate dehydrogenase (> 300 U/L) and serum ferritin (> 500 μg/L) were elevated in all patients, and 16 (94.1%) of 17 patients presented with increased d-dimer levels. The 2-week cumulative survival and 2-year cumulative survival of patients with BMN were 56.5% and 47.4%, respectively. The mortality probability within 2 weeks was 43.5%, and the adjusted mortality probability was 26.7% within 2 weeks to 2 years, indicating that patients with BMN had the greatest risk of death within 2 weeks.ConclusionBMN patients with B lymphocytic leukemia as the background disease had a better prognosis than those with other background diseases. BMN of unknown etiology may have an extremely poor prognosis. Therefore, diagnosing the background disease plays an important role in the treatment of BMN.     

A case of bone marrow necrosis with thrombotic thrombocytopenic purpura as a manifestation of occult colon cancer

Thrombotic thrombocytopenic purpura (TTP) is a disseminated form of thrombotic microangiopathy. Although most cases are held to be idiopathic, its association with malignancy is well recognized and it usually occurs at the terminal stage of cancer. Bone marrow necrosis (BMN) is another rare disorder defined pathologically as the necrosis of myeloid tissue and medullary stroma with preservation of bone. While hematologic malignancy is the most common underlying disease associated with BMN, it can also be caused by solid tumors. Neither TTP nor BMN associated with colon cancer has been reported. We describe here a patient with the rare association of TTP and BMN displayed as the first manifestation of an advanced colon cancer. The anemia and thrombocytopenia responded not to plasma exchange but to the combination chemotherapy. This case indicates that metastatic cancer should be included in the differential diagnosis of TTP and BMN, and that the chemotherapy may improve the detrimental clinical course.     

骨髓坏死6例临床分析

目的:探讨骨髓坏死(BMN)的原发病、发病机理、临床特点及预后。方法:对6例骨髓坏死的临床资料进行分析。结果:6例BMN均以骨髓坏死为首要表现,以骨痛和发热为主要表现。1例原发病不明,其余5例均为恶性疾病,其中急性粒单核细胞白血病1例,急性淋巴细胞白血病2例,骨髓转移瘤2例。2例经积极治疗原发病取得一定疗效。结论:骨髓坏死是一种罕见的临床综合征,诊断难度大,预后差,应积极治疗原发病。     

Bone marrow necrosis

BACKGROUND: In the medical community, little is known regarding bone marrow necrosis (BMN) as a clinicopathologic entity, although to the authors' knowledge it was described for the first time more than 50 years ago. To identify the rate of prevalence, the symptoms and signs, the underlying disease associations, and the usefulness of diagnostic procedures, an extensive literature search was made. METHODS: Only cases identified as extensive necrosis and diagnosed during life were selected. Two hundred forty cases met these criteria. RESULTS: Bone pain (75%) and fever (68.5%) were the most important symptoms, whereas anemia (91%) and thrombocytopenia (78%), associated with a leukoerythroblastic picture (51%), were the most frequent hematologic abnormalities. Nearly 50% of patients showed elevated lactate dehydrogenase and alkaline phosphatase levels. In 90% of the patients an underlying malignancy was identified. CONCLUSIONS: Bone marrow necrosis is caused by hypoxemia after failure of the microcirculation. Given the high rate of malignancy as an underlying disease association, an extensive search for neoplastic disease is justified whenever BMN is diagnosed. Pancytopenia and embolic processes are major complications that should be managed with supportive measures until effective treatment of the underlying disease has been administered. When necrosis resolves, repopulation of the bone marrow cavity with normal hematopoiesis is observed.     

E838对造血组织的放射防护作用

Ｅ８３８是一种新型放射防护剂，为炔雌醇衍生物。小鼠照射８Ｇｙ前第３、２、１天连续口服或腹腔注射Ｅ８３８０．２５μｇ／０．２ｍｌ，结果显示Ｅ８３８对受照小鼠ＣＦＵ－Ｓ（脾集落生成单位）和ＢＭＮ（骨髓有核细胞数）有明显的保护作用（经统计学处理差异有显著性）。为临床应用Ｅ８３８治疗放疗、化疗患者的白细胞减少症提供了依据     

Synthetic lethal targeting of RNF20 through PARP1 silencing and inhibition

Purpose

The identification of novel therapeutic targets that exploit the aberrant genetics driving oncogenesis is critical to better combat cancer. RNF20 is somatically altered in numerous cancers, and its diminished expression drives genome instability, a driving factor of oncogenesis. Accordingly, we sought to determine whether PARP1 silencing and inhibition could preferentially kill RNF20-deficient cells using a synthetic lethal strategy.

Methods

RNF20 and PARP1 were silenced using RNAi-based approaches. Direct synthetic lethal tests were performed by silencing RNF20 with and without PARP1 and the impact on cell numbers was evaluated using semi-quantitative imaging microscopy. Next, Olaparib and BMN673 (PARP1 inhibitors) were evaluated for their ability to induce preferential killing in RNF20 silenced cells, while real-time cell analyses were used to distinguish cell cytotoxicity from cell cycle arrest. Finally, quantitative imaging microscopy was employed to evaluate marks associated with DNA double-strand breaks (γ-H2AX) and apoptosis (cleaved Caspase-3).

Results

We found that PARP1 silencing resulted in a decrease in number of RNF20 silenced cells relative to controls. We further found that Olaparib and BMN673 treatments also resulted in fewer RNF20 silenced cells relative to controls. Finally, we found by quantitative imaging microscopy that RNF20 silenced cells treated with BMN673 exhibited significant increases in γ-H2AX and cleaved Caspase-3, suggesting that these treatments induce DNA double-strand breaks that are not adequately repaired within RNF20-silenced cells.

Conclusions

Collectively, our data indicate that RNF20 and PARP1 are synthetic lethal interactors, suggesting that cancers with diminished RNF20 expression and/or function may be susceptible to PARP1 inhibitors.

     

Loss of expression of the p16INK4/CDKN2 gene in cutaneous malignant melanoma correlates with tumor cell proliferation and invasive stage

The G₁/S checkpoint of the cell cycle is regulated by p16, p53 and RB tumor suppressor genes. Loss of expression of the p16^INK4 tumor suppressor protein, the product of the CDKN2 gene, has been associated with a wide variety of human malignancies. Mutations, loss of heterozygosity and deletions of the CDKN2 locus have been reported in sporadic and familial cutaneous malignant melanomas (CMM). To investigate the role of the alterations of p16 expression in melanoma, we evaluated by immunohistochemistry the p16 expression and cell proliferation in 79 primary CMM and 10 benign melanocytic nevi (BMN). Forty-six melanomas (58%) and all BMN were found to be p16 positive; 33 melanomas (42%) were considered p16 negative. The extent of invasion according to Clark was significantly higher in p16-negative tumors than in p16-positive tumors. Cell proliferation as expressed by the proportion of positive cells in Ki-67 immunostaining was found to be significantly higher in p16-negative tumors than in p16-positive tumors, although there was no significant difference in the mitotic index between p16-positive and p16-negative tumors. In p16-positive tumors, the number of Ki-67-positive cells correlated with the mitotic index; in p16-negative tumors, there was no correlation between these parameters. Our data suggest that loss of p16 expression is more common in advanced melanomas, and that G₁/S checkpoint regulation is disrupted in p16-negative melanomas. Our results show that loss of p16 expression is a common event in primary melanomas, which further substantiates the role of p16 as a major tumor suppressor. Int. J. Cancer 74:255-259, 1997. © 1997 Wiley-Liss, Inc.     

CYP1A1 Gene Polymorphisms: Modulator of Genetic Damage in Coal-Tar Workers

Aim: It is well known that polycyclic aromatic hydrocarbons (PAHs) such as benzo (a) pyrene have carcinogenicproperties and may cause many types of cancers in human populations. Genetic susceptibility might be due tovariation in genes encoding for carcinogen metabolizing enzymes, such as cytochrome P-450 (CYP450). Our studyaimed to investigate the effect of genetic polymorphisms of CYP1A1 (m1 and m2) on genetic damage in 115 coaltarworkers exposed to PAHs at their work place. Methods: Genetic polymorphisms of CYP1A1 were determinedby the PCR-RFLP method. Comet and buccal micronucleus assays were used to evaluate genetic damageamong 115 coal tar workers and 105 control subjects. Results: Both CYP1A1 m1 and CYP1A1 m2 heterozygousand homozygous (wt/mt+mt/mt) variants individually as well as synergistically showed significant association(P<0.05) with genetic damage as measured by tail moment (TM) and buccal micronuclei (BMN) frequencies incontrol and exposed subjects. Conclusion: In our study we found significant association of CYP1A1 m1 and m2heterozygous (wt/mt)+homozygous (mt/mt) variants with genetic damage suggesting that these polymorphismsmay modulate the effects of PAH exposure in occupational settings.     

PARP1 expression,activity and ex vivo sensitivity to the PARP inhibitor,talazoparib (BMN 673), in chronic lymphocytic leukaemia

In chronic lymphocytic leukemia (CLL), mutation and loss of p53 and ATM abrogate DNA damage signalling and predict poorer response and shorter survival. We hypothesised that poly (ADP-ribose) polymerase (PARP) activity, which is crucial for repair of DNA breaks induced by oxidative stress or chemotherapy, may be an additional predictive biomarker and a target for therapy with PARP inhibitors.We measured PARP activity in 109 patient-derived CLL samples, which varied widely (192 – 190052 pmol PAR/10⁶ cells) compared to that seen in healthy volunteer lymphocytes (2451 – 7519 pmol PAR/10⁶ cells). PARP activity was associated with PARP1 protein expression and endogenous PAR levels. PARP activity was not associated with p53 or ATM loss, Binet stage, IGHV mutational status or survival, but correlated with Bcl-2 and Rel A (an NF-kB subunit). Levels of 8-hydroxy-2′-deoxyguanosine in DNA (a marker of oxidative damage) were not associated with PAR levels or PARP activity. The potent PARP inhibitor, talazoparib (BMN 673), inhibited CD40L-stimulated proliferation of CLL cells at nM concentrations, independently of Binet stage or p53/ATM function.PARP activity is highly variable in CLL and correlates with stress-induced proteins. Proliferating CLL cells (including those with p53 or ATM loss) are highly sensitive to the PARP inhibitor talazoparib.     

Treatment of Relapsed/Refractory Germ Cell Tumours: An Equipoise Between Conventional and High Dose Therapy

OPINION STATEMENT: Patients with relapsed germ cell tumors (GCT) are potentially curable despite the failure of initial cisplatin based therapy. The recent identification of robust prognostic markers has helped clarify this area of uncertainty. However, unlike the initial treatment of metastatic disease where cisplatin based combination therapy is standard of care, there is no consensus on treatment in the relapsed setting. Instead there is a genuine equipoise between high dose therapy (HDCT) and conventional dose therapy (CDCT) in this relapsed setting. The randomised data fails to support the use of HDCT although retrospective analysis consistently shows it may be superior, especially if tandem or triple high dose therapy is used. This has resulted in different approaches worldwide with some stating HDCT should not be used outside of a trial and others suggesting it is standard of care. Re-challenging relapsed patients with conventional dose cisplatin based therapy would seem to be counterintuitive, but the addition of drugs such as ifosamide and paclitaxel results in genuine activated in selected patients with relapsed disease. This appears particularly relevant as HDCT is associated with significant morbidity and mortality, which was highlighted in a randomised trial. However large single institution data suggests this treatment related toxicity may not be such as concern and treatment related mortality can be as low as only 3 % in selected centres. Overall there is a need to answer this question of CDCT v.s. HSCT definitively. For this reason a prospective global randomised trial (TIGER trial) comparing conventional dose therapy (paclitaxel, ifosamide and cisplatin [TIP]) and triple high dose therapy (paclitaxel and ifosamide followed by high dose carboplatin and etoposide [TI CE]) is planned for 2012 (TIGER trial). Due to the rarity of this disease and complexities associated with a global trial, this study faces many challenges. Nevertheless it is hoped that it will finally address this area major of uncertainty in GCTs.     

Complete atrioventricular block induced by rituximab in monotherapy in an aged patient with non-Hodgkin’s diffuse large B-cell lymphoma

Rituximab is a treatment option to non-Hodg kin's diffuse large B-cell lymphoma (NHDLBCL) in advanced stage and comorbility. It is known the cardiotoxicity effect of this drug, but there is no previous report describing a complete atrioventricular block (CAVB) secundary to treatment with Rituximab. We present an elderly woman treated with monotherapy with Rituximab who experienced a CAVB after administration of the fifth dose of this drug.     

Follicular non-Hodgkin's lymphoma with refractory paraneoplastic pemphigus: case report with review of novel treatment modalities

In this paper a patient with a non-Hodgkin's lymphoma (NHL) and paraneoplastic pemphigus (PNP) is described. PNP is a very rare, painful mucocutaneous intraepithelial blistering disease associated with occult or confirmed malignancy. Patients with PNP show severe, progressive mucocutaneous disease with a high mortality rate, because of drug-induced infectious complications. The patients sometimes benefit from high doses of oral corticosteroids. However, pulse therapy with high doses of prednisolone (or dexamethasone) in combination with other immunosuppressants induces variable and inconstant results. Intravenous immunoglobulin (IVIg) has been applied in different cases of PNP with encouraging results. Plasmapheresis or plasma exchange (PE) in combination with corticosteroids and/or cyclophosphamide or azathioprine showed similar rapid and beneficial results in association with decreasing auto-antibody levels in this group of refractory pemphigus. Another interesting therapeutic option is rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, which is found on the surface of normal and malignant B-lymphocytes. Administration of rituximab for patients with PNP in combination with follicular NHL is not always successful regarding oral lesions as we report in this case. PE leading to prompt depletion of autoreactive antibodies combined with immunosuppressants or synchronisation of PE with IVIg seems the best treatment modality for this refractory group, but the therapeutic value and appropriate timing of rituximab obviously deserve further evaluation in patients with low grade NHL and PNP.     

Polymorphic hCHK2/hCds1 codon 84 allele and risk of squamous cell carcinoma of the head and neck--a case-control analysis.

Checkpoint kinase 2 (hCHK2/hCds1) is a tumor suppressor gene involved in cell-cycle control. A hCHK2/hCds1 polymorphism in codon 84 (A-->G at nucleotide 252) was recently identified in Li-Fraumeni syndrome patients. Because cell cycle regulates DNA repair that is associated with cancer risk, we hypothesized that this new polymorphism exists in the general population and is associated with cancer risk. To test this hypothesis, we evaluated the role of this polymorphism in a case-control study of 215 non-Hispanic white patients with newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) and 229 frequency-matched cancer-free controls. We found that the hCHK2/hCds1 codon 84 variant was rare and less frequent in non-Hispanic white cases (0.0186) than in controls (0.0437; P = 0.033). Although no variant homozygotes were detected in these cases and controls, heterozygosity protected against SCCHN, representing a 60% reduction of risk (adjusted odds ratio = 0.40; 95% confidence intervals, 0.17-0.93) compared with wild-type homozygotes. The variant allele was also rare in other ethnic groups (0.0487, 0.0095 and 0.0541 in 115 African Americans, 105 Hispanic Americans and 111 native Chinese, respectively), and only one variant homozygous individual (a Chinese subject) was identified. These results suggest that this hCHK2/hCds1 codon 84 polymorphism is rare and may have a protective role in the aetiology of SCCHN in non-Hispanic whites. Larger studies are warranted to confirm this finding and further mechanistic studies are needed to understand biological relevance of this polymorphism.     

A remote temperature sensor for an ultrasound hyperthermia system using the acoustic signal derived from the heating signals

We demonstrate a non-invasive technique, based on the modal frequency shift of a region insonified by a dual-beam ultrasound (US) transducer (region of interest, ROI), to remotely assess the temperature of the region in a tissue-mimicking object. The application is in ultrasound hyperthermia systems for controlled maintenance of tumour temperature during chemotherapy. Towards this, we have characterised the variation of the storage modulus with the temperature of two tissue-mimicking visco-elastic materials. Due to this variation in tissue storage modulus (and viscosity), we have observed a shift in the resonant modes of the ROI, vibrated remotely with a dual-beam focussed ultrasound transducer. A modal analysis of the vibrating ROI is done to identify the modes captured by the detector. A variation in this modal frequency with temperature is computed and matches reasonably well with the experimental measurements. Through this, we demonstrate that an ultrasound hyperthermia system can have a remote temperature sensor without using an additional imaging modality.     

Cytoreductive surgery and intraperitoneal chemotherapy: an evidence-based review—past,present and future

Peritoneal carcinomatosis (PC) has historically been considered a terminal condition with merely palliative treatment achieving a survival rate measured in months. Cytoreductive surgery (CyRS) and intraperitoneal chemotherapy (IPC) have emerged as potentially effective regional treatments with the potential for long-term survival in well-selected patients. The fundamentals of CyRS and IPC are patient selection and complete cytoreduction. Since there is now sufficient evidence for the superiority of CyRS and IPC to systemic chemotherapy alone in a highly select group of patients, surgeons and oncologists should be aware of this modality as a potential benefit for patients with PC. The aim of this report is to highlight cancer-specific evidence in the context of ongoing studies regarding the outcome of this treatment.