Pyoderma gangrenosum due to lenalidomide use for multiple myeloma.

Pyoderma gangrenosum has been described in association with multiple myeloma and usually affects patients with active/untreated disease. This dermatologic condition was shown to resolve after successful anti-myeloma therapy. We report herein occurrence of pyoderma gangrenosum involving bilateral knees in a patient with multiple myeloma responding to lenalidomide therapy. Previous papers claimed usefulness of thalidomide and its newer derivatives for the therapy of this neutrophilic dermatosis. Occurrence of pyoderma gangrenosum in a myeloma patient responding to lenalidomide would argue against its effectiveness in treating this skin condition. Moreover, the clinical setting suggested that lenalidomide either induced or contributed to the occurrence of pyoderma gangrenosum in our patient. If our hypothesis is correct, we expect more reports of pyoderma gangrenosum with the use of this class of pharmaceuticals.

Intravenous ascorbic acid as an adjuvant to interleukin-2 immunotherapy.

Interleukin-2 (IL-2) therapy has been demonstrated to induce responses in 10-20% of advanced melanoma and renal cell carcinoma patients, which translates into durable remissions in up to half of the responsers. Unfortunately the use of IL-2 has been associated with severe toxicity and death. It has been previously observed and reported that IL-2 therapy causes a major drop in circulating levels of ascorbic acid (AA). The IL-2 induced toxicity shares many features with sepsis such as capillary leakage, systemic complement activation, and a relatively non-specific rise in inflammatory mediators such as TNF-alpha, C-reactive protein, and in advanced cases organ failure. Animal models and clinical studies have shown rapid depletion of AA in conditions of sepsis and amelioration associated with administration of AA (JTM 9:1-7, 2011). In contrast to other approaches to dealing with IL-2 toxicity, which may also interfere with therapeutic effects, AA possesses the added advantage of having direct antitumor activity through cytotoxic mechanisms and suppression of angiogenesis. Here we present a scientific rationale to support the assessment of intravenous AA as an adjuvant to decrease IL-2 mediated toxicity and possibly increase treatment efficacy.

Newer developments in the immunotherapy of malignant melanoma.

Individuals with malignant melanoma present a variety of immune abnormalities including but not limited to cellular immune dysfunction, antigen presentation deficits, and cytokine production defects. Therefore, enhancing the immune system potential represents an appealing avenue for melanoma therapy. The authors review the immune therapies currently in clinical use as well as the most promising immunotherapy candidates. Ipilimumab, a monoclonal antibody against the CTLA-4, was approved for the therapy of advanced melanoma in 2011. In addition, sizeable anti-melanoma activity has recently been shown with the use of other agents including anti-PD-1/anti-PD-1 ligand antibodies. Consequently, these experimental immunotherapy agents may soon become important items in the anti-melanoma armamentarium.

Malignant melanoma in pigmented skin: does the current interventional model fit a different clinical, histologic, and molecular entity?

BACKGROUND: Although the incidence of malignant melanoma in African Americans is considerably lower than in Caucasians, African Americans have a less-favorable prognosis related to later presentation and more deeply invasive lesions at diagnosis. OBJECTIVE: To review the current literature addressing the specific clinical, histopathologic, and molecular features of melanoma in darkly pigmented individuals. METHODS: We reviewed the most up-to-date literature pertaining to melanoma in this patient population, including data from clinical studies, epidemiologic analyses, and molecular and genetic studies. RESULTS: Several studies have suggested differences between lightly and darkly pigmented populations with regard to clinicopathologic character and the underlying genetic processes affecting its pathogenesis. CONCLUSION: Further investigation is warranted to better elucidate the clinical and underlying biological differences in melanoma between Caucasians and African Americans. Such research may help to ameliorate the disparities in melanoma outcomes through improved screening, public health measures aimed at prevention, and potentially novel targeted therapeutic approaches.

Etanercept decreases the innate immune wounding response in psoriasis.

Cathelicidin is increased when normal skin is injured and in psoriasis lesions where it has been suggested to play a pivotal role in inflammation through interactions with self-DNA and toll-like receptor 9 (TLR-9) in keratinocytes and plasmacytoid dendritic cells. Because of etanercept's success in treating psoriasis, we hypothesized that etanercept may suppress TLR-9 and cathelicidin induction. Examination of experimentally induced wounds of psoriatic lesional and non-lesional skin, and comparison with wounded normal skin, shows that the induction of cathelicidin and TLR-9 is greatly enhanced in lesional psoriatic skin. Six weeks of etanercept appears not to affect the baseline expression of cathelicidin or TLR-9, but does blunt the induction of cathelicidin in psoriasis with wounding. These findings support the role of cathelicidin in the enhancement of local inflammation in psoriasis and may partially explain one of the mechanisms enabling TNF-α inhibitors to successfully treat this disorder.

Muehrcke's lines (Leukonychia striata) due to transretinoic acid therapy for acute promyelocytic leukemia.

Transverse leukonychia (Leukonychia striata or Muehrcke's lines) has been described with the use of several drugs in oncology, mainly chemotherapeutic agents. This condition is thought to represent an abnormality of the vascular nail bed. As the diagnosis is clinical and the condition is self-limited, referral to other specialists is usually not required. We report the first case of transverse leukonychia related to the use of transretinoic acid for acute promyelocytic leukemia. Physician awareness of transverse leukonychia is important in order to reassure the patients and avoid unnecessary (and often not inexpensive) diagnostic work-up.

Hair repigmentation associated with the use of lenalidomide: graying may not be an irreversible process!

We report the first case of progressive hair repigmentation associated with the use of lenalidomide in an elderly patient with multiple myeloma. The influence of lenalidomide on follicular melanogenesis may involve removing the inhibitory influences of some cytokines such as IL-1, IL-6 and TNF-α. In addition, certain endocrine effects of lenalidomide on the hypophyseal-adrenal axis could explain its action on hair pigmentation. We further hypothesize that lenalidomide may be capable of stimulating migration and/or differentiation of melanocytes to promote repigmentation of gray hair follicles. Pending the clarification of how hair repigmentation occurs with lenalidomide, our observation materializes the concept that hair graying may not be an irreversible process, which opens avenues for targeted therapeutics in the fields of cosmetics and anti-aging medicine.

Exogenous endothelial cells as accelerators of hematopoietic reconstitution.

Despite the successes of recombinant hematopoietic-stimulatory factors at accelerating bone marrow reconstitution and shortening the neutropenic period post-transplantation, significant challenges remain such as cost, inability to reconstitute thrombocytic lineages, and lack of efficacy in conditions such as aplastic anemia. A possible means of accelerating hematopoietic reconstitution would be administration of cells capable of secreting hematopoietic growth factors. Advantages of this approach would include: a) ability to regulate secretion of cytokines based on biological need; b) long term, localized production of growth factors, alleviating need for systemic administration of factors that possess unintended adverse effects; and c) potential to actively repair the hematopoietic stem cell niche. Here we overview the field of hematopoietic growth factors, discuss previous experiences with mesenchymal stem cells (MSC) in accelerating hematopoiesis, and conclude by putting forth the rationale of utilizing exogenous endothelial cells as a novel cellular therapy for acceleration of hematopoietic recovery.

New frontiers in laser surgery.

The simultaneous advances in engineering, medicine, and molecular biology have accelerated the pace of introductions of new light-based technologies in dermatology. In this review, the authors examine recent advances in laser surgery as well as peer into the future of energy-based cutaneous medicine. The future landscape of dermatology will almost undoubtedly include (1) noninvasive imaging technologies and (2) improved "destructive" modalities based on real-time feedback from the skin surface.

Expression of the epigenetic factor BORIS (CTCFL) in the human genome.

BORIS, or CTCFL, the so called Brother of the Regulator of Imprinted Sites because of the extensive homology in the central DNA binding region of the protein to the related regulator, CTCF, is expressed in early gametogenesis and in multiple cancers but not in differentiated somatic cells. Thus it is a member of the cancer testes antigen group (CTAs). Since BORIS and CTCF target common DNA binding sites, these proteins function on two levels, the first level is their regulation via the methylation context of the DNA target site and the second level is their distinct and different epigenetic associations due to differences in the non-homologous termini of the proteins. The regulation on both of these levels is extensive and complex and the sphere of influence of each of these proteins is associated with vastly different cellular signaling processes. On the level of gene expression, BORIS has three known promoters and multiple spliced mRNAs which adds another level of complexity to this intriguing regulator. BORIS expression is observed in the majority of cancer tissues and cell lines analyzed up to today. The expression profile and essential role of BORIS in cancer make this molecule very attractive target for cancer immunotherapy. This review summarizes what is known about BORIS regarding its expression, structure, and function and then presents some theoretical considerations with respect to its genome wide influence and its potential for use as a vaccine for cancer immunotherapy.

Intravenous ascorbic acid to prevent and treat cancer-associated sepsis?

The history of ascorbic acid (AA) and cancer has been marked with controversy. Clinical studies evaluating AA in cancer outcome continue to the present day. However, the wealth of data suggesting that AA may be highly beneficial in addressing cancer-associated inflammation, particularly progression to systemic inflammatory response syndrome (SIRS) and multi organ failure (MOF), has been largely overlooked. Patients with advanced cancer are generally deficient in AA. Once these patients develop septic symptoms, a further decrease in ascorbic acid levels occurs. Given the known role of ascorbate in: a) maintaining endothelial and suppression of inflammatory markers; b) protection from sepsis in animal models; and c) direct antineoplastic effects, we propose the use of ascorbate as an adjuvant to existing modalities in the treatment and prevention of cancer-associated sepsis.

Polycystic ovary syndrome: focus on platelets and prothrombotic risk.

OBJECTIVES: Subjects with polycystic ovary syndrome (PCOS) were shown to carry an increased long-term cardiovascular risk. Systemic inflammation and reactive leukocytosis have also been described in PCOS. Recent research suggests the presence of an increased thrombotic risk in these patients. METHODS: We describe a cohort of PCOS patients presenting with persistent thrombocytosis. Our cohort included women aged 20-37 who also had moderate leukocytosis and neutrophilia. They showed normal mean platelet volume and platelet aggregation. We excluded any myeloproliferative conditions in all patients. RESULTS: The mean platelet count and standard deviation (SD) at presentation were 587 ± 61 × 10/L (normal 140-440 × 10/L). Median C-reactive protein (CRP) was 1.66 (range 1.2-2.2, normal <1 mg/dL). The platelet counts did not correlate with the CRP levels in our patients (Pearson correlation coefficient 0.171 and 0.170, respectively, P = 0.08). CONCLUSION: While the inflammatory state of PCOS could play a role in triggering an increased platelet count, the persistent thrombocytosis in our patients did not correlate with the CRP levels. Therefore, from an etiological perspective, thrombocytosis appears to be at least partially independent from the classical pathways of systemic inflammation. The preexisting procoagulant state in PCOS due to coagulation cascade stimulation, platelet activation, and endothelial dysfunction may be further fueled by the presence of persistent thrombocytosis. We propose a unique model for cardiovascular risk assessment in women with PCOS to include not only the classic cardiovascular risk factors, but also the parameters related to the proinflammatory and procoagulant tendencies manifested in PCOS.

Cutaneous sarcoidosis and malignancy: An association between sarcoidosis with skin manifestations and systemic neoplasia.

BACKGROUND: Whereas the association between multisystem and pulmonary sarcoidosis and malignancy has been documented, a relationship between cutaneous sarcoidosis and neoplasia has not yet been reported. Because cutaneous manifestations are seen in 20-25 percent of cases of sarcoidosis, this association deserves further investigation. METHODS: We reviewed the relevant literature, in addition to our case series, for a total of 110 cases of cutaneous and non-cutaneous sarcoidosis associated with malignancy with the aim of analyzing possible associations between cutaneous sarcoidosis and malignancy and to enhance the dermatologist's understanding of their critical role in the management of this disease. A search for consecutive cases, which were encountered during the past 20 years, identified 10 cases of confirmed cutaneous sarcoidosis. A review of the relevant literature was also conducted to identify cases of malignancy associated with cutaneous and non-cutaneous sarcoidosis. RESULTS: Cutaneous localization of sarcoidosis was identified in 58 of 100 patients with sarcoidosis and cancer found in the literature (58%) and in 4 of 10 patients in our series (40%). In our series, all cases manifested solid tumors, including breast (n=4 tumors), prostate cancer, colon cancer, kidney cancer, and squamous cell carcinoma of the skin (n=1 of each type). Among the 6 patients in our series with cancers and non-cutaneous sarcoidosis, the types of neoplasias encountered were renal cancer (n=1), mycosis fungoides (n=1), diffuse large B-cell lymphoma (n=1), colon cancer (n=1), and ADK of parotid (n=2). Neoplasias developed after an average of 7.14 years in the literature cases and eight years in our series, following the diagnosis of sarcoidosis. Among the 100 cases of cutaneous (n=58) and non-cutaneous (n=42) sarcoidosis associates with malignancy, which were extracted from the literature, hematologic malignancies accounted for 73 percent of cases and sarcoidosis preceded the detection of neoplasia in a majority (76%) of cases. Among 110 total cases analyzed in this paper, cutaneous sarcoidosis was confirmed in 56.4 percent of overall cases, a figure exceeding expected rates of cutaneous involvement (20-25%) in the general sarcoidosis population. CONCLUSIONS: Sarcoidosis with cutaneous manifestations appears to be associated with malignancy, possibly at a higher rate than other systemic forms of sarcoidosis. The predominant occurrence of sarcoidosis before the development of neoplasia may indicate that an immune dysregulation, such as impairment of cellular immunity mediated by sarcoidosis or the effects of treatment may contribute to an increased risk of malignancy in predisposed individuals. Physician recognition of this link between sarcoidosis and malignancy is critical. Dermatologists, in particular, play an important role, given that many of these associated cases manifest initially, or even solely, with cutaneous findings.

On the missing link between inflammation and cancer.

A various array of cutaneous granulomatous disorders have been found to be associated with internal malignancy. Among them, sarcoidosis, granuloma anulare (GA), psoriasis, pyoderma gangrenosum (PG), or other neutrophilic dermatoses such as the Sweet syndrome and subcorneal pustular dermatosis may precede the development of a neoplastic process by months or years. Pathogenic links of inflammation with cancer are discussed, including inflammation, intrinsic immune dysfunction, cytokines and interleukins, angiogenetic factors, and epigenetic changes.

Generalized cerebral atrophy seen on MRI in a naturally exposed animal model for Creutzfeldt-Jakob disease.

BACKGROUND: Magnetic resonance imaging has been used in the diagnosis of human prion diseases such as sCJD and vCJD, but patients are scanned only when clinical signs appear, often at the late stage of disease. This study attempts to answer the questions "Could MRI detect prion diseases before clinical symptoms appear?, and if so, with what confidence?" METHODS: Scrapie, the prion disease of sheep, was chosen for the study because sheep can fit into a human sized MRI scanner (and there were no large animal MRI scanners at the time of this study), and because the USDA had, at the time of the study, a sizeable sample of scrapie exposed sheep, which we were able to use for this purpose. 111 genetically susceptible sheep that were naturally exposed to scrapie were used in this study. RESULTS: Our MRI findings revealed no clear, consistent hyperintense or hypointense signal changes in the brain on either clinically affected or asymptomatic positive animals on any sequence. However, in all 37 PrPSc positive sheep (28 asymptomatic and 9 symptomatic), there was a greater ventricle to cerebrum area ratio on MRI compared to 74 PrPSc negative sheep from the scrapie exposed flock and 6 control sheep from certified scrapie free flocks as defined by immunohistochemistry (IHC). CONCLUSIONS: Our findings indicate that MRI imaging can detect diffuse cerebral atrophy in asymptomatic and symptomatic sheep infected with scrapie. Nine of these 37 positive sheep, including 2 one-year old animals, were PrPSc positive only in lymph tissues but PrPSc negative in the brain. This suggests either 1) that the cerebral atrophy/neuronal loss is not directly related to the accumulation of PrPSc within the brain or 2) that the amount of PrPSc in the brain is below the detectable limits of the utilized immunohistochemistry assay. The significance of these findings remains to be confirmed in human subjects with CJD.

Small cell lung cancer with paraneoplastic lipase production.

Kulchitsky cells represent the cells of origin of small cell lung cancer (SCLC). They display an antigenic makeup characteristic of both the neural crest and epithelium and have been shown to secrete both polypeptide hormones and enzymes. The coexistence of two or more (concomitant or sequential) paraneoplastic endocrine syndromes is possible with SCLC, and paraneoplastic amylase production has also been described with this malignancy. We present here the first patient with an extensive stage SCLC, exhibiting a marked paraneoplastic lipase production and a syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In our patient, the paraneoplastic hyperlipasemia paralleled both the initial SCLC response to chemotherapy and its subsequent clinicoradiological relapse.