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.

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.

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.

Dermatofibrosarcoma Protuberans: The Current State of Multidisciplinary Management.

Dermatofibrosarcoma protuberans (DFSP) is a rare, infiltrative, soft tissue tumor. It has a propensity for deep invasion but a low risk for distant metastasis. The classic presentation is a slowly progressive, painless, and erythematous to purpuric patch on the trunk or arms. A deep, subcutaneous punch biopsy or incisional biopsy should be performed for diagnosis in all suspected cases; wide undermining of the skin is to be avoided for minimizing the risk of tumor seeding and for retaining the feasibility of histopathologic examination of re-excisions. Histopathologic distinction of DFSP from dermatofibroma requires immunohistochemical assessment for CD34, factor XIIIa, nestin, apolipoprotein D, and cathepsin K. Management of this cutaneous sarcoma involves a multidisciplinary oncologic approach. Surgical excision is usually the first step in management. DFSP has a high propensity for local recurrence, even when surgical margins are negative; therefore, radiation therapy or rarely systemic therapy is recommended, especially for locally advanced or metastatic cases. The indolent nature of DFSP requires lifelong surveillance for recurrence; however, most recurrences occur within 3 years of the primary excision. The median time for the development of a local recurrence is estimated to be 32 months. An emerging theragnostic transmembrane receptor target, folate hydrolase-1 (FOLH1; prostate-specific membrane antigen), has been expressed in benign dermatofibromas and in high-grade sarcomatous phenotypes. These findings suggest that DFSP may also express FOLH1, which could allow for surveillance with FOLH1 PET/CT and antibody-mediated brachytherapy.

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.

Follicular Transplantation, Microneedling, and Adjuvant Narrow-band Ultraviolet-B Irradiation as Cost-Effective Regimens for Palmar-Plantar Vitiligo: A Pilot Study.

Treatment of refractory palmar-plantar vitiligo is particularly challenging because the skin in these regions has a limited supply of follicle-derived melanocytic stem cells. Autologous hair transplantation monotherapy is effective in some forms of vitiligo through the provision of melanocytic stem cells. CO2 laser followed by exposure to light (i.e., sunlight or narrow-band ultraviolet-B [nbUVB]) has independently shown to be an effective treatment strategy. Recently, it was found that the combination of hair transplantation and CO2 laser followed by nbUVB exposure had superior efficacy to either modality as monotherapy. Similar to CO2 laser, microneedling produces skin cell proliferation and releases pro-pigmentary cytokines. Given the important role of the cytokines in vitiliginous skin, microneedling may also be an effective therapeutic modality for refractory vitiligo. Herein, we conducted a pilot study to evaluate the efficacy of hair transplantation and CO2 laser or microneedling followed by nbUVB. Microneedling and fractional CO2 laser in combination with hair transplantation and nbUVB both demonstrated utility in the induction of repigmentation in refractory palmar-plantar vitiligo; however, a larger trial would be needed to determine a difference in treatment efficacy. Nonetheless, microneedling is cost-effective and requires minimal training; therefore, microneedling can be easily incorporated into standard dermatological practice.

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.

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.

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.

Recycling of Previously Transplanted Hair: A Novel Indication for Follicular Unit Extraction.

BACKGROUND: Hair transplantation has enhanced the realm of procedural dermatology. Before the advent of follicular transplantation, androgenetic alopecia was a difficult disease to manage, as there is a limited armamentarium of topical and systemic pharmaceuticals. However, as with other novel surgical procedures, there is a steep learning curve, that may result in poor transplantation or cosmesis. CASE REPORT: We present a case of androgenetic alopecia, where previously, poorly implanted hairs were recycled by follicular unit extraction to increase hair density at the vertex of the scalp, which resulted in improved cosmesis and patient satisfaction. CONCLUSION: We have demonstrated that re-transplantation is not only feasible but is effective; therefore redesigning of previous transplantations should be considered as a possible indication follicle unit extraction, particularly in the setting of scarce follicular reserves. The utility of our recycling method may also inspire hope in patients that have undergone failed or unsatisfactory hair transplantations.

Radiotherapy-induced reactivation of neurotrophic human herpes viruses: Overview and management.

PURPOSE: Infection by Human Herpes Viruses (HHV) types 1-3, are prevalent throughout the world. It is known that radiotherapy can reactivate HHVs, but it is unclear how and to what extent reactivations can interact with or affect radiotherapeutic efficacy, patient outcomes and mortality risk. Herein, we aim to summarize what is known about Herpes Simplex Virus (HSV)-1,2 and Varicella Zoster Virus (VZV) pathophysiology as it relates to tumor biology, radiotherapy, chemo-radiotherapy, diagnosis and management so as to optimize cancer treatment in the setting of active HHV infection. Our secondary aim is to emphasize the need for further research to elucidate the potential adverse effects of active HHV infection in irradiated tumor tissue and to design optimal management strategies to incorporate into cancer management guidelines. MATERIALS AND METHODS: The literature regarding herpetic infection, herpetic reactivation, and recurrence occurring during radiotherapy and that regarding treatment guidelines for herpetic infections are reviewed. We aim to provide the oncologist with a reference for the infectious dangers of herpetic reactivation in patients under their care and well established methods for prevention, diagnosis, and treatment of such infections. Pain management is also considered. CONCLUSIONS: In the radiotherapeutic setting, serologic assays for HSV-1 and HSV-2 are feasible and can alert the clinician to patients at risk for viral reactivation. RT-PCR is specific in identifying the exact viral culprit and is the preferred diagnostic method to measure interventional efficacy. It can also differentiate between herpetic infection and radionecrosis. The MicroTrak® HSV1/HSV2/VZV staining kit has high sensitivity and specificity in acute lesions, is also the most rapid means to confirm diagnosis. Herpetic reactivation and recurrences during radiotherapy can cause interruptions, cessations, or prolongations of the radiotherapeutic course, thus decreasing the biologically effective dose, to sub-therapeutic levels. Active HHV infection within the treatment volume results in increased tumor radio-resistance and potentially sub-therapeutic care if left untreated. Visceral reactivations may result in fatality and therefore, a high index of suspicion is important to identify these active infections. The fact that such infections may be mistaken for acute and/or late radiation effects, leading to less than optimal treatment decisions, makes knowledge of this problem even more relevant. To minimize the risk of these sequelae, prompt anti-viral therapy is recommended, lasting the course of radiotherapy.

Impact of postoperative radiation on survival for high-grade soft tissue sarcoma of the extremities after limb sparing radical resection.

OBJECTIVES: To use the Surveillance, Epidemiology, and End Results (SEER) Database to analyze the impact of postoperative radiation after limb sparing surgery for high-grade extremity soft tissue sarcomas (STS). METHODS: We identified patients, aged 20 to 79, who were diagnosed between 1988 and 2006 with high-grade STS of the extremities and underwent radical limb sparing surgery with or without postoperative external beam radiation. Kaplan-Meier and Cox regression analyses were performed to evaluate the effect of postoperative external beam radiation therapy on overall survival (OS) and disease-specific survival (DSS). RESULTS: A total of 983 patients met the selection criteria: 788 (80.2%) received postoperative radiation and 195 (19.8%) underwent surgery alone. For the whole cohort, there were no differences between the groups in OS (P=0.06) or DSS (P=0.20). On subgroup analysis, for tumors ≤5 cm there remained no significant differences in OS (P=0.8) or DSS (P=0.93). However, for tumors >5 cm the 3-year OS improved with the addition of postoperative radiation from 55.6% to 73.4% (P<0.001). Similarly, the 3-year DSS improved from 68.1% to 80.6% (P=0.005). CONCLUSIONS: Because of the retrospective nature of this study and inherent limitations of the SEER database, a large prospective study is needed to further elucidate the relationship between postoperative radiation and survival. However, these data do support the use of adjuvant radiation for patients with high-grade extremity STS measuring >5 cm.

Prostate and seminal vesicle volume based consideration of prostate cancer patients for treatment with 3D-conformal or intensity-modulated radiation therapy.

PURPOSE: The purpose of this article was to determine the suitability of the prostate and seminal vesicle volumes as factors to consider patients for treatment with image-guided 3D-conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT), using common dosimetry parameters as comparison tools. METHODS: Dosimetry of 3D and IMRT plans for 48 patients was compared. Volumes of prostate, SV, rectum, and bladder, and prescriptions were the same for both plans. For both 3D and IMRT plans, expansion margins to prostate+SV (CTV) and prostate were 0.5 cm posterior and superior and 1 cm in other dimensions to create PTV and CDPTV, respectively. Six-field 3D plans were prepared retrospectively. For 3D plans, an additional 0.5 cm margin was added to PTV and CDPTV. Prescription for both 3D and IMRT plans was the same: 45 Gy to CTV followed by a 36 Gy boost to prostate. Dosimetry parameters common to 3D and IMRT plans were used for comparison: Mean doses to prostate, CDPTV, SV, rectum, bladder, and femurs; percent volume of rectum and bladder receiving 30 (V30), 50 (V50), and 70 Gy (V70), dose to 30% of rectum and bladder, minimum and maximum point dose to CDPTV, and prescription dose covering 95% of CDPTV (D95). RESULTS: When the data for all patients were combined, mean dose to prostate and CDPTV was higher with 3D than IMRT plans (P < 0.01). Mean D95 to CDPTV was the same for 3D and IMRT plans (P > 0.2). On average, among all cases, the minimum point dose was less for 3D-CRT plans and the maximum point dose was greater for 3D-CRT than for IMRT (P < 0.01). Mean dose to 30%, rectum with 3D and IMRT plans was comparable (P > 0.1). V30 was less (P < 0.01), V50 was the same (P > 0.2), and V70 was more (P < 0.01) for rectum with 3D than IMRT plans. Mean dose to bladder was less with 3D than IMRT plans (P < 0.01). V30 for bladder with 3D plans was less than that of IMRT plans (P < 0.01). V50 and V70 for 3D plans were the same for 3D and IMRT plans (P > 0.2). Mean dose to femurs was more with 3D than IMRT plans (P < 0.01). For a given patient, mean dose and dose to 30% rectum and bladder were less with 3D than IMRT plans for prostate or prostate+SV volumes <65 (38/48) and 85 cm3 (39/48), respectively (P < 0.01). The larger the dose to rectum or bladder with 3D plans, the larger also was the dose to these structures with IMRT (P < 0.001). For both 3D and IMRT plans, dose to rectum and bladder increased with the increase in the volumes of prostate and seminal vesicles (P < 0.02 to 0.001). CONCLUSIONS: Volumes of prostate and seminal vesicles provide a reproducible and consistent basis for considering patients for treatment with image-guided 3D or IMRT plans. Patients with prostate and prostate+SV volumes <65 and 85 cm3, respectively, would be suitable for 3D-CRT. Patients with prostate and prostate+SV volumes >65 and 85 cm3, respectively, might get benefit from IMRT.

Influence of volumes of prostate, rectum, and bladder on treatment planning CT on interfraction prostate shifts during ultrasound image-guided IMRT.

PURPOSE: The purpose of this study was to analyze the relationship between prostate, bladder, and rectum volumes on treatment planning CT day and prostate shifts in the XYZ directions on treatment days. METHODS: Prostate, seminal vesicles, bladder, and rectum were contoured on CT images obtained in supine position. Intensity modulated radiation therapy plans was prepared. Contours were exported to BAT-ultrasound imaging system. Patients were positioned on the couch using skin marks. An ultrasound probe was used to obtain ultrasound images of prostate, bladder, and rectum, which were aligned with CT images. Couch shifts in the XYZ directions as recommended by BAT system were made and recorded. 4698 couch shifts for 42 patients were analyzed to study the correlations between interfraction prostate shifts vs bladder, rectum, and prostate volumes on planning CT. RESULTS: Mean and range of volumes (cc): Bladder: 179 (42-582), rectum: 108 (28-223), and prostate: 55 (21-154). Mean systematic prostate shifts were (cm, +/-SD) right and left lateral: -0.047 +/- 0.16 (-0.361-0.251), anterior and posterior: 0.14 0.3 (-0.466-0.669), and superior and inferior: 0.19 +/- 0.26 (-0.342-0.633). Bladder volume was not correlated with lateral, anterior/posterior, and superior/inferior prostate shifts (P > 0.2). Rectal volume was correlated with anterior/posterior (P < 0.001) but not with lateral and superior/inferior prostate shifts (P > 0.2). The smaller the rectal volume or cross sectional area, the larger was the prostate shift anteriorly and vice versa (P < 0.001). Prostate volume was correlated with superior/inferior (P < 0.05) but not with lateral and anterior/posterior prostate shifts (P > 0.2). The smaller the prostate volume, the larger was prostate shift superiorly and vice versa (P < 0.05). CONCLUSIONS: Prostate and rectal volumes, but not bladder volumes, on treatment planning CT influenced prostate position on treatment fractions. Daily image-guided adoptive radiotherapy would be required for patients with distended or empty rectum on planning CT to reduce rectal toxicity in the case of empty rectum and to minimize geometric miss of prostate.

Cell-cell interactions in spheroids maintained in suspension.

We have developed a system of mixed aggregates of cultured cells, to model in situ cell interactions. This three-dimensional (3D) system of floating cell aggregates, termed spheroids for their round shape, enables one to monitor their growth in both size and number of constituent clonogens and to measure survival curves for cells having 3D cell-cell interactions. This system was used to measure the three-dimensional cell-cell interactions on growth, and clonogenicity of either AG1522 fibroblasts, or HeLa cervical cancer cells (pure spheroids, or if both feeder and test cells are the same type, pseudohybrid spheroids), and/or of mixtures of both (hybrid spheroids). By following the increase or decrease in size of, or number of clonogens per, spheroid over time, one obtains growth or inhibition curves. By relating these clonogen numbers, one obtains, after a suitable growth period, relative survival. The system allows one to score the effects of irradiation and of other treatments, as well as the effect of interaction of the constituent cells on their survival. Floating pure, or pseudohybrid (composed of 10% live fibroblasts and 90% supralethally irradiated fibroblast feeder cells) spheroids, shrank to about 10-20% of their volume in three days and then remained at that size for up to six days. In contrast, pure spheroids composed of live HeLa cells increased their volume by an order of magnitude over the same period. Survival of cells in spheroids was measured by the ability of individual spheroids to grow beyond a size implying a ten-fold increase. A caveat to be observed is to correct survival for cellular multiplicity, i.e. reduce survival values to compensate for more than one colony former at the time of irradiation. The system of spheroids floating and growing in nutrient medium provides a selective system for evaluating growth of HeLa, and by implication, other neoplastic cells, without interference from (overgrowth by) normal fibroblasts. Thus it is possible to discriminate between normal and neoplastic cells by virtue of whether or not cells grow in suspension. Such a system seems ideal for testing novel strategies (radiation in combination with chemicals), in an in vivo-like environment.

Hybrid spheroids as a tool for prediction of radiosensitivity in tumor therapy.

Optimization in radiotherapy may be conceivably achieved by individualized treatment regimens. For this, the radiosensitivity of the tumor cells to be treated must be known. A method is presented to show that the effect of radiation on tumor cells in spheroids can be quantitatively evaluated without complicated cell determinations of spheroid composition. This evaluation is based on the dynamics of inactivation of the colony forming ability of whole spheroids composed chiefly of non-transformed diploid fibroblasts and a minority of HeLa "test" cells. Here, spheroids of identical composition, but of different sizes are inactivated proportional to their sizes, thus obviating the need for tedious single cell procedures. The use of spheroids of different sizes permits the deduction of dose-effect relationships, and the innate radiosensitivity of tumors cells. This is a novel method for measuring the radio and chemosensitivity of tumors in primary culture, i.e. cells directly isolated from tumors.