Darier disease, radiation therapy, and herpesvirus -- an unfortunate triad.

Darier disease (DD) is a rare autosomal dominant keratinizing disorder often characterized by brown scaly pruritic papules over the face, neck, and trunk. Herein is reported a patient who developed secondary cutaneous herpes simplex virus (HSV) following exacerbation of his DD as a result of radiation therapy. In November 2020, a 78-year-old man presented to clinic for a pruritic rash on his back consistent with DD. He had developed the rash after the conclusion of chemoradiation therapy for recently diagnosed urothelial carcinoma of the bladder with squamous differentiation. However, he returned two weeks later complaining of a marked worsening of the rash associated with a pain and burning sensations. Histopathology was non-conclusive, but the lesions were found to be positive for HSV-1 by PCR. The patient recovered without complication over a period of two weeks following a course of valacyclovir. There is precedent in the literature for ionizing radiation inducing flares of DD lesions in overlying skin. In addition, DD has been shown to put a patient at increased risk for secondary infections such as HSV. This case report demonstrates that HSV could pose a significant risk to those with DD receiving radiation therapy and thus could warrant prophylactic treatment.

Interstitial Granulomatous Drug Reaction to Ustekinumab.

Interstitial granulomatous drug reaction (IGDR) is a distinct inflammatory process that often presents as annular, violaceous plaques distributed on the extremities, proximal trunk, and intertriginous areas. The list of drugs implicated for inciting IGDR is growing, but most prominently includes ACE inhibitors, antihistamines, beta-blockers, antidepressants, and anticonvulsants. Ustekinumab is a human monoclonal antibody that targets inflammatory cytokines IL-12 and IL-23 and has been have shown to be effective in treating IGDR. However, we present a case that suggests ustekinumab can also act as an inciting agent for IGDR.

Randomized clinical trial comparing open with video-assisted minimally invasive parathyroid surgery for primary hyperparathyroidism.

BACKGROUND: : Previous studies of video-assisted techniques for parathyroidectomy in patients with primary hyperparathyroidism have found similar or better results compared with bilateral neck exploration. The aim of the present study was to compare open minimally invasive parathyroidectomy with the video-assisted technique for primary hyperparathyroidism in a multicentre randomized trial. METHODS: : Some 143 patients were randomized to open (n = 75) or video-assisted (n = 68) parathyroidectomy after positive sestamibi scintigraphy. There were no differences in preoperative data. The open operation was performed through a 15-mm incision. The video-assisted techniques used were minimally invasive video-assisted parathyroidectomy (MIVAP) or video-assisted parathyroidectomy using the lateral approach (VAPLA). Data were collected prospectively including postoperative pain scoring. RESULTS: : The procedure was significantly quicker for the open compared to the video assisted operations: mean(s.d.) 60(35) versus 84(47) min (P = 0.001). Both groups of patients had similar conversion rates and the same outcome, with comparable incision lengths, low scores for postoperative neck discomfort, high cosmetic satisfaction and low complication rates. CONCLUSION: : Open minimally invasive parathyroidectomy for primary hyperparathyroidism was quicker than either video-assisted technique. REGISTRATION NUMBER: NCT00877981 (http://www.clinicaltrials.gov)

Use of the harmonic scalpel versus conventional haemostatic techniques in patients with Grave disease undergoing total thyroidectomy: a prospective randomised controlled trial.

INTRODUCTION: Thyrotoxicosis is often considered to be the most difficult thyroid operation because of the high vascularisation and the risk of bleeding. The conventional haemostatic technique in thyroidectomy today include knot tying and electrocoagulation. The introduction of the harmonic scalpel (HS) has led to further research if the use of the HS has any benefits in thyroid surgery. To our knowledge, no previous study has evaluated the HS dissection technique in a homogenous group of patients with Graves' disease undergoing total thyroidectomy. MATERIALS AND METHODS: Fifty-one patients (39 women and 12 men) with the pre-operative diagnosis of Graves' disease treated at two endocrine centers were randomised to total thyroidectomy with the use of the HS or with conventional haemostatic techniques. RESULTS: Twenty-seven patients were randomised to the harmonic group and 24 to the conventional group. The operating time was shorter in the HS group (median, 121 min; range, 84-213 min) compared to the conventional group (median, 172 min; range, 66-268 min; p = 0.011). CONCLUSION: The use of the HS was associated with a significant reduction in operating time compared to the use of the conventional haemostatic techniques in patients with Graves' disease undergoing total thyroidectomy.

High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families.

BACKGROUND: : Inherited mutations in the CDKN2A tumor suppressor gene, which encodes the p16(INK4a) protein, and in the cyclin-dependent kinase 4 (CDK4) gene confer susceptibility to cutaneous malignant melanoma. We analyzed families with two or more cases of melanoma for germline mutations in CDKN2A and CDK4 to elucidate the contribution of these gene defects to familial malignant melanoma and to the occurrence of other cancer types. METHODS: : The entire CDKN2A coding region and exon 2 of the CDK4 gene of an affected member of each of 52 families from southern Sweden with at least two cases of melanoma in first- or second-degree relatives were screened for mutations by use of polymerase chain reaction-single-strand conformation polymorphism analysis. Statistical tests were two-sided. RESULTS: : CDKN2A mutations were found in 10 (19%) of the 52 families. Nine families carried an identical alteration consisting of the insertion of arginine at position 113 of p16(INK4a), and one carried a missense mutation, in which the valine at position 115 was replaced with a glycine. The 113insArg mutant p16(INK4a) was unable to bind cdk4 and cdk6 in an in vitro binding assay. Six of the 113insArg families had at least one member with multiple primary melanomas; the 113insArg families also had a high frequency of other malignancies-in particular, breast cancer (a total of eight cases compared with the expected 2.1; P =.0014) and pancreatic cancer (a total of six cases compared with the expected 0.16; P<.0001). Families with breast cancer also had a propensity for multiple melanomas in females, suggesting that a sex-dependent factor may modify the phenotypic expression of CDKN2A alterations. CONCLUSIONS: : Our findings confirm that the majority of CDKN2A-associated melanoma families in Sweden are due to a single founder mutation. They also show that families with the CDKN2A 113insArg mutation have an increased risk not only of multiple melanomas and pancreatic carcinoma but also of breast cancer.

Novel germline p16 mutation in familial malignant melanoma in southern Sweden.

The p16 (CDKN2/MTS1/INK4a) malignant melanoma susceptibility gene was analyzed in 10 melanoma kindreds from southern Sweden using single-stranded conformation polymorphism analysis of all three exons and flanking intron regions followed by sequence analysis. A novel germline mutation, constituting an in-frame 3-bp duplication at nucleotide 332 in exon 2, was identified in two families (Lund M2 and M9). The mutation results in an insertion of Arg at codon 105, which interrupts the last of the four ankyrin repeats of the p16 protein, motifs which have been demonstrated as important in binding and inhibiting the activity of cyclin D-dependent kinases 4 and 6 in cell cycle G1 phase regulation. All five tested individuals of Lund M2 and M9 affected by melanoma were mutation carriers, as were five melanoma-free individuals. Other malignancies observed in gene carriers or obligate carriers included cervical, breast, and pancreatic carcinomas and a non-Hodgkin's lymphoma. Analysis of microsatellite markers adjacent to the p16 gene at chromosomal region 9p21 revealed that both families share a common haplotype, in keeping with a common ancestor.

Risk factors for reoperation due to chronic groin postherniorrhaphy pain.

BACKGROUND: Chronic groin postherniorrhaphy pain (CGPP) is common and sometimes so severe that surgical treatment is necessary. The aim of this study was to identify risk factors for being reoperated due to CGPP. METHODS: All 195,707 repairs registered in the Swedish Hernia Register between 1999 and 2011 were included in the study. Out of these, 28,947 repairs were excluded since they were registered as procedures on the same patient after a previous repair. Age, gender, hernia anatomy (indirect reference), method of repair (anterior sutured repair reference) and postoperative complications were included in a multivariate Cox analysis with reoperation due to CGPP as endpoint. RESULTS: Of the patients included in the study cohort, 218 (0.13%) later underwent reoperation due to CGPP, including 31 (14%) women. Median age at the primary repair was 61.5 years. Risk factors for being reoperated were age < median [hazard ratio (HR) 3.03, 95% confidence interval (CI) 2.22-4.12], female gender (HR 2.13, CI 1.41-3.21), direct hernia (HR 1.35, CI 1.003-1.81), other hernia (HR 6.03, CI 3.08-11.79), Lichtenstein repair (HR 2.22, CI 1.16-4.25), plug repair (HR 3.93, CI 1.96-7.89), other repair (HR 2.58, CI 1.08-6.19), bilateral repair (HR 2.58, CI 1.43-4.66) and postoperative complication (HR 4.40, CI 3.25-5.96). CONCLUSIONS: Risk factors for being reoperated due to CGPP in this cohort included low age, female gender, a direct hernia, a previous Lichtenstein or plug repair, bilateral repair and postoperative complications. Further research on how to avoid CGPP and explore the effectiveness of surgery for CGPP is necessary.

At what age do sunburn episodes play a crucial role for the development of malignant melanoma.

The age relationship between sunburns and malignant melanoma was investigated in a population-based, matched, case-control study from the South Swedish Health Care Region (the highest risk area for melanoma in Sweden). Between 1988 and 1990, a total of 400 patients with a first diagnosis of malignant melanoma and 640 healthy controls aged 15-75 years answered a comprehensive questionnaire including questions regarding ultraviolet radiation exposure. In addition, a literature review was performed. The average number of episodes of sunburn per year was significantly associated with malignant melanoma (relative risk, RR = 1.9 for > or = three episodes per year versus never). Outdoor employment during the summer was associated with a decreased risk for the development of malignant melanoma (RR = 0.8). Data from case-control studies and migration studies concerning age relationship between sunburns and melanoma are inconsistent. From our own data, we did not find a higher risk of melanoma developed in individuals who had experienced severe sunburns in childhood. Instead, a significantly increased risk was associated with sunburns after age 19 years, RR = 2.2 for a history of more than five times versus never. Even if the hypothesis is biologically plausible, that episodes of sunburn early in life are associated with a higher risk of melanoma, so far epidemiological evidence is scarce. There is a need for better prospective epidemiological studies addressing this issue.

Reproducibility of a self-administered questionnaire for assessment of melanoma risk.

BACKGROUND: The reproducibility of a self-administered questionnaire on different epidemiological variables was examined in a random sample of a cohort of healthy women from the South Swedish Health Care Region. An identical questionnaire has previously been used for assessment of melanoma risk, in a population-based, matched, case-control study from the same region. METHODS: Repeat questionnaires were completed on two occasions, 1-3 years apart, by 670 randomly selected subjects. In addition, exposure data from a case-control study were used to estimate the effect of misclassification. RESULTS: Overall, there was a fair to good consistency between the answers on the two occasions for the various epidemiological variables. Exposure variables identified as risk factors for melanoma development were reasonably reproducible. The estimated proportion of agreement, A, ranged from 0.74 to 0.92, the average correct classification rate (assuming common sensitivity and specificity), pi, was > or = 0.85 and the kappa coefficient, kappa, ranged between 0.52 and 0.83. However, the question on number of raised naevi on the arm was an exception since it had a lower test-retest reliability (A = 0.62, pi = 0.77, kappa = 0.40). When using data from the case-control study, the effect of the estimated random misclassification was found to only slightly bias odds ratios toward one. CONCLUSION: Our questionnaire, used for assessment for melanoma risk, provided information with fair to good test-retest reliability, and corrected odds ratios were found to be only slightly higher than observed odds ratios.

Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism.

HYPOTHESIS: A variety of clinical and biochemical variables may be associated with hypocalcemia after surgery for parathyroid adenoma. DESIGN: A prospective study of patients who underwent surgery for solitary parathyroid adenoma. SETTING: A university hospital department of surgery. PATIENTS: Eighty-six consecutive patients who underwent surgery for solitary parathyroid adenoma. INTERVENTION: Parathyroidectomy according to the principles of unilateral neck exploration. MAIN OUTCOME MEASURES: Clinical and biochemical risk factors for early (< or =4 days after surgery) and late (1 year after surgery) postoperative symptomatic and biochemical hypocalcemia. RESULTS: Twenty-two patients developed early symptomatic hypocalcemia. The difference in total serum calcium levels between patients, with and without early symptomatic hypocalcemia, was evident on the third and fourth postoperative days. Serum level of osteocalcin greater than 6.0 microg/L, bilateral neck exploration, and history of cardiovascular disease were risk factors for symptomatic hypocalcemia (odds ratios [95% confidence intervals]: 4.4 [1.4-14.1], 3.8 [1.3-11.6], and 0.1 [0.02-0.60], respectively). Patients with up to 1 risk factor had a possibility of only 7% to develop early symptomatic hypocalcemia. One year after surgery, 16 patients had low levels of total serum calcium (late biochemical hypocalcemia) and were asymptomatic. Preoperative intermittent hypercalcemia was associated with an increased risk for late biochemical hypocalcemia (odds ratio, 3.9; 95% confidence interval, 1.0-16.3). CONCLUSIONS: Clinical and biochemical risk factors for early and late postoperative hypocalcemia in patients who underwent surgery for solitary parathyroid adenoma were found. A clinically useful prognostic index for early symptomatic hypocalcemia was constructed using these risk factors.

Prognostic factors in invasive cutaneous malignant melanoma: a population-based study and review.

A population-based study from Sweden identified 711 patients with cutaneous malignant melanoma diagnosed in 1965, 1975, 1985 and 1989. Prognostic factors were evaluated and a review of the literature was performed. On univariate analysis, thick tumours (> 0.8 mm) (odds ratio [OR] 1.8, 95% confidence interval [CI] 1.6-2.1), increasing Clark level (OR 1.8, 95% CI 1.6-2.0), ulceration (OR 1.8, 95% CI 1.6-2.0), nodular melanoma (OR 1.5, 95% CI 1.3-1.6) and increasing age (continuous variable, P < 0.0001) were associated with a shorter survival. Location on extremities (OR 0.8, 95% CI 0.7-0.9), inflammation (OR 0.8, 95% CI 0.7-0.9) and female gender (OR 0.8, 95% CI 0.8-0.9) were associated with improved survival. On multivariate analysis, thick tumours (> 0.8 mm) (OR 1.5, 95% CI 1.2-1.7) and ulceration (OR 1.4, 95% CI 1.2-1.6) were independently related to a poor prognosis, while location on extremities (OR 0.8, 95% CI 0.7-0.9), inflammation (OR 0.8, 95% CI 0.7-0.9) and female gender (OR 0.8, 95% CI 0.8-1.0) were associated with improved survival. No difference in mean tumour thickness was seen over time, but there was a significant increase in the percentage of thin melanomas (< 0.8 mm) in 1985 (P = 0.01) and 1989 (P = 0.002) compared with 1965. The incidence of melanomas with inflammation increased significantly (P = 0.04), as did age at diagnosis (P = 0.005).

Clinical and histopathological characteristics in relation to aetiological risk factors in cutaneous melanoma: a population-based study.

In this population-based, case-control study from Sweden using data collected from 1988 to 1990, an increased risk of melanoma was associated with the number of sunburns, propensity to freckle, the number of raised naevi and a family history of melanoma. Furthermore, a decreased risk was associated with occupational sun exposure. The purpose of this study was to investigate whether different histopathological features of the melanoma and clinical factors were related to the different aetiological risk factor patterns. All the confirmed primary cutaneous melanomas (n = 366) were included in the study. Both univariate analyses with tests for interaction and multivariate analyses were performed. Patients with melanoma on the trunk and patients with thin melanomas had an excess of close relatives with a history of melanoma (odds ratios [ORs] = 2.7 and 2.3, respectively). A relationship was also seen between melanomas in younger persons and a family history of melanoma (OR = 2.6). The presence of raised naevi on the arm had a tendency to be closer related to melanoma of the nodular type (OR = 4.3) than melanoma of the superficial spreading type (OR = 1.6). Patients with outdoor occupations during summer had a decreased risk of developing melanoma on the extremities. Melanoma diagnosed in patients born before 1939 had an association with sunburns (OR = 1.9) and freckling (OR = 2.0), while melanomas in patients born in 1939 or later were related to a family history of melanoma (OR = 2.2). These results suggest that different histopathological and clinical features of melanoma are associated with different risk factor patterns, which may imply diverging tumour genesis.

Is the use of sunscreens a risk factor for malignant melanoma?

The relation between use of sunscreens, different host factors and malignant melanoma was investigated in a population-based, matched case-control study of malignant melanoma in the South Swedish Health Care Region, which has the highest risk for melanoma in Sweden, between 1 July 1988 and 30 June 1990. In total, 400 melanoma patients and 640 healthy controls aged 15-75 years answered a comprehensive questionnaire regarding different epidemiologic variables, including questions on use of sunscreens and different constitutional factors. The use of sunscreens was not found to protect against developing malignant melanoma. Instead, an unexpected relation between the use of sunscreens and the risk of developing malignant melanoma was seen (odds ratio (OR) 1.8 for almost always vs never using sunscreens). A tentative dose-response relation was found. Virtually the same ORs were seen in both sexes. Furthermore, persons younger than 50 years had a higher OR than persons older than 50 years. When different melanoma presentation sites were considered, lesions of the trunk were associated with sunscreen use in females (adjusted OR = 3.7 for almost always vs never using sunscreens), while lesions of the extremity or head and neck were associated with sunscreen use in males (adjusted OR = 3.2 for almost always vs never using sunscreens). Raised naevi on the left arm and freckling were shown to be the major constitutional risk factors (OR = 3.9 for more than three naevi vs none and OR = 1.4, respectively). The results were essentially unaltered in a histopathologically re-examined material. Further investigations are needed in order to form a basis for melanoma prevention.

Clinical and histopathological features of malignant melanoma in germline CDKN2A mutation families.

Primary cutaneous malignant melanomas (CMMs) from 26 individuals belonging to nine families with an identified mutation were clinically and histopathologically compared with 78 matched CMM controls and with a population-based series of CMMs ( = 667). All tumours were histopathologically re-examined. CDKN2A-associated cases were significantly less invasive compared with the matched controls, with an adjusted odds ratio (adjOR) of 2.9 and a 95% confidence interval (CI) of 1.0-8.1 ( = 0.04). According to the odds ratio (OR) values, CDKN2A-associated cases seemed to have tumours more often located on the head and neck (adjOR 2.9, 95% CI 0.6-13.7), with less inflammation (adjOR 0.7, 95% CI 0.3-1.8) and regression (adjOR 0.6, 95% CI 0.2-1.8) but more frequent histological ulceration (adjOR 1.9, 95% CI 0.6-5.8). In comparison with the population-based material, CDKN2A-associated cases were significantly younger at diagnosis (crude OR 3.5, 95% CI 1.6-7.5, divided at 50 years) and had less regressive reaction in their tumours (crude OR 0.35, 95% CI 0.2-0.8). No significant differences were seen for tumour thickness between the different groups. On multivariate analysis, the overall survival was significantly worse for thicker tumours and older age ( = 0.04 for both). To our knowledge this is the first description of the histopathological features of CMMs from families with mutations in the CDKN2A gene.

Southern travelling habits with special reference to tumour site in Swedish melanoma patients.

Southern travelling habits were recorded for 127 melanoma patients from southern parts of Sweden (the 56th latitude), 55 thyroid cancer patients, 100 non-Hodgkin's patients and 794 healthy controls from the same region. Melanoma patients were found to travel significantly more often south of the 45th latitude, as compared with patients with non-Hodgkin's lymphoma or thyroid carcinoma (RR = 2.2 for a difference of + 10 trips), and with the healthy controls (RR = 1.4 for a difference of + 10 trips). Considering men and women separately, the difference was significant only for men. Patients with melanoma had a higher educational level than the tumour controls and the healthy controls (p < 0.001 and p < 0.001 respectively). There was a significant correlation between high travelling frequency and high education. An increased risk related to southern travelling was present for patients with melanoma on the extremities and head and neck, as well as for patients with truncal melanoma. These findings support the concept that acute exposure to sunburn may be a risk factor for malignant melanoma.

Recurrence of exocrine pancreatic cancer--local or hepatic?

The results of radical surgery for pancreatic cancer depend, like all other cancer surgery, on the technique used, and the biology of the disease. We have analysed the site and time of recurrence after pancreatectomy for exocrine pancreatic cancer in 74 patients who died more than six months postoperatively. All patients had recurrent disease, 64 patients had local recurrence in the pancreatic bed and 68 had liver metastases. Local recurrence without liver metastases was found in six patients, and ten had liver metastases, but no local recurrence. Both the time from operation to clinically evident recurrence and the postoperative survival time were significantly longer for patients with local recurrence only. Although not statistically significant, there was a tendency (5 out of 8) for smaller, well-differentiated tumors without spread outside the pancreas to be associated with local recurrences without liver metastases. We conclude that, in retrospect, the surgical procedures used were inappropriate and inadequate. To cure these patients, a more radical operation and/or effective adjuvant treatment is needed.

A prospective study of 100 roboticallyassisted laparoscopic adrenalectomies.

We evaluated robotically assisted laparoscopic adrenalectomy (RLA) in a prospective study of 100 consecutive patients (60 women and 40 men) undergoing unilateral adrenalectomy at the University Hospital. The median age was 59 (24-82) years and BMI 27.6 (17.1-40.9) kg/m(2). Preoperative diagnoses were Conn's syndrome 30%, pheochromocytoma 23%, Cushing syndrome 27% and non-functional tumor 20%. The median tumor size was 53 (10-106) mm. The majority of the 7% of the patients who were converted to open surgery were in the early phase after the introduction of the technique. The BMI of the patients who were converted to open surgery was significantly higher, 31.5 (range 25.3-37.8) compared to, 27.5 (range 17.1-40.9) in patients without conversion (P = 0.047). The median weight of the tumor was 51 g for patients with conversion (range 18-97 g) and 30 g (range 8-128 g) for patients without conversion (P = 0.066). The median console operation time for the whole series was 88 min (range 39-397 min). The console operation time decreased significantly with the numbers of patients operated (r = 0.372; P = 0.0003). There was an association between the weight of the specimen and operation time (r = 0.42; P = 0.0001). RLA is a safe and a feasible surgical alternative for treating all kind of adrenal disorders, particularly large tumors and more complex circumstances. The present study clearly shows that a learning curve is present for the console surgeon and assistants.

Hemithyroidectomy: long-term effects on parathyroid function--preliminary report.

Early hypocalcemia after thyroid surgery has frequently been reported, whereas data regarding long-term effects on calcium homeostasis are scarce. We have previously studied patients after hemithyroidectomy with an oral calcium load test and found normal parathyroid hormone (PTH) suppression. However, the 1,25-dihydroxyvitamin D concentration was decreased and the phosphate concentration increased, implying parathyroid insufficiency. We therefore proceeded to investigate PTH secretion and suppression in 10 euthyroid patients subjected to hemithyroidectomy due to benign thyroid disease before and at 1 year after surgery. In addition, biochemical variables known to influence calcium homeostasis were analyzed. Basal, maximal, and total PTH secretion were unaltered 1 year postoperatively. However, maximal PTH secretion was reached at a lower serum level of ionized calcium, and there was a tendency toward increased parathyroid sensitivity to ionized calcium. Furthermore, compared to preoperative, total serum calcium, 1,25-dihydroxyvitamin D, and free thyroxine (T4) concentrations were decreased at follow-up. Total serum calcium and 1,25-dihydoxyvitamin D concentrations were decreased 1 year after hemithyroidectomy. These changes were not due to parathyroid insufficiency. Instead, our results imply increased parathyroid sensitivity to calcium and possibly reduced peripheral sensitivity to PTH.