Bone mineral density, turnover, and microarchitecture assessed by second-generation high-resolution peripheral quantitative computed tomography in patients with Sheehan's syndrome.

Sheehan's syndrome (SS) is a rare but well-characterized cause of hypopituitarism. Data on skeletal health is limited and on microarchitecture is lacking in SS patients. PURPOSE: We aimed to explore skeletal health in SS with bone mineral density (BMD), turnover, and microarchitecture. METHODS: Thirty-five patients with SS on stable replacement therapy for respective hormone deficiencies and 35 age- and BMI-matched controls were recruited. Hormonal profile and bone turnover markers (BTMs) were measured using electrochemiluminescence assay. Areal BMD and trabecular bone score were evaluated using DXA. Bone microarchitecture was assessed using a second-generation high-resolution peripheral quantitative computed tomography. RESULTS: The mean age of the patients was 45.5 ± 9.3 years with a lag of 8.3 ± 7.2 years prior to diagnosis. Patients were on glucocorticoid (94%), levothyroxine (94%), and estrogen-progestin replacement (58%). None had received prior growth hormone (GH) replacement. BTMs (P1NP and CTX) were not significantly different between patients and controls. Osteoporosis (26% vs. 16%, p = 0.01) and osteopenia (52% vs. 39%, p = 0.007) at the lumbar spine and femoral neck (osteoporosis, 23% vs. 10%, p = 0.001; osteopenia, 58% vs. 29%, p = 0.001) were present in greater proportion in SS patients than matched controls. Bone microarchitecture analysis revealed significantly lower cortical volumetric BMD (vBMD) (p = 0.02) at the tibia, with relative preservation of the other parameters. CONCLUSION: Low areal BMD (aBMD) is highly prevalent in SS as compared to age- and BMI-matched controls. However, there were no significant differences in bone microarchitectural measurements, except for tibial cortical vBMD, which was lower in adequately treated SS patients.

Osteoporosis and Obesity.

Introduction: This article concisely overviews the complex relationship between obesity and bone health. Obesity, characterized by excessive fat accumulation, has been traditionally associated with higher bone mineral density. Also, recent data suggest a favorable bone microarchitecture profile in these patients. However, the increase in bone mineral density does not necessarily confer protection against fractures, and the risk of fractures may vary depending on the skeletal sites. Factors affecting bone health: Various factors, including mechanical factors, hormones, cytokines, inflammation, and bone marrow adiposity, contribute to the adverse effect of obesity on bone. The article explores these factors alongside non-invasive techniques and tools like the Fracture Risk Assessment (FRAX) to evaluate fracture risk. Bone and Adipose tissue: This article also highlights the essential roles of hormones such as vitamin D, Parathormone (PTH), FGF-23 (Fibroblast Growth Factor 23), which affect bone health, and some of the hormones secreted from the adipose tissues such as adiponectin and leptin. Obesity Paradox and Sarcopenic Obesity: The article delves into the intriguing obesity paradox, where an increased BMI correlates with higher bone mineral density but not necessarily reduced fracture risk. Sarcopenic obesity, a combination of excessive fat accumulation and reduced muscle mass, further complicates the relationship between obesity and bone health. Conclusions: Physicians should keep a comprehensive approach to treating obese patients with osteoporosis, including lifestyle modifications, weight management, fall prevention strategies, and pharmacological interventions. Further research is needed to better understand the relationship between obesity and bone health.

Efficacy, safety, and dose-response effects of calcifediol supplementation on 25-hydroxyvitamin D, parathyroid hormone, and 1,25-dihydroxyvitamin D levels in healthy adults: An open-label, interventional pilot study.

BACKGROUND: Vitamin D deficiency (VDD) is highly prevalent across the globe. Cholecalciferol (Vitamin D3) fails to attain sufficient serum concentrations of 25-hydroxyvitamin D (25(OH)D) in a significant proportion of supplemented individuals. Calcifediol (25-hydroxyvitamin D3) is less studied in healthy adults and its effects on 25(OH)D, parathyroid hormone (PTH), and 1,25-dihydroxyvitamin D (1,25(OH)2D) at higher doses are not well known. MATERIALS AND METHODS: The study was an open-label, interventional trial recruiting consecutive participants with VDD who were allocated to receive either 2 capsules (50 µg-group) or 1 capsule (25 µg-group) daily doses of calcifediol. Baseline assessment included clinicodemographic parameters, dietary calcium, calcemic (calcium, inorganic phosphate, albumin, alkaline phosphatase, urine spot calcium/creatinine), and hormonal parameters (25(OH)D, PTH, and 1,25(OH)2D). Participants were followed up at 4 and 8 weeks with repeat assessments of calcemic and hormonal parameters. RESULTS: There were 64 participants, 35 (50 µg-group) and 29 (25 µg-group), without any significant difference in any of the baseline parameters. 97.1% participants in the 50 µg-group (at 4 and 8 weeks) and 93.1% (at 4 weeks) and 96.5% (at 8 weeks) in the 25 µg-group attained 25(OH)D sufficiency (≥30 ng/ml) with calcifediol. The mean serum 25(OH)D was 84.0 ± 27.7 ng/ml in the 50 µg-group and 58.0 ± 23.6 ng/ml in the 25 µg-group group at 4 weeks, which later rose to 94.3 ± 21.8 ng/ml and 76.0 ± 16.4 ng/ml, respectively, at 8 weeks. PTH levels decreased in both groups at both time points. 1,25(OH)2D rose significantly in both groups at 4 and 8 weeks but was not significantly different between both groups. There was no case of incident hypercalcemia or symptomatic nephrolithiasis. CONCLUSION: Calcifediol is a safe and efficacious alternative for oral Vitamin D supplementation in young adults. Increment in 25(OH)D levels is rapid and dose-dependent.

A Rare Case of Headache in a Patient With McCune-Albright Syndrome: A Triple Threat.

A 26-year-old male presented with facial asymmetry since 11 years of age and painless progressive diminution of vision in the left eye since 16 years of age. He presented with an exacerbation of headaches for the past two months. On examination, he was tall and had acral enlargement, craniofacial deformity, and bilateral asymmetric testicular enlargement. Investigations revealed high insulin-like growth factor 1, non-suppressible growth hormone on oral glucose tolerance tests, and multiple pituitary hormone deficiencies. MRI showed pituitary macroadenoma with craniofacial and sphenoid fibrous dysplasia as well as multiple tuberculomas. Cerebrospinal fluid testing showed high protein, low glucose, and high adenosine deaminase, all consistent with a diagnosis of central nervous system (CNS) tuberculosis. His headache did not respond significantly to either octreotide or zoledronic acid. The patient was then initiated on antitubercular therapy, which led to near-complete resolution of the headache and CNS lesions within three months of therapy. CNS tuberculosis was a masquerader in the index case of acrogigantism due to McCune-Albright syndrome. Headaches may be multifactorial in a given case of acromegaly, and investigating for alternative or additional causes especially when dealing with treatment-refractory cases can be rewarding.

Normative Data on Dehydroepiandrosterone Sulphate (DHEAS) and its Attributes in Healthy Indian Children and Adolescents.

Dehydroepiandrosterone sulphate (DHEAS), the biochemical indicator of adrenarche and pubarche, is of paramount importance in the evaluation of puberty-related disorders. The reference range of DHEAS should be ethnicity, age, sex, pubarche and Tanner stage specific. Anthropometry, puberty assessment and hormonal parameters were estimated using electrochemiluminescence assay. Bone age was estimated using the BoneXpert software. Of 2191 healthy Indian children aged 5-18 y screened at Chandigarh, 1919 were included in the final analysis (994 boys). The median DHEAS levels at pubarche stage P2 were 82.10 (55.0-129.0) g/dl in girls and 132.50 (95.12-205.50) g/dl in boys. By ROC analysis, the level of DHEAS at pubarche was 63.7 g/dl (sensitivity 72.6%, specificity 64.4%) in girls and 82.2 g/dl (sensitivity 81.8%, specificity 68.8%) in boys. The median age at adrenarche was 9.5 y in both sexes. On multivariate regression analysis; bone age, body mass index (BMI), gonadal steroids, and insulin-like growth factor-1 (IGF-1) significantly correlated with serum DHEAS levels in either sex.

Unusual and lesser-known rare causes of adult growth hormone deficiency.

Growth hormone is among the most common hormones to be deficient in pituitary insult. It can occur either in isolation or combined with other hormone deficiencies. Growth hormone deficiency in adults (AGHD) can be due to causes acquired in adulthood or have a childhood-onset etiology, but the former is about three times more common. Usual causes of AGHD include mass effects due to a pituitary tumour, and/or its treatment (surgery, medical therapy, or radiotherapy), or radiotherapy to the head and neck region for non-pituitary lesions. The unusual or lesser-known causes of AGHD, are usually due to non-tumoral etiology and range from vascular and infective to inflammatory and miscellaneous causes. These not only expand the spectrum of AGHD but may also contribute to increased morbidity, adverse metabolic consequences, and mortality due to the primary condition, if unrecognised. The review features these lesser-known and rare causes of AGHD and highlights their clinical and diagnostic implications.

Impulse Control Disorders with Short-term Use of Cabergoline in Macroprolactinomas: A Prospective Study with a Brief Review of Literature.

Impulse control disorders (ICDs) are less-emphasized adverse effects of dopamine agonists. Evidence on prevalence and predictors of ICDs in patients with prolactinomas is limited and confined chiefly to cross-sectional studies. This was a prospective study performed to investigate ICDs in treatment-naïve patients with macroprolactinomas (n = 15) using cabergoline (Group I), compared to consecutive patients of nonfunctioning pituitary macroadenomas (n = 15) (Group II). Clinical, biochemical, radiological parameters and psychiatric comorbidities were evaluated at baseline. ICD was assessed by Minnesota impulsive disorder interview, modified hypersexuality and punding questionnaires, South Oaks gambling scale, kleptomania symptom assessment scale, Barratt impulsive scale (BIS), and internet addiction scores (IAS) at baseline and 12 weeks. Group I had a significantly lower mean age (28.5 vs. 42.2 years) with a female predominance (60%) compared to group II. Median tumor volume was lower in group I (4.92 vs. 14 cm3) despite significantly longer symptom duration (2.13 vs. 0.80 years) than in group II. Serum prolactin decreased by 86% (P = 0.006) and tumor volume decreased by 56% (P = 0.004) at 12 weeks in group I, with a mean weekly cabergoline dose of 0.40 ± 0.13 mg. There was no difference between both groups in hypersexuality, gambling, punding, and kleptomania symptom assessment scale scores at baseline and 12 weeks. Mean BIS showed a more remarkable change in group I (16.2% vs. 8.4%, P = 0.051), and 38.5% of patients transitioned from average to above-average IAS in group I. The current study found no increased risk of ICD with short-term use of cabergoline in patients with macroprolactinomas. The use of age-appropriate scores (such as IAS in younger individuals) may help diagnose subtle alterations in impulsivity.

Approach to the Patient: A Case With an Unusual Cause of Hypopituitarism.

Hypopituitarism, which refers to insufficiency of one or more hormones of the pituitary, can be due to myriad causes. The clinical and radiological spectrum of the condition is heterogeneous, based on the patient's age, gender, clinical setting, and/or other past medical history. Hypopituitarism includes central hypocortisolism, hypothyroidism, hypogonadism, and growth hormone deficiency. Both hypo- and hyperprolactinemia can be associated with hypopituitarism, with low prolactin signifying more extensive pituitary damage. Posterior pituitary insufficiency (arginine vasopressin deficiency) occurs either in isolation or with anterior pituitary hormone deficiency. Clinical symptomatology of hypopituitarism is usually nonspecific and insidious in onset and progression. Overall, the most common cause of hypopituitarism is a pituitary adenoma and/or its management (surgery, radiotherapy, pharmacotherapy, or a combination of these). However, it is this subset of patients which is more likely to be identified and managed in a timely manner, possibly alleviating the premature mortality associated with hypopituitarism. What is more challenging is the recognition of hypopituitarism in less common settings, which may be either due to direct involvement of the pituitary (infection, traumatic brain injury, or infiltrative causes) or indirectly as a consequence of the primary process (thalassemia, vasculotoxic snakebite, subarachnoid hemorrhage). These entities are often under-recognized, and increased awareness can help in greater recognition of the burden. Further, pituitary insufficiency in most of these settings is dynamic and may progress, or rarely, show recovery of function. This renders complexity to the problem, but makes it even more imperative to suspect, screen, and appropriately manage patients with less common causes of hypopituitarism.

Long-term hepatic and cardiac health in patients diagnosed with Sheehan's syndrome.

PURPOSE: Sheehan's syndrome (SS) is characterised by chronic pituitary insufficiency following a vascular insult to the pituitary in the peripartum period. There is a lack of substantial evidence on the long-term hepatic and cardiac consequences in these patients, following hormone replacement. METHODS: Patients with a diagnosis of SS were recruited for the study. Detailed clinico-biochemical and radiological evaluation were performed in all patients (n = 60). Hepatic and cardiac complications were assessed using fibroscan and echocardiography (2D speckle-tracking) respectively, in a subset of patients (n = 29) as well as age-and BMI-matched controls (n = 26). Controlled attenuation parameter (for steatosis) and liver stiffness measurement (for fibrosis) were used to define non-alcoholic fatty liver disease (NAFLD). Diastolic cardiac function was evaluated using standard criteria and systolic function by ejection fraction and global longitudinal strain (GLS). RESULTS: The mean age of the cohort was 42.7 ± 11.6 years. Multiple (≥ 2) hormone deficiencies were present in 68.8% of patients, with hypothyroidism (91.4%), hypocortisolism (88.3%), and growth hormone (GH) deficiency (85.7%) being the most common. At a mean follow-up of 9.8 ± 6.8 years, NAFLD was present in 63% of patients, with 51% having severe steatosis, which was predicted by the presence of GH deficiency and higher body mass index. Though the ejection fraction was similar, increased left ventricular GLS (18.8 vs. 7.7%) was present in a significantly higher number of patients versus controls. CONCLUSION: NAFLD, especially severe hepatic steatosis, is highly prevalent in SS. Subclinical cardiac systolic dysfunction (impaired GLS) is also more common, but of mild intensity.

Pheochromocytoma in Pregnancy: A Syndromic Association.

Introduction: Pheochromocytoma during pregnancy is a rare cause of secondary hypertension with lethal consequences to both mother and fetus. As patients are young, the possibility of syndromic associations like MEN-2, VHL, NF-1, etc., needs to be considered. Methodology: Three primigravida were diagnosed before the 20th week of gestation when they presented with classical triad of pheochromocytoma. Results: Diagnosis of pheochromocytoma was confirmed by 24 h urinary metanephrine/normetanephrine or epinephrine/norepinephrine levels. Non-contrast MRI abdomen could localize the tumor. One patient had medullary thyroid carcinoma with hyperparathyroidism, indicative of MEN-2A. Another patient had brain stem hemangioblastoma, pancreatic cysts and family history of spinal hemangioblastoma, so diagnosed to have Von Hippel-Lindau (VHL) syndrome. Whereas, the third patient had sporadic pheochromocytoma. Preoperatively, they required antihypertensive medications including prazosin and metoprolol. They underwent laparoscopic/open adrenalectomy between 19th and 21st week of gestation without complication. Histopathology in all the three patients revealed low-grade pheochromocytoma by pheochromocytoma of the adrenal gland scaled score. None required antihypertensive medications after surgery. All the three newborns were small for gestational age, while one neonate expired due to intra-cardiac rhabdomyoma. So, the timely evaluation and surgical intervention for pheochromocytoma avoid lethal consequences. Conclusions: Pregnancy leads to unmasking of pheochromocytoma as it is physiological stress. The syndromic association is more frequent as the population is younger. A poor fetal outcome like IUGR can be explained by endovascular changes in uterine vessel or due to the associated manifestations of MEN-2A, VHL syndromes. Family members should be screened for associated syndromic feature.

Camurati-Engelmann Disease Complicated by Hypopituitarism: Management Challenges and Literature Review of Outcomes With Bisphosphonates.

Background: Camurati-Engelmann disease (CED) is a rare bone dysplasia characterized by diffuse diaphyseal osteosclerosis. Skull base involvement in CED can result in hypopituitarism but is seldom reported. Our objective was to report a patient with acquired hypopituitarism due to CED and assess the management challenges. Case Report: A 20-year-old boy presented with lower limb pain. He had walking difficulty in childhood, which was diagnosed as CED and managed with prednisolone. He later discontinued treatment and was lost to follow-up. Current re-evaluation showed short stature (-3.6 standard deviation), low weight (-4.3 standard deviation), and delayed puberty with delayed bone age (13 years). He was found to have secondary hypogonadism (luteinizing hormone level, 0.1 mIU/mL [1.7-8.6 mIU/mL]; follicle-stimulating hormone level, 1.0 mIU/mL [1.5-12.4 mIU/mL]; and testosterone level, 0.087 nmol/L [9-27 nmol/L]), growth hormone deficiency (low insulin-like growth factor I level, 120 ng/mL [226-903 ng/mL] and peak growth hormone level of 7 ng/mL on insulin-induced hypoglycemia), and secondary hypocortisolism (cortisol level, 105 nmol/L [170-550 nmol/L] and adrenocorticotropic hormone level, 6 pg/mL [5-65 pg/mL]). Serum prolactin level was normal (8.3 ng/mL [5-20 ng/mL]), and he was euthyroid on levothyroxine replacement. Magnetic resonance imaging revealed a partially empty sella. Sanger sequencing revealed a missense mutation (p.R218C/c.652C>T) in exon 4 of the TGFß1 gene. The patient was treated with zoledronate, losartan, and oral prednisolone and continued on levothyroxine and testosterone replacement, which resulted in symptomatic improvement. Discussion: The index case manifested severe CED requiring multimodality therapy. Later, he developed combined pituitary hormone deficiencies, which were managed with thyroid and gonadal hormone replacement with the continuation of glucocorticoids. The partial efficacy of bisphosphonates in CED has been reported in the literature. Conclusion: Skull base involvement in CED can lead to structural and functional hypopituitarism as a result of intracranial hypertension.

Thyroid eye disease with concurrent orbital lymphoma: a radiological surprise.

Summary: Thyroid eye disease (TED) is the most common extra-thyroidal manifestation in Graves' disease (GD). Additional/concurrent/synchronous pathologies may be present, especially in elderly patients who present with atypical features such as non-axial (or eccentric) proptosis, absence of lid lag and restricted superior extra-ocular movements. A 70-year-old female presented with progressive proptosis of her left eye and diplopia. She was diagnosed with GD a year prior and initiated on carbimazole. On examination, she had eccentric proptosis, restricted superior extra-ocular movements and a palpable mass in the supero-temporal quadrant of the left eye. Her T3 (1.33 ng/mL) and T4 (8.85 µg/dL) were normal with carbimazole. Thyroid-stimulating hormone (TSH)-receptor antibody was positive (3.15 IU/L, reference range <1.75). MRI revealed an enhancing lesion infiltrating the left superior rectus, with concurrent characteristic muscle belly involvement bilaterally. Orbital biopsy showed atypical lymphoid cells (CD20+), suggesting marginal zone lymphoma. CT thorax and abdomen, fluorodeoxyglucose-positron emission tomography and bone marrow examination were normal. The patient was administered orbital radiotherapy for her localised lymphoma and carbimazole was continued. TED is the most common cause of orbital involvement overall and in GD. However, additional or alternative pathology may be present which requires evaluation. MRI can be a useful adjunct in these patients. Orbital lymphoma needs to be staged with workup for disseminated disease. Radiotherapy is the treatment of choice for localized disease. The index case provides evidence for synchronous presentation of dual pathology and highlights the importance of astute clinical examination as well as keeps a low threshold for MRI in selected cases. Learning points: Thyroid eye disease can co-exist with other ocular pathology, especially in elderly individuals. Eccentric proptosis, absent lid lag and restriction of eye movements (suggesting tendon involvement) should alert towards the presence of alternative pathology. Orbital imaging using MRI not only has greater sensitivity in diagnosing radiologically bilateral disease in patients who have unilateral involvement clinically but is also useful to identify concurrent neoplasms.

The role of steroid receptors, peptides and growth factors in the aetiopathogenesis of idiopathic gynecomastia.

Idiopathic gynecomastia is a diagnosis of exclusion. We aimed to evaluate the role of steroids, peptides and growth factors in these patients. Those with bilateral idiopathic gynecomastia (n = 29) (Simon's grade IIb or III) who underwent gland excision were evaluated by immunohistochemical techniques using semi-quantitative grading for oestrogen receptor (ER), progesterone receptor (PR), aromatase, androgen receptor (AR), peptides (IGF-1, IGF-2, HER-2, parathyroid-hormone related peptide [PTHrP]) and growth factors (EGFR, TGFß). The cohort comprised 29 patients, with a mean age of 25.3 ± 5.1 years and a mean body mass index of 27.2 ± 2.3 kg/m2 . Grade IIb gynecomastia was present in 79.1% and moderate-to-severe insulin resistance (HOMA-IR >3) in 53.7% of patients. ER expression was positive in 100% samples, followed by AR (96.5%), aromatase (96.5%) and PR (93.1%). IGF-1 was expressed in 86.2% of the cohort, IGF2 in 27.5% and HER-2 in only two samples, with both showing weak immunoexpression. None of the patients had positive expression of EGFR, TGF-ß or PTHrP. There was no association between immunoexpression and gynecomastia grade. This study demonstrates the predominant role of oestrogen, aromatase and insulin resistance in the aetiopathogenesis of idiopathic gynecomastia and implicates the paracrine hyperestrogenic milieu in its causation as circulating hormones were normal.

Paediatric Pituitary Adenomas: Clinical Presentation, Biochemical Profile and Long-Term Prognosis.

Context: Paediatric pituitary adenomas (PPAs) are uncommon, with evidence confined to small cohorts. Aim: We aimed to elucidate the baseline profile and outcomes of PPAs in a large, contemporary, monocentric cohort. Settings, Design: Pituitary clinic at PGIMER over 8 years (2010-2018). Subjects and Methods: PPAs in patients (≤20 years at diagnosis) were included. A retrospective review of their baseline clinico-biochemical and radiological profiles and outcomes post pituitary surgery/medical management was performed. Results: There were a total of 74 patients, of which 42 were female. The median age was 15 (IQR 13-18) years. Corticotropinomas (32.4%) and somatotropinomas (25.7%) were common, with 1 case of TSHoma and pituitary blastoma. The most common presentation was headache (57%) overall and menstrual irregularities (64.2%) in girls. Most (78%) had macroadenomas. Prolactinomas showed an excellent response to primary medical therapy (83.3%). Transsphenoidal surgery was performed in 81% of patients. Diabetes insipidus (30%) and hyponatremia (26.7%) emerged as common postoperative complications. Adjuvant medical management was required in 25%, and radiotherapy in 18%. Remission rates in Cushing's and acromegaly were 62.5% and 57.8%, respectively, with long-term hormone deficits noted in one-third of patients. Conclusion: PPAs have unique features and management challenges, including effects on growth and puberty. Functional tumours and macroadenomas are common. Remission can be achieved in more than half of the patients, with endocrine deficits persisting in about a third of cases, needing long-term surveillance.

Temozolomide Nonresponsiveness in Aggressive Prolactinomas and Carcinomas: Management and Outcomes.

CONTEXT: Temozolomide (TMZ) is endorsed as the treatment of choice in aggressive or malignant pituitary adenomas. OBJECTIVE: Herein we describe a case of an aggressive prolactinoma that was resistant to TMZ. We performed a literature review of similar nonresponsive, aggressive prolactinomas. METHODS: A 40-year-old woman presented with a giant prolactinoma that required cabergoline, transsphenoidal surgery, and radiotherapy to achieve near-normal prolactin and apparently no residual tumor. A year later, she presented with multiple cranial nerve involvement due to a recurrent tumor extending to the infratemporal fossa. She underwent transfrontal surgery, second radiotherapy, and was started on TMZ. Despite 8 cycles of temozolomide (200 mg/m2, 5/28-day cycle), she had progressive disease and ultimately succumbed to the disease. PubMed/MEDLINE, Google Scholar, and prior review articles were searched for manuscripts about patients with aggressive prolactinomas who had been treated with TMZ. Data on demography, duration of therapy, and management outcomes were analyzed in those with progressive disease. RESULTS: We identified 94 cases of patients with aggressive/malignant prolactinomas in the literature who had received TMZ. Progressive disease despite TMZ was present in 36 cases (38%). There was a male preponderance (65%) among these and 40% had aggressive prolactinomas, whereas the rest had carcinomas. Patients received a median of 8 cycles (interquartile range, 3.5-11.5) of TMZ. O6-methylguanine-DNA-methyltransferase (MGMT) immunostaining was negative in 35%. Overall mortality at the time of publication was 40%, at a duration varying from 2 to 20 years from diagnosis. CONCLUSION: TMZ resistance in aggressive/malignant prolactinomas is challenging. Progressive disease on optimal TMZ treatment entails the use of newer agents.