Preservation of male fertility in patients undergoing pelvic irradiation.

As the number of cancer survivors increases, so does the demand for preserving male fertility after radiation. It is important for healthcare providers to understand the pathophysiology of radiation-induced testicular injury, the techniques of fertility preservation both before and during radiation, and their role in counseling patients on the risks to their fertility and the means of mitigating these risks. Impaired spermatogenesis is a known testicular toxicity of radiation in both the acute and the late settings, as rapidly dividing spermatogonial germ cells are exquisitely sensitive to irradiation. The threshold for spermatogonial injury and subsequent impairment in spermatogenesis is ~ 0.1 Gy and the severity of gonadal injury is highly dose-dependent. Total doses < 4 Gy may allow for recovery of spermatogenesis and fertility potential, but with larger doses, recovery may be protracted or impossible. All patients undergoing gonadotoxic radiation therapy should be counseled on the possibility of future infertility, offered the opportunity for semen cryopreservation, and offered referral to a fertility specialist. In addition to this, every effort should be made to shield the testes (if not expected to contain tumor) during therapy.

Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1ß Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation.

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet's disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1ß were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

Computational simulations establish a novel transducer array placement arrangement that extends delivery of therapeutic TTFields to the infratentorium of patients with brainstem gliomas.

BACKGROUND AND PURPOSE: Tumor treating fields (TTFields) are a non-invasive, efficacious treatment modality currently approved for supratentorial glioblastomas. Despite their ability to improve overall survival in supratentorial tumors, the current placement of arrays is limited to the supratentorial head, precluding its use in infratentorial tumors. Infratentorial malignancies are in need of new therapy modalities given their poor prognoses in both children and adults. The aim of this research is to determine whether rearrangement of TTFields may allow for management of infratentorial tumors. MATERIALS AND METHODS: Delivery of TTFields using Novocure's prototype Optune™ device human male head model was simulated based on brain MRIs from patients with brainstem gliomas to develop a novel array layout designed to extend adequate infratentorial coverage. RESULTS: Array placement on the vertex, bilateral posterolateral occiput, and superior-posterior neck achieved intensities above 1.1 V/cm (average 1.7 V/cm; maximum 2.3 V/cm) in the vertical field direction and above 1 V/cm (average 2 V/cm; maximum 2.8 V/cm) in the horizontal field direction of the infratentorium. The calculated field intensity within the simulated tumors were in the therapeutic range and demonstrated the effective delivery of TTFields to the infratentorial brain. CONCLUSIONS: Our findings suggest that rearrangement of the TTFields standard array with placement of electrodes on the vertex, bilateral posterolateral occiput, and superior-posterior neck allows for adequate electric field distribution in the infratentorium that is within the therapeutic range.

Pilot Study of Hyperfractionated Dosing of Lutetium-177-Labeled Antiprostate-Specific Membrane Antigen Monoclonal Antibody J591 (177 Lu-J591) for Metastatic Castration-Resistant Prostate Cancer.

LESSONS LEARNED: Hyperfractionation of lutetium-177 (177 Lu)-J591 for patients with metastatic castration-resistant prostate cancer did not appear to have any additional advantage over the single dose 177 Lu-J591 or fractionated two-dose 177 Lu-J591 therapy. Definite conclusions were challenging because of the small sample size of this study, and so further studies are needed to evaluate the viability of the hypothesis. On the basis of available data, a registration study of 177 Lu-J591 (also known as TLX591) is planned and will use the two-dose fractionation schedule (Telix Pharma Q3 2019 update https://telixpharma.com/news-media/). BACKGROUND: Phase I and II single-dose studies of lutetium-177 (177 Lu)-J591, a radio-labeled antibody binding prostate-specific membrane antigen (PSMA), demonstrated safety and efficacy with dose response. Modest dose fractionation of 177 Lu-J591 (2 doses) has less myelosuppression per similar cumulative dose, allowing higher doses to be administered safely. We hypothesized that additional dose fractionation would allow a higher cumulative dose, potentially with less toxicity and more efficacy. METHODS: Men with progressive metastatic castration-resistant prostate cancer and adequate organ function were enrolled. 177 Lu-J591 was administered at 25 mCi/m2 every 2 weeks until the emergence of related grade 2 toxicity. 177 Lu-J591 imaging was performed and circulating tumor cell (CTC) counts were measured before and after treatment along with standard monitoring. RESULTS: Six subjects in a single cohort, with a median age of 68.6 years, were enrolled. Patients received three to six doses (cumulative 75-150 mCi/m2 ). Two (33%) patients had >30% prostate-specific antigen (PSA) decline and three (50%) had CTC count decline. Two (33%) experienced grade (Gr) 4 neutropenia (without fever), three (50%) had Gr 4 thrombocytopenia (without hemorrhage), and two (33%) required platelet transfusions. Following hematological improvement, two patients developed worsening cytopenia during prostate cancer progression; bone marrow biopsies revealed infiltrative tumor replacing normal marrow elements without myelodysplasia. Targeting of known disease sites was seen on planar imaging in all. CONCLUSION: Hyperfractionation of 177 Lu-J591 is feasible but does not seem to have significant advantages over the two-dose fractionation regimen.

Prostatic irradiation-induced sexual dysfunction: A review and multidisciplinary guide to management in the radical radiotherapy era (Part II on Urological Management).

Prostate cancer is the most common malignancy in men and the second leading cause of cancer-related death in men. Radiotherapy is a curative option that is administered via external beam radiation, brachytherapy, or in combination. Sexual dysfunction is a common toxicity following radiotherapy, similar to men undergoing radical prostatectomy, but the etiology is different. The pathophysiology of radiation-induced sexual dysfunction is multi-factorial, and the toxicity is a major cause of impaired quality of life among long-term prostate cancer survivors. Management of a patient's sexual function during and after radiotherapy requires multidisciplinary coordination of care between radiation oncology, urology, psychiatry, pharmacy, and dermatology. This review provides a framework for clinicians to better understand prostatic radiotherapy-induced sexual dysfunction diagnosis, evaluation, and a patient-centered approach to toxicity preventive strategies and management.

Prostatic irradiation-induced sexual dysfunction: a review and multidisciplinary guide to management in the radical radiotherapy era (Part I defining the organ at risk for sexual toxicities).

Prostate cancer is the most common malignancy and the second leading cause of cancer-related death in men. Radiotherapy is a curative option that is administered via external beam radiation, brachytherapy, or in combination. Erectile, ejaculatory and orgasm dysfunction(s) is/are known potential and common toxicities associated with prostate radiotherapy. Our multidisciplinary team of physicians and/or scientists have written a three (3) part comprehensive review of the pathogenesis and management radiation-induced sexual dysfunction. Part I reviews pertinent anatomy associated with normal sexual function and then considers the pathogenesis of prostate radiation-induced sexual toxicities. Next, our team considers the associated radiobiological (including the effects of time, dose and fractionation) and physical (treatment planning and defining a novel Organ at Risk (OAR)) components that should be minded in the context of safe radiation treatment planning. The authors identify an OAR (i.e., the prostatic plexus) and provide suggestions on how to minimize injury to said OAR during the radiation treatment planning process.

Prostatic irradiation-induced sexual dysfunction: A review and multidisciplinary guide to management in the radical radiotherapy era (Part III on Psychosexual Therapy and the Masculine Self-Esteem).

Psychological morbidity, sexuality, and health/system information have been identified as the highest areas of support needs in patients undergoing management of their prostate cancer (PCa). Management of a patient's sexual function prior to, during and after PCa radiotherapy requires multidisciplinary coordination of care between radiation oncologists, urologists, dermatologists, pharmacists, and psychiatrists. The finale of this three-part review provides a framework for clinicians to better understand the role of mental healthcare providers in the management of sexual toxicities associated with prostatic radiotherapy. The authors recommend that patients be referred for psychological evaluation and possibly to individual, couples or group general or cognitive behavioral sex therapy at the time of their PCa diagnosis, for a more specialized focus on management of sexual toxicities and sexual recovery. The importance and implications of the masculine self-esteem, sexual orientation, gender identification, cultural expectations, relationship status and patient education are reviewed. Well-informed patients tend to have a better quality of life outcomes compared to patients that take on a passive role in their cancer management.

Intralesional triamcinolone alone or in combination with botulinium toxin A is ineffective for the treatment of formed keloid scar: A double blind controlled pilot study.

Cutaneous injury can ignite excessive fibroproliferative growth that results in keloid formation. Keloids are associated with significant morbidity related to disfigurement and/or symptoms (e.g., pain and pruritus). First-line treatment of formed keloids involves topical or intralesional steroids. Recurrent or resistant keloids are managed by surgical excision or cryotherapy, followed by steroidal application or adjuvant irradiation. Although adjuvant irradiation appears to be most efficacious, alternative therapeutic options are needed for patients without access to radiation centers. Botulinum Toxin A (BTA) appears to have similar inhibitory effects to irradiation on the cell cycle via downregulation of pathogenic cytokines. Herein, we conducted a study to compare the efficacy of intralesional triamcinolone used alone, or in combination with BTA, in the treatment of formed keloid scars. Twenty patients with a cumulative of 40 keloids completed the study. There was no significant difference between treatment arms with respect to height vascularization, pliability, and pigmentation scores. The addition of BTA resulted in significant symptomatic improvement of pain and pruritus as compared to intralesional triamcinolone alone (p < 0.001). Irradiation is only effective when administered in the adjuvant setting where inhibitory effects on cell cycle and migration are optimized. Future studies with intralesional triamcinolone and BTA should be performed adjuvantly.

Fractional CO2 Laser Pretreatment to Autologous Hair Transplantation and Phototherapy Improves Perifollicular Repigmentation in Refractory Vitiligo: A Randomized, Prospective, Half-Lesion, Comparative Study.

BACKGROUND: Fractional CO2 laser and autologous hair transplantation are independently effective in the treatment of refractory and stable vitiligo. OBJECTIVE: The authors' purpose was to evaluate the therapeutic efficacy of fractional CO2 laser pretreatment compared with autologous hair transplantation and phototherapy alone for refractory and stable vitiligo. METHODS: A total of 20 patients with refractory and stable vitiligo were enrolled from our clinic. Resistant lesions randomly divided into 2 regions as follows: (1) Part A: fractional CO2 laser pretreatment followed by autologous transplantation and phototherapy, and (2) Part B: autologous transplantation and phototherapy alone. Five days after fractional CO2 laser application to Part A, both treatment regions received a transplant of scalp grafts. On Day 11, the entire lesion was exposed to narrow-band UVB phototherapy, twice a week for 12 weeks. The diameter of perifollicular repigmentation was measured monthly with a caliper. RESULTS: Perifollicular repigmentation was detectable surrounding 74% of grafted hair follicles by Month 3. Furthermore, Part A demonstrated a significantly greater diameter of repigmentation with 6.6 ± 5.8 mm in Part A compared with 4.3 ± 1.8 mm in Part B (p = <.001). CONCLUSION: In this study, our results demonstrate improved efficacy of autologous hair transplantation and narrow-band UVB with fractional CO2 laser pretreatment in refractory and stable vitiligo.

Role of PET/Computed Tomography in Gastric and Colorectal Malignancies.

This article focuses on the role of PET/computed tomography in evaluating and managing gastric cancer and colorectal cancer. The authors start with describing the common aspects of imaging with 2-deoxy-2-18F-d-glucose, followed by tumor-specific discussions of gastric and colorectal malignancies. Finally, the authors provide a brief overview of non-FDG tracers including their potential clinical applications, and describe future directions in imaging these malignancies.

Continuous versus intermittent therapy for moderate-to-severe psoriasis.

Psoriasis is a chronic immune-mediated inflammatory disease of unknown etiology. Unlike other chronic inflammatory diseases receiving continuous treatment, psoriasis has traditionally been treated intermittently secondary to concern for cumulative toxicity of conventional systemic therapies. However, the development of targeted anti-inflammatory biologic agents allowed for continuous therapy for most patients. Herein, we review the literature for intermittent versus continuous use of widely available therapies for moderate-to-severe psoriasis: phototherapy, topical corticosteroids, conventional systemic therapies and biologic agents. These data support continuous treatment in biologic therapy, such as etanercept, adalimumab, infliximab, and ustekinumab. Intermittent therapy with biologic agents leads to decreased efficacy and sometimes increased side effects. When conventional systemic therapy is used continuously, it is more efficacious; however the data support intermittent use of methotrexate and cyclosporine due to cumulative toxicities. Psoriasis severity may wax and wane, but it is a chronic disease requiring continuous treatment for optimal control of inflammatory activity and to minimise cutaneous involvement.

Acquired perforating dermatosis: a clinical and dermatoscopic correlation.

Acquired Perforating Dermatosis (APD) is a perforating disease characterized by transepidermal elimination of dermal material [1,2]. This disease usually develops in adulthood. APD has been reported to occur in association with various diseases, but is most commonly associated with dialysis-dependent chronic renal failure (CRF) or diabetes mellitus (DM) [1,2,3,4]. Morton et al found that APD occurs in up to 10% of patients undergoing hemodialysis [5]. Additionally, Saray et al found that sixteen of twenty-two cases with APD were associated with CRF [3].

Koebner Phenomenon: Café-au-Lait Spots Developing after a Secondary-Degree Burn in a Patient with Neurofibromatosis Type 1.

An 18-year-old woman with an established history of neurofibromatosis type 1 (NF-1) presented for her 1-year dermatologic follow-up. Physical examination revealed two subcutaneous nodules on her right arm, axillary freckling, scattered café-au-lait macules (CALMs) on the trunk, and a 12 cm × 17 cm hyperpigmented rectangular region on her right flank (Figure 1). The pigmented patch contained numerous new CALMs that were morphologically consistent with CALMs identified on prior examinations; neither the patch nor the CALMs within it were present at prior examinations. Interestingly, the appearance of the patch and associated CALMs was preceded by a rectangular-shaped, second-degree thermal burn. On further questioning, the patient revealed that she had burned herself with hot water 4 months prior to her presentation in clinic, and noted the development of multiple CALMs within the skin area of her prior burn approximately 4 weeks after the incident. Of note, her left flank had sparsely scattered CALMs, which was consistent with her prior skin examinations (Figure 2). A depigmenting cream was to be applied to the rectangular pigmented patch; unfortunately, post-inflammatory hyperpigmentation from the burn and the adjoining lesions resulting from the Koebner phenomenon continue to be refractory to treatment.

Review of Lutetium-177-labeled Anti-prostate-specific Membrane Antigen Monoclonal Antibody J591 for the Treatment of Metastatic Castration-resistant Prostate Cancer.

Prostate cancer is the most common non-cutaneous cancer in men in the United States and is the second most common cause of cancer deaths after lung cancer in men. Despite all advances in the field of prostate cancer imaging and treatment, currently, it is sub-optimally responsive to all available treatment options. Radioimmunotherapy with a monoclonal antibody (mAb), J591, has shown promising results in the treatment of prostate cancer. J591 is a deimmunized mAb that targets the extracellular domain of prostate-specific membrane antigen (PSMA), a surface-bound and internalizing glycoprotein that is upregulated in prostate cancer. Phase I/II clinical trials have shown accurate tumor targeting, biochemical and radiographic responses, and increased overall survival in patients with mCRPC with tolerable, predictable, and reversible myelotoxicity. Ongoing studies focus on improving the therapeutic index of radiolabeled J591. Herein, the literature on published clinical trials involving therapeutic J591 conjugated to b-emitter, lutetium-177 for mCRPC, is sequentially reviewed.

Prostate-specific Membrane Antigen Based Antibody-drug Conjugates for Metastatic Castration-resistance Prostate Cancer.

Cancer cells can be selectively targeted by identifying and developing antibodies to specific antigens present on the cancer cell surface. Cytotoxic agents can be conjugated to these antibodies that bind to these cell surface antigens in order to significantly increase the therapeutic index of whichever cytotoxic agent is utilized. This approach of conjugating the cytotoxic drugs to antibodies to target specific surface antigens enhances the anti-tumor activity of antibodies and improves the tumor-to-normal tissue selectivity of chemotherapy. Critical parameters in the development of these antibody-drug conjugates include: 1) selection of most appropriate antigen, 2) the ability of an antibody to be internalized after binding to the antigen, 3) cytotoxic drug potency and 4) stability of the antibody-drug conjugate. For prostate cancer, prostate-specific membrane antigen (PSMA, also known as folate hydrolase-1) is the most validated theragnostic target to date. PSMA is overexpressed on the prostate cancer cell surface, which makes it an even better target for selective drug delivery through conjugated antibodies. Here, we review the PSMA-based antibody-drug conjugates for metastatic castration-resistance prostate cancer (mCRPC).

Pseudo-dense Hair Transplantation: Strategy of "Less Inside, More Outside" and Central Bulking with Curled Chest Hairs as Treatment for Scalp Scars.

Hair transplantation in areas of scalp scars is a clinical challenge. However, by creating the visual illusion of central bulking with the use of peripherally transplanted curled chest hairs, cicatricial alopecia can perhaps be cosmetically improved. In a case of a 34-year-old affected man, this strategic procedure was implemented with positive results, as the transplantation was successful, the scar was far less noticeable, and the patient was satisfied with the results. The "pseudo-dense hair transplantation" method can be applied to similar patients, noting that a more succinct procedure will need to be elucidated for the varying etiologies of cicatricial alopecia.

The effect of low-dose isotretinoin therapy on serum androgen levels in women with acne vulgaris.

BACKGROUND: Acne vulgaris is a common dermatologic disease that causes significant social and psychological morbidity. Isotretinoin, as a vitamin A derivative, is the most effective agent in the treatment of acne. Evidence suggests that isotretinoin's therapeutic function is independent of hormonal mediation; however, the effect of isotretinoin on serum androgens and precursor androgen levels in humans remains unclear. OBJECTIVE: Herein, we aim to investigate the effect of low-dose isotretinoin on androgen levels in women and postulate the role of concomitant anti-androgen therapy (e.g., spironolactone). METHODS: A total of 36 women, age 18 to 30 years, with moderate-to-severe nodulocystic acne were treated with 20 mg isotretinoin (Roaccutane) daily for 3 months. A hormone panel was obtained at baseline and after completion of the treatment course. The panel included dehydroepiandrosterone (DHEA), 17-hydroxyprogestrone, testosterone, free testosterone, dihydrotestosterone (DHT), luteinizing hormone, follicle stimulating hormone, and prolactin. RESULTS: Serum levels of testosterone (p = .015), prolactin (p = .001), and DHT (p = .001) were significantly decreased, while serum levels of DHEA (p = .001) significantly increased after isotretinoin treatment. No significant change was found in the other hormones evaluated. LIMITATIONS: The distribution of acne was not assessed in our patient population. We did not directly evaluate for associations between elevated DHEA levels and clinical response rates. CONCLUSION: Isotretinoin alone can decrease androgen levels, but increase an important driver of acne pathogenesis (i.e., DHEA). The co-administration of an anti-androgenic agent (e.g., spironolactone) may optimize the therapeutic efficacy of isotretinoin by limiting iatrogenic increases in DHEA and perhaps allow for more widespread use of low-dose isotretinoin.