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Background Talimogene laherparepvec (T-VEC), an oncolytic virus, was designed to selectively replicate in and lyse tumor cells, releasing tumor-derived antigen to stimulate a tumor-specific immune response. Methods In this phase II study in patients with unresectable stage IIIB-IV melanoma, we evaluated non-injected lesions to establish whether baseline or change in intratumoral CD8 + T-cell density (determined using immunohistochemistry) correlated with T-VEC clinical response. Results Of 112 enrolled patients, 111 received ≥1 dose of T-VEC. After a median follow-up of 108.0 weeks, objective/complete response rates were 28%/14% in the overall population and 32%/18% in patients with stage IIIB-IVM1a disease. No unexpected toxicity occurred. Baseline and week 6 change from baseline CD8 + T-cell density results were available for 91 and 65 patients, respectively. Neither baseline nor change in CD8 + T-cell density correlated with objective response rate, changes in tumor burden, duration of response or durable response rate. However, a 2.4-fold median increase in CD8 + T-cell density in non-injected lesions from baseline to week 6 was observed. In exploratory analyses, multiparameter immunofluorescence showed that after treatment there was an increase in the proportion of infiltrating CD8 + T-cells expressing granzyme B and checkpoint markers (programmed death-1, programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen-4) in non-injected lesions, together with an increase in helper T-cells. Consistent with T-cell infiltrate, we observed an increase in the adaptive resistance marker PD-L1 in non-injected lesions. Conclusions This study indicates that T-VEC induces systemic immune activity and alters the tumor microenvironment in a way that will likely enhance the effects of other immunotherapy agents in combination therapy. Trial registration number NCT02366195. © Author(s) 2021.

The epidemiologic correlation of melanoma and chronic lymphocytic leukemia (CLL) has been the subject of several population studies. In the present article, through the presentation of five illustrative cases of patients with melanoma and CLL, several aspects of this complex relationship are highlighted, with a focus on the increased incidence of melanoma in patients with CLL, its speculated etiology, and the impact of CLL stage and disease duration on the incidence and prognosis of melanoma. Furthermore, the rare entity of the synchronous diagnosis of melanoma and CLL in biopsied lymph nodes is discussed, along with its implications on the diagnostic and therapeutic procedures. In addition, the available data on the treatment choices in patients with melanoma and CLL are presented and the efficacy and safety of fludarabine, anti-CD20 monoclonal antibodies, new targeted therapies for CLL, and checkpoint inhibitors are further discussed. Finally, since no formal guidelines are available for the management of this group of patients, guidelines are proposed for skin-cancer screening in patients with CLL, for the correct interpretation of BRAF mutation analysis in lymph-node specimens with ‘collision of tumors,’ and for the optimal use of imaging studies in the diagnosis of metastatic disease in patients with CLL and melanoma, while a treatment approach for such patients is also suggested. The information and proposed guidelines provided in the present article comprise a useful guide for physicians managing such patients, focusing on diagnostic challenges and therapeutic dilemmas posed by the coexistence of the two disease entities. © The Author(s), 2020.

Transient receptor potential vanilloid 1 (TRPV1) receptor antagonists have gained much attention for their potential to treat inflammatory and neuropathic pain. However, systemic administration of TRPV1 antagonists induces a period of hyperthermia, a potential liability for small molecule development. Here we characterize the effects of the TRPV1 antagonist A-425619 on body temperature (T(b)) in the rat when administered: (1) alone at different times of the circadian cycle, (2) as repeated hourly or daily treatment, (3) as pre-treatment to prevent capsaicin-induced hypothermia, (4) to capsaicin-desensitized animals, and (5) prior to a heat challenge. Changes in T(b) were compared with compound exposure data, locomotor activity, and time course of efficacy in inflammatory pain models. Without affecting locomotor activity, oral administration of A-425619 induced a transient period of hyperthermia that was followed by a period of hypothermia, a profile unique among reported TRPV1 antagonists. Repeated hourly administration of A-425619 produced an increase in T(b) similar to a single administration. A-425619 had no effect on T(b) when administered to capsaicin-desensitized rats. The duration of A-425619-induced hyperthermia, but not hypothermia, was dependent on the time of the circadian cycle when administered. Pre-treatment with A-425619 attenuated capsaicin-induced hypothermia and did not potentiate T(b) or alter thermoregulatory behavioral responses during a heat challenge. These results indicate that A-425619-induced hyperthermia is transient, circadian-dependent, not related to exposure levels, locomotor activity, or time course of analgesic action, and does not affect the ability to thermoregulate during a heat challenge.

Surgery remains the mainstay of melanoma therapy at all sites. Melanoma is widely believed to be a radioresistant tumor, a misconception that has historically led to the limited use of RT for its treatment. We searched pubmed from 1978 until 2010 by means of prospective randomized trials. The aim was to assess the potential impact of radiotherapy (RT) on local control, quality of life and overall survival. Radiotherapy should be considered in lentigo maligna, especially in elderly patients with extensive or unresectable disease in difficult areas on the face, with adequate tumor control with good cosmetic and functional results. In addition, radiation therapy provides effective palliation in patients with metastatic malignant melanoma. Doses up to 30 Gy or BED > 39.0Gy were found to be associated with prolonged palliation. These findings should be viewed with caution because the lack of data regarding performance status as well as other unknown confounding factors limits the applicability of retrospectives studies. We recommend that higher doses of RT be considered when using RT for the palliation of patients with metastatic melanoma and a performance status that could tolerate such therapy. In the futute, the combination of radiation therapy with hyperthermia may be a reasonable therapeutic option. © 2011 Bentham Science Publishers Ltd.

The two most commonly used alternative strategies of endocrine treatment in postmenopausal women with hormone-receptor-positive breast cancers are either the interference with estrogen signaling by a selective estrogen-receptor modulator, such as tamoxifen, or the inhibition of endogenous estrogen production via an aromatase inhibitor (Al). Tamoxifen has been used effectively for over 30 years and it is generally accepted that it exerts a beneficial effect on lipid profiles. Still, its use has been questioned especially in recent years, following indication of an increased risk of endometrial cancer, thromboembolic events and tolerability concerns, along with, most importantly, the development of resistance during long-term adjuvant treatment. On the other hand, inhibition of aromatase, the enzyme that converts androgens to estrogens, with an Al has been shown to be an effective alternative to tamoxifen in multiple clinical trials with anastrozole, letrozole and exemestane. At the same time, due to the high levels of estrogen deprivation caused by Als, there is uncertainty over the long-term safety of these agents, in particular with respect to the effects on bone metabolism of postmenopausal women and the lipid profile, and thus, cardiovascular disease. Current data on Als showing favorable, neutral or unfavorable effect on different lipid parameters in various studies, do not allow the drawing of any final conclusions about their effect on lipid metabolism. However, considering disease outcome, particularly in high-risk patients, the benefits of receiving an Al are likely to outweigh the disadvantages of any changes to lipid profiles. Therefore, each patient should be carefully evaluated before the appropriate therapy is decided and blood lipid levels should be monitored during adjuvant hormonal treatment; the instigation of lipid-lowering treatment should be undertaken if required.

Background: Cystosarcoma phylloides (CP) is an extremely rare form of breast cancer with an unpredictable clinical course. The histological characteristics of this neoplasm have not proved to offer much in the estimation of prognosis of these patients. Patients and methods: In our clinics, in a time period of 38 years, 22 patients with cystosarcoma phylloides were treated. There were 5 cases of malignancy, 15 cases with benign tumors, and two cases histologically characterized as borderline neoplasia. Metastases were manifested in one patient. All patients were on a 5-year follow-up, except in five cases, one operated three years ago and four operated within the last two years. Results: 16 of 22 patients did not present any signs of local recurrence or metastases. There were three patients that manifested local recurrence and underwent supplementary ongectomy or mastectomy and are free of recurrence ever since. One patient with metastatic CP died. Conclusion: Independently of its histopathological behavior, CP is a tumor difficult to be treated. Meticulous follow-up is mandatory in order to manage possible recurrence of the neoplasm. © 2009 Stamatakos et al; licensee BioMed Central Ltd.

s / Drug and Alcohol Dependence 140 (2014) e2–e85 e81 Opioids with lower brain uptake are less recognizable in rat drug discrimination tests and thus potentially less subject to abuse Stephen D. Harrison1, H. Gursahani1, J. Pfeiffer1, K. Gogas1, J. Riggs1, T. Riley1, D. Gauvin2, S. Doberstein1 1 Nektar Therapeutics, San Francisco, CA, United States 2 MPI Research, Inc., Mattawan, MI, United States Aims: Prescription opioids are the mainstay of analgesic therapy, although their abuse is rising to epidemic proportions. A solution to this problemwould be to separate opioid analgesia from abuse potential. Drugs that are readily recognized as opioids are considered more prone to abuse. We have tested whether lowering the rate of brain entry of an opioidwillmake it less recognizable in rat drug discrimination assays. Methods: Various mu-opioid agonists were assessed for different properties: (1) potency by receptor binding and elicitedfunction in vitro; (2) brain-uptake rate relative to an antipyrine control compound by in situ brain perfusion; (3) potential to be recognized as a mu-opioid agonist by rats trained to recognize oxycodone in the drug discrimination assay. Correlations between these parameters were made to establish underlying relationships between them. Results: The rate of brain uptake and potency of mu-opioid agonists both correlate inversely with the minimum discriminable dose (MDD) in the rat drug discrimination assay. The highest MDD was observed for opioids with dramatically reduced brain uptake rates (between 0.01 and 0.1 relative to antipyrine) compared to commercially used opioids (brain uptake rates between 0.5 and 10 relative to antipyrine). Conclusions: Opioid agonists that have a high potency against the mu-opioid receptor and which have a high rate of entry into the brain are more likely to be recognized as a mu-opioid agonists. A low MDD is considered to be reflective of potential abuse liability and consequently opioids with low brain entry rates, and thus higher MDD values, may have less abuse potential. Consequently it may be possible to maintain analgesic efficacy and yet reduce the potential for the abuse, by reducing brain entry rate. Mu-opioid agonists with an engineered reduction in brain uptake rate offer a potential approach to achieving this goal. Financial support: Nektar Therapeutics. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.239 Differences in cannabis withdrawal symptoms between individuals with and without attention deficit hyperactivity disorder Karen Hartwell1,2, E. Chauchard3,4, D.A. Gorelick3, Aimee McRae-Clark1 1 Department of Psychiatry, MUSC, Charleston, SC, United States 2 Ralph H. Johnson VAMC, Charleston, SC, United States 3 Intramural Research Program, NIDA, Bethesda, MD, United States 4 Toulouse University Octogone-CERPP, Toulouse

s / Drug and Alcohol Dependence 140 (2014) e169–e251 e239 therefore be an appropriate and potentially effective cognitive rehabilitation tool in this population. Financial support: NIDA, NIMH. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.660 Abuse potential assessment of novel opioid analgesic NKTR-181: Implications for labeling and scheduling Lynn R. Webster1, S. Smith2, J. Silowsky2, K. Gogas2, A. Odinecs2, M. Eldon2, N. Abrouk2, R. Medve2, J. Henningfield3, A. Buchhalter3, E. Cone3, R. Fant3, S. Schnoll3 1 CRI Lifetree, Salt Lake City, UT, United States 2 Nektar, San Francisco, CA, United States 3 PinneyAssociates, Bethesda, MD, United States Aims: Discuss challenges to opioid development when early data suggest the possibility of less restrictive scheduling than CII. Thiswill be illustratedby initial findings forNKTR-181.NKTR-181 is a newmolecule intended to provide analgesic efficacy of prototypic mu-opioids but with reduced respiratory depression, sedation and abuse potential. Mu-opioid activity of NKTR-181 is retained in a morphinan core to which polymers are covalently bound resulting in slower and lower brain penetration upon oral or parenteral administration to animals than prototypic opioids. Morphinans are placed inSchedule II duringdevelopmentandcanonlybe rescheduled if the abuse potential assessment by FDA (during review of the New Drug Application) warrants less restrictive scheduling. This regulatorychallenge isnotunique toNKTR-181butdata concerning NKTR-181 will be included to support the commentary. Although oralNKTR-181 is readily absorbed, time course of pupil constriction lags drug plasma appearance 2–3h, consistent with a reduced rate of CNS uptake. These effects are maintained after repeat administration with no evidence of tolerance. Nonclinical studies suggest mu-opioid CNS effects are of substantially lower potency for NKTR181 compared to other opioids with mixed findings across models, e.g., NKTR-181 produced dose-related generalization similar to prototypic opioids at doses many times analgesic doses but with significantly reduced reinforcing effects. Opioid-like side-effects linked with abuse potential (e.g., “dreamy”, “sleepy”, “high”) were not reported in healthy volunteers at expected therapeutic doses with central effects no different than placebo. Conclusions: A preliminary 8-factor analysis of NKTR-181 suggests lower abuse potential than prototypic Schedule II opioids. How FDA addresses this challenge to drug development and scheduling will have implications for other drugs in development. Financial support: Nektar. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.661 Brief screening for alcohol and drug problems among prisoners Matthew Webster, Carl Leukefeld, Michele Staton-Tindall, Jamieson L. Duvall, Carrie B. Oser, Jennifer R. Havens Center on Drug & Alcohol Research, University of Kentucky, Lexington, KY, United States Aims: Although drug and alcohol abuse rates are high among prisoners, these problems often go undetected, which represent lost treatment opportunities. Brief, no-cost screening instruments can be used to efficiently identify individuals who could be further assessed and who may benefit from treatment. The purpose of this study is to examine the feasibility of using the Alcohol Use Disorders Identification Test (AUDIT) as a brief screener for alcohol use among prisoners and whether it can identify other drug problems. Methods: The AUDIT and the NIDA-modified Alcohol, Smoking, Substance Involvement Screening Test (NM-ASSIST) were administered to 382 prisoners in four Kentucky state prisons who were approaching release and consented to participate in NIDA Criminal Justice Drug Abuse Treatment Studies (CJDATS 2) cooperative agreement protocols. Participants were divided into two groups based on whether they screened positive (n=189) or negative (n=193) on the AUDIT. NM-ASSIST Substance Involvement (SI) scores were calculated for each of the nine drugs measured by the NM-ASSIST and compared between AUDIT groups. Results: No significant differences in age, race, or rurality for AUDIT groups were found, but the AUDIT positive group had a significantly higher percentage of males (73.0% vs. 61.5%). ANCOVAs, controlling for gender, found significantly higher SI scores (p< .05) for the AUDIT positive group for cannabis (15.0 vs. 10.3), cocaine (15.3 vs. 8.0), prescription stimulants (5.0 vs. 1.9), inhalants (0.6 vs. 0.2), sedatives (10.7 vs. 5.7), hallucinogens (1.1 vs. 0.5), and prescription opiates (15.6 vs. 11.1). No differences were found for SI scores for methamphetamine or street opioids. Conclusions: Findings suggest that prisoners who screen positive on the AUDIT have higher drug risk than those who screen negative, which suggests that the AUDIT may be an indirect screening for other substance problems. The majority of SI scores fell in the moderate risk range (4–26), suggesting that prisoners have drug risk for multiple drugs. Financial support: CJDATS 2 is funded by NIDA in collaboration with SAMSHA and DOJ. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.662 Association of the A335G polymorphism with striatal dopamine D2/3 receptor availability in healthy men and women Elise Weerts, M. McCaul, H. Kuwabara, M. Stephens, X. Xu, D. Wong, G.S. Wand Johns Hopkins University, Baltimore, MD, United

Aims: Estimation of prevalence of autoimmune thyroid disorders in Greek breast cancer patients (prospective study). Methods: The prevalence of autoimmune thyroiditis was estimated in 310 Greek breast cancer patients, in 100 women with benign breast disease and in 190 women without any breast disease, by submitting them to clinical examination, ultrasound thyroid evaluation, serum thyroid antibody determination and fine needle aspiration (FNA) of the thyroid gland. Results: Autoimmune thyroiditis was found in 136/310 (43.9%) breast cancer women: 95 were diagnosed by positive autoantibodies, 19 had positive FNA findings and 22 had both positive autoantibodies and positive FNA findings. In 117 cases, thyroid autoantibodies were positive (37.7% whereas the control groups had respective rates of 19% and 18.4% autoantibody positivity). Conclusions: There is evidence of high incidence of autoimmune thyroiditis in Greek breast cancer patients, increasing in relation to cancer stage. (C) 2001 Harcourt Publishers Ltd.

Objectives: to assess the incidence and the rate of progression of internal carotid artery (ICA) stenosis and to determine the related risk factors. Design: open prospective study. Materials and methods: between 1988-1947, 442 carotid al arteries with various degrees of stenosis were followed using colour duplex ultrasonography every 6 months. Of these arteries, 290 (66%) were asymptomatic, 62 (14%) had caused transient ischaemic attack and 90 (20%) a stroke. In 145 eases (33%), there was concomitant coronary artery disease (CAD), in 134 (30%) diabetes mellitus, in 248 (56%) hypertension, in 139 (31%) hypercholesterolaemia and in 370 (84%) history of smoking. Of the plaques, 44 (10%) were uniformly echolucent, 19 (4%) haemorrhagic, 136 (31%) predominantly echolucent, 146 (33%) predominantly echogenic and 97 (22%) uniformly echogenic. Results: significant progression of stenosis occurred in 82 cases (19%). The mean progression rate in these cases was 15% annually (range: 5-50%). There uns no statistically significant correlation between the progression of the ICA stenosis and initial neurological status, age, gender, diabetes mellitus, hypertension, hypercholesterolaemia and smoking habit. Stenosis progression was correlated only with CAD and the ultrasonographic characteristics of the plaques. Patients with CAD as well as those with uniformly echolucent plaques presented a higher incidence and rate of stenosis progression (p

In 42, postmenopausal women with breast cancer aged 48-85 (mean age 62.4) years, the blood sex hormone levels were measured before and after 6 months of tamoxifen administration (20 mg daily). Follicle-stimulating hormone and luteinizing hormone levels decreased after tamoxifen administration (p < 0.001), but remained in the postmenopausal range, oestradiol levels increased (p < 0.05), sex hormone binding globulin levels increased (p < 0.001), testosterone levels remained stable (p > 0.1), free testosterone levels decreased (p < 0.001), Delta(4)-androstenedione, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate levels remained unchanged (p > 0.1), and basal prolactin levels and their response to thyrotrophin-releasing hormone injection decreased significantly (p < 0.001) after tamoxifen therapy, It is concluded that tamoxifen has many and diverse effects on sex hormone levels, and its adverse effects do not affect the biological status of the patient, except perhaps for oestradiol, that increases in some cases, whose possible effect must be studied.

The DNA content of ductal breast carcinomas of varying histological grade was measured using static image cytometry and correlated with pS(2) expression in the tumour cells. Our study was performed on imprint of surgical biopsies of 60 women with ductal breast cancer. A statistically significant difference was observed between pS(2)(+) expression and grade of malignancy (P

OBJECTIVE: To investigate pS2 protein expression and estrogen (ER) and progesterone receptor (PR) status of imprints from surgical biopsies of breast cancer cases in relation to the histologic grade of malignancy. STUDY DESIGN: The study group consisted of 50 cases of primary breast carcinomas. For the demonstration of pS2 protein expression an immunocytochemical avidin-biotin complex technique was applied. Monoclonal antibody pS2 was used as the primary antibody, diaminobenzidine as the chromogene and hematoxylin as the counterstain. For the evaluation of ERs and PRs, a biochemical method was applied. RESULTS: Sixty-two percent of breast cancer cases showed positive expression of pS2. Of the 31 pS2+ cases, 74% had positive ERs and PRs. A statistically significant difference was observed between pS2 protein expression, ER+, PR+ and histologic grade of malignancy (P ’ .001). CONCLUSION: Two groups of breast cancer cases can be distinguished: one group that is ER+, PR+ and pS2+, with low malignancy potential, and another group that is ER1, PR1 and pS21, with high malignancy potential. © 1997 The International Academy of Cytology Acta Cytologica.

Bone mineral density (BMD) in postmenopausal women with breast cancer and the effect of tamoxifen administration on it has not been adequately studied. For this reason we investigated the long-term effect of tamoxifen on bone mineral density (BMD) of postmenopausal women with breast cancer. Three groups of postmenopausal women with histologically diagnosed breast cancer were studied. The first group consisted of 64 women, aged 48-79 years, who had not taken tamoxifen and their BMD was measured at the beginning of the study. The results were compared with those of 321 healthy postmenopausal women matched for age and years since menopause. 26 of the 64 women in the first group, aged 48-79 years, formed a second group and their BMD was measured before, 6 and 12 months after tamoxifen administration (20 mg daily). The third group consisted of 27 women, aged 48-75 years, who had been on tamoxifen therapy for 0.5-10 years (mean time 2.5 years) and their BMD was measured at the beginning of the study, 6 and 12 months later on tamoxifen therapy. It was found that BMD in postmenopausal women with breast cancer was decreased when compared to that of normal postmenopausal women (p < 0.001). BMD did not decrease in women with breast cancer when measured before, 6 and 12 months after tamoxifen therapy (p > 0.1) and in the women who were on long-term tamoxifen therapy and their BMD did not change, 6 and 12 months later (p > 0.1). It is concluded that postmenopausal women with breast cancer have lower BMD when compared to that of normal postmenopausal women and that tamoxifen does not increase the age-related bone loss in these women. © 1994.