Online prediction tools for melanoma survival: A comparison.

BACKGROUND: Breslow thickness, patient age and ulceration are the three most valuable clinical and pathological predictors of melanoma survival. A readily available reliable online tool that accurately considers these and other predictors could be valuable for clinicians managing melanoma patients. OBJECTIVE: To compare online melanoma survival prediction tools that request user input on clinical and pathological features. METHODS: Search engines were used to identify available predictive nomograms. For each, clinical and pathological predictors were compared. RESULTS: Three tools were identified. The American Joint Committee on Cancer tool inappropriately rated thin tumours as higher risk than intermediate tumours. The University of Louisville tool was found to have six shortcomings: a requirement for sentinel node biopsy, unavailable input of thin melanoma or patients over 70 years of age and less reliable hazard ratio calculations for age, ulceration and tumour thickness. The LifeMath.net tool was found to appropriately consider tumour thickness, ulceration, age, sex, site and tumour subtype in predicting survival. LIMITATIONS: The authors did not have access to the base data used to compile various prediction tools. CONCLUSION: The LifeMath.net prediction tool is the most reliable for clinicians in counselling patients with newly diagnosed primary cutaneous melanoma regarding their survival prospects.

Merkel cell carcinoma update: the case for two tumours.

Merkel cell carcinoma (MCC) is an aggressive tumour with neuroendocrine differentiation. Clinically significant differences within the entity we know as MCC are apparent. This review aims to evaluate the evidence for differences in tumours within Merkel cell carcinoma and to stratify these. A literature search of research pertaining to various characteristics MCC was undertaken from 1972, when Merkel cell carcinoma was first described, to 2018, using PubMed and similar search engines. A total of 41 papers were analysed, including clinical trials, laboratory-based research and reviews. A proportion of MCC has Merkel cell polyomavirus genome integrated (MCPyV+) while others do not (MCPyV-). Both types have a different mutation burden. MCPyV+ tumours are likely true neuroendocrine carcinomas, with a dermal origin, probably from fibroblasts which have been transformed by integration of the viral genome. MCPyV-tumours are likely derived from either keratinocytes or epidermal stem cells, are probably squamous cell carcinomas with neuroendocrine differentiation, and are related to sun damage. Prognostic factors (apart from tumour stage) include the MCPyV status, with MCPyV+ tumours having a better prognosis. P63 expression confers a worse prognosis in most studies. CD8+ lymphocytes play an important role, providing a possible target for PD1/PD-L1 blockade treatment. The incidence of MCC varies from country to country. Countries such as Australia have a high rate and a far greater proportion of MCPyV- tumours than places such as the United Kingdom. MCC doubtlessly encompasses two tumours. The two tumours have demonstrated differences in prognosis and management. One is a neuroendocrine carcinoma related to MCPyV integration likely derived from fibroblasts, and the other is a UV-related squamous cell carcinoma with neuroendocrine differentiation, presumptively derived from either keratinocytes or epidermal stem cells. We propose naming the former Merkel type sarcoma and the latter squamous cell carcinoma, Merkel type.

Dermoid cyst of the caecum: case report.

Benign dermoid cysts of the caecum are rare. We present a case of benign dermoid cyst of the caecum and discuss the various explanations of pathogenesis. Various possible explanations exist, including embryological sequestration, implantation following surgery, squamous metaplasia of enterogenous cysts and teratoma. In this case there was also a finding of intratubular germ cell neoplasia of one testis, detected on follow-up studies on the patient. The significance of this is discussed.

Thalidomide: when everything old is new again.

Thalidomide is an anti-angiogenesis agent that currently is being evaluated in the treatment of various types of cancer. The teratogenic effects of thalidomide are well-known, and patients who are prescribed this drug often are fearful of its effects. Because of the potential for teratogenicity, patients must adhere to the System for Thalidomide Education and Prescribing Safety (STEPS). Side effects of thalidomide include sedation, dose-related peripheral neuropathy, constipation, thrombiotic events, and skin rash. Nurses have a major role in educating patients about this drug, its effects, and necessary precautions.

Phase II study of combination taxol and estramustine phosphate in the treatment of recurrent glioblastoma multiforme.

Taxol has activity in the treatment of high grade gliomas but estramustine phosphate (EMP) has not been used in this setting. In vitro data demonstrates that EMP is cytotoxic to glioma cell lines and estramustine binding proteins are expressed by glioma cells. The combination of Taxol and EMP is reported to be active in the treatment of hormone-refractory prostate cancer and in taxane-resistant breast and ovarian cancer. We therefore performed a phase II study to assess the activity and toxicity of this combination in high grade gliomas. Taxol was given at a dose of 225 mg/m2 intravenously over three hours on day 1 and EMP was given at a dose of 900 mg/m2 orally on days 1 through 3. Cycles were repeated every three weeks. Twenty patients with recurrent glioblastoma multiforme (GBM) were enrolled: 11 male, median age 45 years. All patients received anti-epileptic medications and 17 (80%) had received prior chemotherapy. Of 18 evaluable patients, two had partial responses (11) and six had stable disease (33%) for a minimum of eight weeks. Treatment was well tolerated with grade 3 neutropenia occurring in only three patients. There were no other grade 3 or 4 toxicities. The median time to progression for the cohort was only six weeks (range 3-60+ weeks). The median overall survival was 12 weeks (range 3-60+ weeks). In conclusion, the combination of Taxol and EMP is well tolerated and has modest activity in the treatment of recurrent GBM.

A phase I/II study of carboplatin combined with hyperfractionated radiotherapy for brainstem gliomas.

BACKGROUND: Brainstem gliomas often respond to radiotherapy but long term disease control is exceptional. The concomitant administration of a chemotherapy agent with radiosensitizing properties such as carboplatin may increase the efficacy of radiotherapy. METHODS: A dose escalation schedule of carboplatin was devised to determine the maximum tolerated dose (MTD) of intravenous carboplatin when given on a twice-weekly schedule during a course of hyperfractionated, involved field radiotherapy (100 centigrays [cGy] twice daily to 7200 cGy). The starting dose was 20 mg/m(2) and the dose was increased by 15 mg/m(2) after every 3 patients provided no Grade 3 or 4 (according to the National Institutes of Health Common Toxicity Criteria) toxicity occurred. Magnetic resonance imaging (MRI) scans (brain and spine) were obtained before treatment and at the time of disease progression. Clinical entry criteria included an MRI scan demonstrating a diffuse intrinsic pontine tumor and a typical 2-3-month history of evolving cranial neuropathies and a gait disorder. Biopsy-confirmed evidence of a high grade glioma was required for nonpontine brain stem tumors. RESULTS: A total of 34 patients were enrolled. The median age of the patients was 7.8 years (range, 3.6-15.4 years) and the median prodrome duration was 1.5 months (range, 0.25-36 months). The MTD was 110 mg/m(2) or a total cumulative dose of 1540 mg/m(2) over 7 weeks. The dose-limiting toxicity was hematologic. The median progression free survival was 8 months (range, 0-104+ months) and the overall survival was 12 months (range, 5-104+ months). At last follow-up there were 5 long term survivors (15%) who remained in continuous remission after a mean follow-up period of 79 months (range, 46-104 months). Fifteen of the 29 patients (52%) with recurrence and or disease progression developed leptomeningeal/intraaxial tumor spread beyond the local radiation field. CONCLUSIONS: The cumulative MTD for carboplatin is 1540 mg/m(2) when administered concomitantly with involved field, hyperfractionated radiotherapy in a twice-weekly schedule for 7 weeks. Subsequent Phase II and III clinical trials can be conducted safely at this level.

Carboplatin chemotherapy before irradiation in newly diagnosed glioblastoma multiforme.

The authors evaluated the efficacy of neoadjuvant carboplatin chemotherapy before external-beam irradiation in patients who had histologically proven glioblastoma multiforme. Twenty-five patients were treated with carboplatin, 600 mg/m2, intravenously once every 4 weeks for a total of 4 planned cycles. External-beam irradiation (60 Gy involved field) was planned after carboplatin. Of 15 patients who had residual tumor assessable for response, seven had stable disease, six had partial responses, one had a complete response, and one had progressive disease. Two of the patients who had partial responses progressed before radiotherapy. Of 10 who had gross total resections, two progressed after 3 to 4 cycles. The median time to tumor progression was 8.4 months. Median survival was 19.2 months. Myelotoxicity and other side effects of treatment were modest. Carboplatin chemotherapy after biopsy or resection of glioblastoma multiforme before irradiation is feasible. These results warrant further clinical investigation of the role that carboplatin chemotherapy may have in the treatment of patients who have newly diagnosed glioblastoma multiforme.

Ataxia telangiectasia with long survival.

A few patients with ataxia telangiectasia survive into the 3rd decade. In the central nervous system, dilated meningeal veins have been noted in a few cases but as a rule the vasculature in both brain and spinal cord appears normal. We present the case of the longest reported surviving patient with ataxia telangiectasia who died at the age of 34 years and showed numerous vascular malformations with gliosis and haemosiderin in the cerebral white matter and spinal cord. These are similar to the features described in three previously reported long surviving cases of ataxia telangiectasia. In addition, however, numerous corpora amylacea were present, a finding not previously described. Also presented is the magnetic resonance imaging (MRI) scan which was of diagnostic-value; there have been very few MRI scans recorded in ataxia telangiectasia. It showed lesions consistent with vascular malformations in cerebral white matter with surrounding abnormal tissue consistent with gliosis. Gross cerebellar atrophy was also demonstrated. It is significant that MRI scans 6 months apart at the age of 32 years showed progression of the lesions.

Thyroid dysfunction as a late effect in survivors of pediatric medulloblastoma/primitive neuroectodermal tumors: a comparison of hyperfractionated versus conventional radiotherapy.

BACKGROUND: Primary hypothyroidism is a common sequela of craniospinal radiotherapy in the treatment of pediatric brain tumors. METHODS: The authors compared the incidence of primary hypothyroidism after hyperfractionated radiotherapy (HFRT) (n = 14 patients) versus conventionally fractionated radiotherapy (CRT) (n = 34 patients) in a group of pediatric patients with medulloblastoma/primitive neuroectodermal tumors (MB/PNET). RESULTS: The mean age at the time of tumor diagnosis was 7.9 years in the HFRT group and 8.4 years in the CRT group. The patients were followed for a mean of 4.6 years (HFRT) and 8.3 years (CRT) after diagnosis. Mean radiation doses to the thyroid were similar in both radiotherapy groups (29 gray [Gy] [HFRT] vs. 24 Gy [CRT]). Approximately 14% of the HFRT and 62% of the CRT patients developed primary hypothyroidism within a similar period after irradiation (3.2 years [HFRT] vs. 3.0 years [CRT]). Analysis by cumulative incidence function demonstrated a significant difference in the risk of developing thyroid dysfunction between these two groups of patients (P = 0.02). CONCLUSIONS: The current study findings suggest that the use of HFRT in the treatment of pediatric patients with MB/PNET is associated with a lower risk of these patients developing primary hypothyroidism.

Impaired early growth of infants perinatally infected with human immunodeficiency virus: correlation with viral load.

OBJECTIVE: To evaluate the effect of viral load on the early growth of infants infected with human immunodeficiency virus (HIV). METHODS: Plasma concentrations of p24-antigen and HIV ribonucleic acid were measured retrospectively and correlated with growth parameters for the first 18 months of life in a cohort of 47 term infants born to HIV-infected mothers prospectively enrolled in a study of perinatal HIV transmission. Comparisons of the mean weight and length of the 18 HIV-infected and 29 uninfected infants for each interval and across intervals were made. Viral load was correlated with standard deviation scores. Infants were stratified by high and low viral load during the first 6 months of life. RESULTS: At birth, no difference in weight and length was observed between HIV-infected and uninfected infants. Between birth and 6 months of age, the infected infants grew less rapidly than the uninfected infants, a finding temporally associated with an exponential increase in HIV viremia. The linear growth of infected infants remained consistently less than that of the uninfected infants after 6 months of life, although the differences were no longer statistically significant and tended to decrease with age in parallel with declines in viral load. The median plasma concentration of HIV ribonucleic acid was significantly higher at 3, 6, 12, and 18 months in infected infants in whom growth failure developed. Infants who had a high viral load in the first 6 months of life were significantly more likely to have severe growth failure. Though the mean SD for weight of the infected infants was always less than that of the uninfected infants, the differences were small and not significant. CONCLUSIONS: Our results confirm the observation that stunting is an early frequent finding in perinatal HIV infection. The deleterious effect of HIV on linear growth appears to be correlated with the level of postnatal HIV viremia, although the exact mechanism of this association remains to be elucidated.

Hypothalamic-pituitary-adrenal function following cranial irradiation.

We assessed the effect of cranial irradiation on hypothalamic-pituitary (HP)-adrenal function in 17 patients (12 females, 5 males) treated with cranial/ craniospinal irradiation for acute leukemia (2 patients) or tumors distant from the hypothalamus and pituitary (8 medulloblastoma, 3 astrocytoma, 3 rhabdomyosarcoma, 1 ependymoma). Estimated doses of radiation (RT) to the HP region ranged from 18 to 72 Gy. Thirteen of seventeen patients were also treated with chemotherapy. Patients were a median of 3.75 years of age (1.5-19 years) at diagnosis and were studied at a median of 5 years (0.1-20 years) after RT. Patients received corticotropin-releasing factor (oCRF, 1 microgram/kg i.v.), and sampling for cortisol and ACTH levels was performed at -15, 0, 15, 30, 60, 90 and 120 min. The-5- and 0-min levels were combined for a standardized baseline value (Base). Cortisol levels at 0, Base, 30 and 120 min, as well as the peak cortisol response, were significantly lower in the patients. Twelve of seventeen patients' peak cortisol levels fell below the normal range. The patients' mean integrated values for cortisol (area under the curve) were not, however, different from controls. The ACTH responses to oCRF did not differ between patients and controls. No relationship was observed between ACTH or cortisol responses and the time elapsed from treatment or dose of HP RT. Further, in 10 of 12 patients, 0-min dehydroepiandrosterone sulfate levels were lower than the expected normal mean levels for age, sex and pubertal status, and in 4 of these 10 patients the values were below the normal range. These data suggest that some patients treated with HP RT may be at risk for adrenal insufficiency.

Hyperfractionated craniospinal radiotherapy and adjuvant chemotherapy for children with newly diagnosed medulloblastoma and other primitive neuroectodermal tumors.

PURPOSE: This single-institution Phase III study conducted from 1989 to 1995 evaluates the feasibility of a multimodality protocol combining hyperfractionated craniospinal radiotherapy (HFRT) followed by adjuvant chemotherapy in 23 patients with newly diagnosed primitive neuroectodermal tumors (PNET) arising in the central nervous system. METHODS AND MATERIALS: All 23 patients had a histologically confirmed PNET and were over 3 years of age at diagnosis. The eligibility criteria for PNET patients with cerebellar primaries (medulloblastoma) included either a high T stage (T3b or 4) or high M stage (M1-3). All patients with noncerebellar primaries were eligible regardless of T or M stage. The median age of the 23 patients was 9 years (mean 3-25); 11 were female. The primary tumor arose in the cerebellum in 19. Of these medulloblastoma patients, 15 had high T stages (T3b or T4) with large locally invasive tumors and no evidence of metastases (M0), constituting Group 1. Thirteen (86%) of these patients had gross total resections. Four other medulloblastoma patients had both high T and high M stages, constituting Group 2. Group 3 consisted of four other patients with exocerebellar primaries (two brain, one brain stem, and one cauda equina), three of whom were M3. Hyperfractionated radiotherapy was administered within 4 weeks of surgery. Twice-daily 1-Gy fractions were administered separated by 4-6 h. The total dose to the primary intracranial tumor and other areas of measurable intracranial disease was 72 Gy. The prophylactic craniospinal axis dose was 36 Gy, and boosts of 44-56 Gy were administered to metastatic spinal deposits. Following radiotherapy, monthly courses of multiagent chemotherapy were administered sequentially (cyclophosphamide-vincristine followed by cisplatin-etoposide followed by carboplatin-vincristine) for a total of 9 months. RESULTS: All patients completed radiotherapy as planned. Only three patients lost >10% of their body weight. One patient had clinically apparent radiation-induced esophagitis. The mean white blood count (WBC) nadir was 2.5/dl, and hematologic recovery occurred in all within 4 weeks of completing HFRT without the need of granulocyte-colony-stimulating factor. Two patients refused adjuvant chemotherapy, 3 patients experienced tumor progression during chemotherapy, and 2 of 18 remaining patients could not tolerate the full 9 months owing to hematologic toxicity. Of the 15 patients (93%) in Group 1, 14 remain in continuous remission for a median of 78 months, and none have died. Two of four patients in Group 2 are in continuous remission at 67 and 35 months, and two died at 18 and 30 months. One of the two patients in Group 2 who died refused adjuvant chemotherapy and developed tumor progression in the bone marrow. None of the three patients in Group 3 with evaluable disease (M3) had a complete response to therapy, and eventually all four died of progressive or recurrent disease. CONCLUSION: This multimodality protocol is feasible in the short term, and long-term monitoring of neurocognitive and neuroendocrine effects are in progress. Excellent long-term disease control has been achieved for medulloblastoma patients with high T stages who were M0 at diagnosis (Group 1), the majority of whom had gross total resections. This group has a progression-free survival of 95% after a median period of follow-up of 6.5 years. Alternative treatment strategies must be developed for patients with high M stages, as five of seven patients died of progressive or recurrent disease.

Non-primary cervical adenocarcinomas.

We reviewed 16 non-primary cervical adenocarcinomas collected during a six year period. Ten tumors originated in the endometrium, three in the ovary and one each in the bladder, colon and fallopian tube. Tumor spread was identified by combined lymphovascular involvement and stromal invasion in five of the 16 cervices, lymphovascular involvement alone in four cervices, stromal invasion alone in two cervices, lymphovascular involvement with stromal invasion and cervical implantation in two cervices and cervical implantation alone in three cervices. The three tumors with surface implantation alone were of endometrial origin, had minimal if any myometrial invasion, no extrauterine metastases and two had malignant peritoneal washings. Of the 13 tumors with cervical lymphovascular involvement and/or stromal metastases, 11 had ovarian, nodal and/or peritoneal metastases. We conclude that cervical implantation occurs exclusively with endometrial adenocarcinomas, that it follows previous cervical instrumentation and that the prognosis is dependent on the histoprognostic features of the primary endometrial tumor. In contrast, cervical lymphovascular involvement and/or stromal metastases usually reflects disseminated pelvic or abdominal malignancy with a poor prognosis. However histological examination may not afford separation of these two lesions if local cervical invasion is advanced, if spread has occurred by more than one mode or if insufficient clinical/surgical information is provided.

Age at onset of puberty following high-dose central nervous system radiation therapy.

OBJECTIVE: To determine if a relationship exists between age at irradiation, sex of the patient, and age at onset of puberty and pubarche in children treated with high-dose radiation to the central nervous system. DESIGN: Case series. SETTING: Tertiary care institutional practices and clinics. PATIENTS: Thirty-six children treated with high-dose irradiation (hypothalamic pituitary dose, 30-72 Gy) by conventional (n = 29) or hyperfractionated (n = 7) schedules. Girls were treated before age 8 years and boys before age 9 years. Twenty-six of the 36 children also received chemotherapy. All tumors were distant from the hypothalamic-pituitary region. MAIN OUTCOME MEASURE: Age at onset of puberty and pubarche. RESULTS: In girls, the median age at onset of puberty was 9.3 years vs 10.9 years for controls (P < .01); pubarche occurred at 9.4 years vs 11.2 years for controls (P < .01). In boys, the median age at onset of puberty--genital II--was 11.0 years vs 11.5 years for controls (P = .30); pubarche occurred at a median age of 10.5 years vs 12 years for controls (P = .25). A censored-data normal linear regression model was used to account for children (n = 6) who had not reached puberty. Age at diagnosis (P < .01) and sex (P = .01) were significant predictors of age at onset of puberty. Body mass index SD score (z score) was inversely related to age at onset of puberty (r = -0.77) and was greater at onset of puberty in girls than in boys. CONCLUSION: In children who have received high-dose cranial radiation therapy, a significant positive correlation exists between age at diagnosis and age at onset of puberty in boys and girls.

Metastatic carcinoma infiltrating lung mimicking BOOP.

A 38 year old female with treated carcinoma of the breast presented with a clinical and radiological diagnosis of bronchiolitis obliterans organising pneumonia. Based on these findings a biopsy was not performed and she was treated with steroids. Following lack of response to steroid therapy a lung biopsy was performed showing peribronchiolar, lymphatic, venular and arteriolar metastatic carcinoma. Her symptoms responded to chemotherapy. Interstitial and intracellular spread of carcinoma should be considered in the differential diagnosis of the radiological appearance of BOOP, and therefore a histological diagnosis should be obtained to determine appropriate management.

Primary vulvar sarcomas.

Vulvar sarcomas are uncommon, comprising only approximately 2% of all vulvar malignancies. Consequently, most reported series contain only a few cases. We add to the literature 10 cases of various primary sarcomas of the vulva, including previously unreported cases of angiosarcoma and a neoplasm resembling Ewing's sarcoma. The only histologic feature helpful in determining prognosis was tumor necrosis.