Long-term use of burosumab for the treatment of tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumoral overproduction of FGF-23. Due to local recurrence, we describe the long-term efficacy and safety profile of burosumab, an anti-FGF-23 monoclonal antibody, in a TIO patient after three unsuccessfully surgical attempts. INTRODUCTION: TIO is a rare paraneoplastic syndrome caused by tumoral overproduction of fibroblast growth factor 23 (FGF23), resulting in hyperphospaturia, hypophosphatemia, and osteomalacia. Surgery is the only definitive treatment, but tumor can locally recur, even after years from primary surgery. Furthermore, some tumors cannot be removed by surgery due to their location. METHODS: We describe the case of a 54-year-old woman affected by recurrent TIO who, after three unsuccessful surgical attempts of tumor removal, was treated with burosumab, an anti-FGF-23 monoclonal antibody. RESULTS: The patient was referred to our Bone Unit after experiencing several fractures in different sites, both traumatic and non-traumatic. At the time of first evaluation, at the age of 46, serum-phosphate (SP) was 1.2 mg/dL (reference range (RR) 2.5-4.5), 24-h urinary phosphate was 842 mg (RR 400-1000), and intact-FGF-23 was 117 pg/mL (RR 25-45). Imaging showed a metabolic pre-sacral lesion that firstly underwent to exploratory laparotomy. Then, patient underwent to surgical excision of tumor. After 18 months of well-being, tumor relapsed and even the subsequent surgery was not able to completely remove it. Since 2015, patient was maintained in phosphorus supplements and 1,25(OH)2vitamin D3, but SP levels never normalized. In September 2019, she was started on burosumab, initially at the dose of 0.3 mg/kg/month, progressively increased to the current 0.8 mg/kg/month, with great improvement of pain, physical performance, and normalization of SP levels. Burosumab was temporary and cautionary discontinued for COVID-19 pneumonia, with a worsening of SP. After restart of burosumab, biochemistry returned to normal. CONCLUSIONS: To our knowledge, this is the first European patient affected by TIO treated with burosumab for more than 2 years. Burosumab is a promising therapy in the medical treatment of TIO refractory or not eligible for definitive surgery, with good efficacy and safety profile.

Favorable effects of burosumab on tumor-induced osteomalacia caused by an undetectable tumor: A case report.

RATIONALE: Tumor-induced osteomalacia (TIO) is curable by tumor resection, but detection of the tumor can be challenging. Overproduction of fibroblast growth factor 23 (FGF23) by the tumor causes hypophosphatemia and consequently induces inappropriate bone turnover. Conventionally oral phosphate supplementation was the only treatment for TIO, but had risks of hypercalciuria and nephrocalcinosis. Burosumab, a human monoclonal anti-FGF23 antibody, was recently post-marketed in Japan against for FGF23-related hypophosphatemia. Herein, we present a case of TIO with undetectable tumor that was successfully treated with burosumab. PATIENT CONCERNS: A 47-year-old woman was forced to use a wheelchair because of pain in both feet. DIAGNOSIS: Laboratory findings showed hypophosphatemia, elevated bone markers, and high serum FGF23 without renal tubular defects. Imaging studies revealed bone atrophy in the feet, decreased bone density, and multiple pseudofractures in the talar, sacral, and L5 vertebral regions. After excluding drug-induced and hereditary osteomalacia, we diagnosed her as TIO. INTERVENTIONS: Comprehensive imaging studies and stepwise venous sampling failed to localize the tumor, and we started to administer subcutaneous burosumab. OUTCOMES: After administration of burosumab, her serum phosphate was normalized without phosphate supplementation within 2 months. Improvement of pseudofractures, relief of pain evaluated by a visual analog scale, and normalization of bone biomarkers were observed. The patient was able to stand by herself after 6 months administration of burosumab. LESSONS: This is the first report in clinical practice to demonstrate favorable effects of burosumab, including not only normalization of serum phosphate but also improvements of pseudofractures and subjective pain, in a patient with TIO and undetectable tumor.

Integrated therapy decreases the mortality of patients with polymyositis and dermatomyositis: A Taiwan-wide population-based retrospective study.

ETHNOPHARMACOLOGICAL RELEVANCE: The issue of whether integrated treatment with conventional medicine (CM) and herbal medicine (HM) can reduce mortality in patients with polymyositis/dermatomyositis (PM/DM) had not been addressed. AIM OF THE STUDY: In this study, we investigated the effect of integrated therapy on mortality in a retrospective PM/DM cohort in the Taiwan National Health Insurance Research Database (NHIRD). MATERIALS AND METHODS: Patients with PM/DM were retrospectively enrolled from the PM/DM Registry of Catastrophic Illnesses cohort in the Taiwan NHIRD between 1997 and 2011. The patients were divided into an integrated medicine (IM) group that received CM and HM and a non-IM group that received CM alone. The Cox proportional hazards regression model and Kaplan-Meier method were used to evaluate the hazard ratio (HR) for mortality. RESULTS: Three hundred and eighty-five of 2595 patients with newly diagnosed PM/DM had received IM and 99 had received non-IM. The adjusted HR for mortality was lower in the IM group than in the non-IM group (0.42, 95% confidence interval 0.26-0.68, p < 0.001). The adjusted HR for mortality was also lower in the IM group that had received CM plus HM than in the group that received CM alone (0.48, 95% confidence interval 0.28-0.84, p < 0.05). The core pattern of HM prescriptions integrated with methylprednisolone, methotrexate, azathioprine, or cyclophosphamide to decrease mortality included "San-Qi" (Panax notoginseng), "Bai-Ji" (Bletilla striata), "Chen-Pi" (Citrus reticulata), "Hou-Po" (Magnolia officinalis), and "Dan-Shan" (Salvia miltiorrhiza). CONCLUSION: Integrated therapy has reduced mortality in patients with PM/DM in Taiwan. Further investigation of the clinical effects and pharmaceutical mechanism involved is needed.

Occult phosphaturic mesenchymal tumour of femur cortex causing oncogenic osteomalacia - diagnostic challenges and clinical outcomes.

BACKGROUND: Tumor induced osteomalacia (TIO) are extremely rare paraneoplastic syndrome with less than 300 reported cases. This report highlights the pitfalls and challenges in diagnosing and localizing TIO in patients with refractory and resistant osteomalacia. PATIENT AND METHODS: 41- year gentleman with 4-year history of musculoskeletal weakness and pathologic fractures presented in wheelchair bound incapacitated state of 1-year duration. Investigations were significant for severe hypophosphatemia, severe phosphaturia, normal serum calcium, reduced 1,25-dihydroxy vitamin-D, elevated ALP, elevated intact parathyroid hormone (iPTH), and pseudo-fractures involving pelvis and bilateral femur. Whole body MRI and 99mTc methylene diphosphonate bone-scan were also normal. Whole body FDG-PET scan involving all 4 limbs revealed a small FDG avid lesion at lateral border of lower end of left femur (SUV max 3.9), which was well characterized on 3-dimensional CT reconstruction. Plasma C-terminal fibroblast growth factor (FGF)-23 was 698 RU/ mL (normal < 150 RU/ml). Wide surgical excision of the tumor was done. Histopathology confirmed mesenchymal tumor of mixed connective tissue variant. Serum phosphorous normalized post-surgery day-1. High dose oral calcium and vitamin-D was continued. FGF-23 normalized post surgery (73RU/ml). Physical strength improved significantly and now he is able to walk independently. CONCLUSION: TIO is frequently confused with normocalcemic hyperparathyroidism and vitamin-D resistant rickets/osteomalacia, which increases patient morbidity. Imaging for tumor localization should involve whole body from head to tip of digits, cause these tumors are notoriously small and frequently involve digits of hands and legs. Complete surgical removal of the localized tumor is key to good clinical outcomes.

Tumor-induced Osteomalacia in a 3-Year-Old With Unresectable Central Giant Cell Lesions.

Tumor-induced osteomalacia (TIO) is a rare cause of hypophosphatemia involving overproduction of fibroblast growth factor 23. TIO has been described largely in adults with small mesenchymal tumors. We report a case of TIO in a child who presented with knee pain and radiographic findings concerning for rickets, and was found to have maxillomandibular giant cell lesions. The patient was treated with oral phosphorus and calcitriol, surgical debulking, and intralesional corticosteroids, which resulted in tumor regression and normalization of serum fibroblast growth factor 23 and phosphorus. This case illustrates the occurrence of this rare paraneoplastic syndrome in children and adds to our knowledge about clinical manifestations and pathologic findings associated with pediatric TIO.

A Case of Severe, Prolonged, Refractory Hypophosphatemia After Zoledronic Acid Administration.

Zoledronic acid (ZA) administration has been associated with electrolyte abnormalities, including hypocalcemia, hypomagnesemia, hypokalemia, and hypophosphatemia. We describe a case of severe, refractory hypophosphatemia in a patient who received ZA for hypercalcemia of malignancy (HCM). Little data are available that describe the incidence or degree of severity of hypophosphatemia that can occur following ZA administration. In addition, no formal recommendations exist to guide monitoring for or management of electrolyte derangements in the setting of bisphosphonate use. Our patient required daily, high-dose phosphorus replacement beginning day 4 following ZA administration. The average daily dose of phosphorus, including both intravenous and enteral administration, was highest in the first 2 weeks after ZA, averaging 77 mmol/d days 4 through 15, and does not include sources of phosphorus from the patient's nutrition support. Despite this high amount of supplementation, which was well beyond what meets normal daily requirements and the amount expected to treat "usual" hypophosphatemia, the patient did not achieve sustained normal serum phosphorus levels for over 30 days after ZA. ZA is a favorable option for treating HCM because of its longer duration of action, potent serum calcium-lowering effects, and favorable safety profile. The risk of hypophosphatemia with ZA use is reviewed.

Denosumab in hypercalcemia of malignancy: a case series.

BACKGROUND: Denosumab is a nuclear factor-kappa ligand monoclonal antibody whose FDA-approved indications include treatment of osteoporosis, bone loss with certain anticancer hormonal agents, and prevention of skeletal-related events in patients with bone metastases from solid tumors. In clinical trials, the incidence of severe hypocalcemia has been reported as 3.1-10.8%. To date, case reports and two clinical trials have reported the use of denosumab in the management of hypercalcemia of malignancy. No reports of denosumab-induced hypocalcemia have been reported for the hypercalcemia of malignancy population. METHODS: We performed a retrospective chart review of all patients who received denosumab for hypercalcemia of malignancy to describe the effects of denosumab on calcium levels at our institution. RESULTS: Seven patients received doses of denosumab for hypercalcemia of malignancy. The most common tumor types were breast cancer (n = 3) and hematologic malignancies (n = 2). All patients had bone involvement. Two patients received single doses of 60 mg. The other five patients received 120 mg. The mean corrected calcium levels were 13.7 mg/dL and 12.24 mg/dL for the days of admission and denosumab administration, respectively (p = 0.1889). The mean corrected calcium level for the last known value was 9.92 mg/dL, while in house (p = 0.0016). Supportive care prior to denosumab included hydration (n = 7), bisphosphonates (n = 6), and calcitonin (n = 5). One patient had a calcium level of 6.6 mg/dL on day 4 after denosumab, requiring calcium supplementation and telemetry. Of the seven patients treated with denosumab for hypercalcemia of malignancy at our institution, six patients were discharged alive. Of these, one patient died two days after discharge. Last-known follow-up was a median of 26 days, range, 3-195, for all patients. CONCLUSIONS: Denosumab helped decrease calcium in patients with hypercalcemia of malignancy. However, symptomatic hypocalcemia may result from denosumab in hypercalcemia of malignancy.

[Metabolic bone disease osteomalacia]. / Metabolische Knochenkrankheit Osteomalazie.

Osteomalacia is a rare disorder of bone metabolism leading to reduced bone mineralization. Underlying vitamin D deficiency and a disturbed phosphate metabolism (so-called hypophosphatemic osteomalacia) can cause the disease. Leading symptoms are dull localized or generalized bone pain, muscle weakness and cramps as well as increased incidence of falls. Rheumatic diseases, such as polymyalgia rheumatica, rheumatoid arthritis, myositis and fibromyalgia must be considered in the differential diagnosis. Alkaline phosphatase (AP) is typically elevated in osteomalacia while serum phosphate and/or 25-OH vitamin D3 levels are reduced. The diagnosis of osteomalacia can be confirmed by an iliac crest bone biopsy. Histological correlate is reduced or deficient mineralization of the newly synthesized extracellular matrix. Treatment strategies comprise supplementation of vitamin D and calcium and for patients with intestinal malabsorption syndromes vitamin D and calcium are also given parenterally. In renal phosphate wasting syndromes substitution of phosphate is the treatment of choice, except for tumor-induced osteomalacia when removal of the tumor leads to a cure in most cases.

Refractory hypercalcaemia secondary to parathyroid carcinoma: response to high-dose denosumab.

OBJECTIVE: Hypercalcaemia is an important cause of increased morbidity and mortality in patients with parathyroid carcinoma. Surgical resection is the mainstay of treatment but, equally, managing hypercalcaemia is of paramount importance. At present, few therapies have been shown to be effective in the most severe cases. This report describes the efficacy of denosumab in a patient with parathyroid carcinoma when conventional therapies had been shown to be relatively ineffective.SUBJECT, METHODS AND RESULTS: A 50-year-old man presented with symptomatic hypercalcaemia 1 year after the surgery for his parathyroid carcinoma. Investigations revealed raised serum calcium and parathyroid hormone concentrations consistent with the recurrence of the disease. Imaging failed to localise any surgically remediable foci. Medical management with loop diuretics, calcimimetics and bisphosphonates failed to provide a sustained response. Denosumab, as a monthly injection, led to a gradual decrement in his peak calcium concentrations with the values now persistently below 3 mmol/l. CONCLUSIONS: Denosumab, a fully human MAB that binds to the 'receptor activator of nuclear factor κB ligand (RANKL)', was shown to have a profound effect in modulating malignant hypercalcaemia. This medication should be considered as an effective option in patients with refractory hypercalcaemia secondary to parathyroid carcinoma.

Denosumab should be the treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy.

Denosumab, a fully humanised monoclonal antibody, is licensed for treatment of postmenopausal osteoporosis, hormone ablation-induced bone loss and for prevention of skeleton-related events in patients with bone metastases from solid tumours. In pivotal phase 3 randomised trials, denosumab caused profound hypocalcaemia in patients with normocalcaemia despite oral calcium and vitamin D supplementation. This significant hypocalcaemic effect can be exploited to treat hypercalcaemia of malignancy (HCM). Recent reports from the USA suggest that denosumab is an effective treatment of HCM. According to our knowledge, we report the first two cases in UK with bisphosphonate refractory hypercalcaemia who responded to denosumab injections. Our first case gained 7 months of stabilisation of hypercalcaemia following prolonged admissions with life-threatening levels, while our second case achieved rapid normalisation of serum calcium levels for the first time in 14 months. We conclude that denosumab should be the treatment of choice for patients with bisphosphonate refractory hypercalcaemia.

[New therapeutic approaches for polymyositis and dermatomyositis]. / A polymyositis és dermatomyositis modern kezelési lehetoségei.

Inflammatory myopathies are chronic, immune-mediated diseases characterized with progressive proximal muscle weakness. They encompass a variety of syndromes with protean manifestations. The aims of therapy are to increase muscle strength, prevent the development of contractures, and to manage the systemic manifestations of the disease. This is a complex treatment which requires routine and wide knowledge. The most important task is to recognize the disease and guide the patient to immunologic center. Although the first line of therapy continues to include corticosteroids, there are a multitude of agents available for treating patients with myositis. There are several different immunosuppressive agents which may be applied alone or in combination with each other, as well as an increasing number of novel and exciting biologic agents targeting molecules participating in the pathogenesis of inflammatory myopathy. Physiotherapy and rehabilitation in the remission period may significantly improve the functional outcome of patients with these disorders.

Paraneoplastic dermatomyositis accompanying nasopharyngeal carcinoma: diagnosis, treatment and prognosis.

Dermatomyositis (DM) is a multisystem inflammatory disorder primarily affecting the skin and muscles. Its pathophysiology is still very poorly understood, but humoral and cellular immune dysregulation is apparent. Diagnosis of DM is based on five criteria: proximal limb muscle weakness, serum muscle enzyme elevation, histopathologic muscle abnormalities on muscle biopsy, electromyographic abnormalities, and clinical inflammatory dermatological manifestations (heliotrope rash, poikiloderma, and inflammatory lesions on the hands and facing joints). DM is frequently associated with certain cancers, and may appear before, concurrent with, or after diagnosis of cancer. DM has been reported to be associated with approximately one per 1000 cases of nasopharyngeal carcinoma. Treatment is based on long-course nonselective immunosuppression, particularly corticosteroids, by general route, even when malignancy is present, but new-targeted therapies may modify the treatment strategy in the near future. Despite iatrogenic immunosuppression, the prognosis of nasopharyngeal cancer is not worse in patients with paraneoplastic DM. We report one case as an illustration of this paraneoplastic course (evolving in parallel with the cancer), and to make an update on the state of knowledge on paraneoplastic DM in such cancers.

Mycosis fungoides after solid-organ transplantation: report of 2 new cases.

Long-term survival after solid-organ transplantation is increasing because of recent advances, including new immunosuppressive regimens to avoid graft rejection. However, the resultant modification of the immune system is associated with an increased risk of several cancers. The most common are skin cancers, and lymphomas are second in frequency. Nevertheless, posttransplant primary cutaneous lymphomas (PCLs) are rare, and their incidence is not well known currently. From the files of the Nephrology and Cardiology Departments of University Hospital "12 de Octubre" of Madrid, we obtained clinical data from 1612 transplanted patients and only found 2 cases of posttransplant PCLs, both were T-cell PCL. We reviewed the clinical, histopathological, and immunohistochemical characteristics; both cases were T-cell posttransplant PCLs manifested clinically as mycosis fungoides. One was a 57-year-old woman who had received a cadaveric kidney transplant, and the other was a 60-year-old man with a heart transplant. Histology and immunohistochemistry were consistent with the features of mycosis fungoides when lesions were completely developed. Up to 20% of all organ transplant recipients will suffer some form of malignancy. Unlike general population, 70% of PCLs in transplant recipients are B cell in origin and frequently show positivity for Epstein-Barr virus markers; whereas only 30% are cutaneous T-cell lymphomas. Different pathogenic hypothesis including reduced immune surveillance, chronic antigenic stimulation by transplant grafts, and the direct oncogenic effects of immunosuppressive drugs have been suggested. Although cutaneous B-cell lymphomas are more common, dermatopathologists should be aware that cutaneous T-cell lymphomas may also appear.

Carcinoma tubárico primitivo y polimiositis / Primary primitive fallopian tube carcinoma and polymiositis

Los autores aportan un caso de asociación de un carcinoma tubárico primitivo a una polimiositis. Se trata de una paciente de 53 años, que consultó por dolores pelvianos, metrorragias y leucorreas amarillentas, con una masa pelviana de difícil movilización y móvil a la exploración clínica, y una masa laterouterina derecha con hidrosálpinx en la ecografía pelviana. El diagnóstico definitivo lo aportó el examen ana tomoclínico de la pieza de anexectomía derecha. La histerectomía total sin conservación anexial no dejó residuo tumoral. La paciente perdió contacto con nosotros sin tratamiento complementario y reconsultó 3 años después por una impotencia funcional de los miembros superiores, seguida de los inferiores, mialgias, alteraciones de la deglución y aparición de una adenopatía supraclavicular izquierda. Los exámenes clínicos, paraclínicos y anatomopatológicos mostraron que se trataba de un adenocarcinoma tubárico derecho con recaída ganglionar pelviana y metastásica supraclavicular izquierda, con polimiositis paraneoplásica. La paciente se ha beneficiado de 6 sesiones de quimioterapia, después de radioterapia en el hueco subclavicular izquierdo, a la dosis de 45 Gy. La respuesta al tratamiento ha sido excelente, y la paciente está en remisión completa después de un margen de 50 meses tras el diagnóstico. La asociación de cáncer de la trompa con una polimiositis es excepcional, y es necesaria una terapia antineoplásica rápida para tratar el cáncer y la polimiositis paraneoplásica (AU)

We report a case of a primitive fallopian tube carcinoma associated with polymyositis. A 53­year-old woman consulted for pelvic pain, metrorrhagia, and leukorrhea. Physical examination revealed a renitent and mobile mass in the pelvis. Ultrasonography showed a right lateral uterine mass with hydrosalpinx. Pathological examination of the right annexectomy specimen provided the definitive diagnosis. No residual tumor was found at total hysterectomy with bilateral annexectomy. The patient was lost to follow-up for 3 years without complementary treatment and then consulted again for functional disability first of the upper limbs and subsequently of the lower limbs with myalgia, swallowing disorders and left supraclavicular node enlargement resulting from pelvic relapse of the right fallopian tube adenocarcinoma and left supraclavicular metastasis with paraneoplastic polymyositis. The patient was given 6 courses of chemotherapy with radiotherapy (45 Gy) centered on the left clavicular region. The patient showed excellent response to treatment, and remains in complete remission 50 months after diagnosis. The association of fallopian tube carcinoma with polymyositis is exceptional, requiring rapid treatment effective against the cancer and paraneoplastic polymyositis (AU)

Severe muscle weakness secondary to paraneoplastic hypophosphatemia in neuroblastoma.

We report a 28-year-old woman who presented with severe proximal muscle weakness secondary to paraneoplastic hypophosphatemia and associated with recurrent neuroblastoma. The biochemical findings included hyperphosphaturia, a reduced serum level of 1,25-dihydroxyvitamin-D3, elevated alkaline phosphatase and normocalcemia which are pathognomic for paraneoplastic hypophosphatemia. Following systemic chemotherapy and supplementation of 1,25-dihydroxyvitamin-D3 a complete remission of the neuroblastoma was achieved and all features of the paraneoplastic hypophosphatemia gradually disappeared. In the differential diagnosis of muscle weakness, hypophosphatemia should be included. Paraneoplastic hypophosphatemia associated with metastatic neuroblastoma has not been reported previously. Diagnosis, mechanism and therapy of paraneoplastic hypophosphatemia are shortly reviewed.

Bazex syndrome (acrokeratosis paraneoplastica).

A 67 year old woman with an extensive oropharyngeal carcinoma developed acrokeratosis paraneoplastica. She suffered severe pain in the fingers and toes and experienced some symptomatic relief with psoralen ultraviolet A therapy.

[Mycosis fungoides bullosa]. / Mycosis fungoides bullosa.

We report on a male patient with mycosis fungoides (MF) with blisters mainly occurring on clinically uninvolved skin. This rare association has to be differentiated from other bullous diseases of the skin. The clinical picture has been known since the end of the last century and has been described as mycosis fungoides bullosa. The pathomechanism, however, has not yet been exactly identified. The different clinical and histological features of the disease are discussed.

Oncogenic osteomalacia: imaging studies.

X-ray und NMR imaging studies of a 34-year-old patient with tumor-induced hypophosphatemic osteomalacia (OM) are presented. Besides typical features of OM, periosteal new bone formation was noticed initially. After 17 months of conservative treatment with supplements of inorganic phosphorus and 1,25-dihydroxyvitamin D, bone density had increased but Looser's zones were still present, while periosteal new bone formation was strikingly less evident. At this time a tumor in the first left metatarsal space became palpable, was surgically excised and proved to be a low-grade synovial sarcoma with hypervascular and partially calcified structures. Six months later an X-ray survey showed no more signs of metabolic osteopathy. Preoperatively, the pronounced vascularity of the tumor could be demonstrated by angiography and NMR scanning.

[Systemic photochemotherapy (PUVA) in acanthosis nigricans maligna: regression of keratosis, hyperpigmentation and pruritus]. / Systemische Photochemotherapie (PUVA) bei Acanthosis nigricans maligna: Regression von Keratose, Hyperpigmentierung und Pruritus.

We report on a 60-year-old patient, who developed malignant acanthosis nigricans (MAN) with intense itching 2 years after a large-cell bronchial carcinoma had been diagnosed and found inoperable. The MAN became manifest at a phase of full clinical remission of the lung tumor, which had been treated with cytostasis (cisplatin, vindesine), high energy irradiation, and extirpation of the lymph node metastases. One year after onset of MAN, the lung tumor relapsed, accompanied by an elevated serum level of carcinoembryonic antigen (CEA). The patient was slightly obese, but not diabetic. The generalized MAN was treated with 18 exposures to systemic PUVA (photochemotherapy) over 9 weeks. The patient received 8-methoxypsoralene (8-MOP) orally and a total UVA dose of 52 J/cm2; the last exposure amounted to a maximum dose of 4 J/cm2. Under this treatment, the patient was completely relieved from tormenting pruritus; in addition, we observed significant regression of the pigmented keratoses as well as the intertriginous maceration.