Timing of administration of antenatal magnesium sulphate and correlation with umbilical cord blood magnesium levels in preterm babies.

BACKGROUND: The effectiveness of MgSO4 for foetal neuroprotection is acknowledged, but the best time to provide it in relation to birth is a conundrum, and dose schedule is yet unknown. Understanding the determinants of the magnesium levels in cord blood aids in determining the appropriate timing and length of administration. AIM AND OBJECTIVE: To assess the cord blood magnesium concentration in relation to the timing of MgSO4 and delivery. To achieve ROC in relation to optimum level of cord blood magnesium concentration in relation to neonatal outcome variables. STUDY DESIGN: A prospective observational study conducted in a tertiary care hospital over 2 years in women having preterm delivery from 26 weeks to 33 + 6 weeks, who received Neuroprophylaxis. Cord blood was collected for magnesium level estimation. Baby followed 24 h after delivery. ROC analysis performed for predicting an optimal cut-off for a continuous predictor predicting binary outcome. RESULTS: 85 recruited cases divided into bolus group, bolus + infusion group. The mean cord blood magnesium (n = 85) was 3.8 mg/dl. The AUROC for Gestational Age at Administration predicting Baby Outcome: 0.699, It was statistically significant (p = 0.034). The AUROC for Cord Blood Mg predicting Baby Outcome: 0.606, It was not statistically significant (p = 0.262). CONCLUSION: Mean cord blood magnesium levels served as a tool to determine the timing and duration of Neuroprophylaxis. Mean cord blood magnesium of 3.8 mg/dl should be achieved to serve the purpose of Neuroprotection. To achieve this, Bolus followed by Infusion should be administered for at-least 6 h prior to delivery.

Elucidating the Effect of Antenatal Corticosteroids in the Late Preterm Period.

Aim and Objective: To determine the efficacy of antenatal corticosteroids given in the late preterm period. Methodology: We conducted a retrospective case-control study on patients with singleton pregnancies who were at a risk of delivering in the late preterm period (34 weeks to 36 weeks 6 days). A total of 126 patients who had received antenatal corticosteroids (prenatal administration of either betamethasone or dexamethasone, minimum one dose) during the late preterm period were taken as cases, and 135 patients who had not received steroids antenatally due to various reasons, for example, who were clinically unstable, presented with active bleeding, non-reassuring foetal status that obligated an imminent delivery and those in active labour were included as controls. The various neonatal outcomes like APGAR score at one and five minutes, incidence of admission and duration of stay in neonatal intensive care unit (NICU), respiratory morbidity, requirement of assisted ventilation, intraventricular haemorrhage (IVH) necrotizing enterocolitis, transient tachypnea of the newborn, respiratory distress syndrome, use of surfactant, neonatal hypoglycaemia, hyperbilirubinemia requiring phototherapy, sepsis and neonatal mortality were compared between the two groups. Results: The baseline characteristics of both groups were comparable. There was a lower incidence of admissions to neonatal intensive care unit (NICU) (15% vs. 26%, p = 0.05), respiratory distress syndrome (5% vs. 13%, p = 0.04), requirement of invasive ventilation (0% vs. 4%, p = 0.04) and hyperbilirubinemia requiring phototherapy (24% vs. 39%, p = 0.02) in the babies of the group that received steroids compared to the control group. The rate of overall respiratory morbidity in the neonates was lowered after giving steroids (16% vs. 28%, p = 0.04). The incidence of neonatal necrotizing enterocolitis, hypoglycaemia, IVH, TTN, sepsis and mortality between the two groups was not significant (p > 0.05). Conclusion: Antenatal corticosteroids administered to patients between 34 and 36 weeks 6 days of gestation reduce respiratory morbidity, requirement of invasive ventilation, respiratory distress syndrome, hyperbilirubinemia requiring phototherapy and the incidence of NICU admissions in the newborns. Supplementary Information: The online version contains supplementary material available at 10.1007/s13224-022-01664-5.

Influence of transcutaneous electrical nerve stimulation on pain intensity and functional activities following lower segment cesarean section.

BACKGROUND: Postoperative incisional pain following lower segment cesarean section (LSCS) is one of the commonly reported complaints which may affect mother-infant bonding, and restrict mobility and functional activities. PURPOSE: To study the influence of transcutaneous electrical nerve stimulation (TENS) on pain intensity and functional activities using the Numerical Pain Rating Scale (NPRS) and the Patient Specific Functional Scale (PSFS) following LSCS from the postoperative day (POD) 1 to POD 4. METHODS: This quasi-experimental study consisted of 50 postpartum women who underwent LSCS and were assigned to an intervention group (IG) that received TENS and a control group (CG) that received routine hospital care. RESULTS: NPRS scores between CG and IG (pre-TENS application) showed a statistically significant difference (ηp2 = 0.542, p < .001) from POD 1 to POD 4. Study participants showed an improvement in PSFS scores (ηp2 = 0.412, 0.488, 0.661, 0.304, 0.262, and 0.395, p < .001) in IG compared to CG for bed transitions, bed transfers, sitting, sit to stand, walking, and toileting activities respectively from POD 1 to POD 4 which was statistically significant. CONCLUSIONS: Our study results suggest that administration of TENS following LSCS shows an improvement in pain intensity and functional activities as reported on NPRS and PSFS respectively.

Effectiveness of a peanut ball device during labour on maternal and neonatal outcomes: protocol for a randomised controlled trial.

Frequent positional changes and movements during labour is one of the recommendations by the World Health Organization (WHO) to prevent prolonged labour, thereby avoiding cesarean sections. However, labour induction, continuous fetal monitoring in supine position and immobilising the women during labour are standard practices in most private hospitals. To combat these problems and to implement WHO recommendations, the peanut ball is an effective device through which frequent positional changes will be achieved without disrupting the labour procedures. The current study aims to evaluate the effectiveness of the peanut ball device during labour on maternal and neonatal outcomes and assess the stress response induced by labour in terms of maternal and neonatal cortisol in low-risk primigravid women. The study is a prospective, block randomised controlled trial with parallel arms. A total of 768 study participants will be randomised to the peanut-ball group (intervention) and standard care group (control). The intervention group will receive different peanut ball positions during labour at or after 4 cm of cervical dilatation. The primary outcomes of the study are maternal outcome that includes measurement of duration of the active and the second stage of labour, stress level as measured by serum cortisol level at 3-4 cm and at 10 cm of cervical dilatation, mode of delivery, perception of pain, behavioural response during the active stage of labour and neonatal outcomes, which includes the pattern of fetal heart rate, APGAR score, birth injuries, and umbilical serum and salivary cortisol level. The collected data will be compared between the intervention and control groups.  Trial Registration: This research is registered under the CTRI (Clinical Trials Registry of India) ( CTRI/2019/08/020802) (21/8/2019).

In vivo spectroscopy: optical fiber probes for clinical applications.

INTRODUCTION: Fiber optic probe-based in vivo spectroscopy techniques are fast and highly objective methods for intraoperative diagnoses and minimally invasive surgical interventions for all procedures where endoscopic observations are carried out for cancers of different types. The Raman spectral features provide molecular fingerprint-type information and can reveal the subjects' pathological state in label-free manner, making endoscopy multiplexed fiber optic probe-based devices with the potential for translation from bench to bedside for routine applications. AREAS COVERED: This review provides a general overview of different fiber-optic probes for in vivo measurements with emphasis on Raman spectroscopy for biomedical application. Various aspects such as fiber-optic probe, radiation source, detector, and spectrometer for extracting optimum spectral features have also been discussed. EXPERT OPINION: Optical spectroscopy-based fiber probe systems with 'Chip-on-Tip' technology, combined with machine learning, can in the near future, become a complementary diagnostic tool to magnetic resonance imaging (MRI), computed tomography (CT) scan, ultrasound, etc. Hyperspectral imaging and fluorescence-based devices are in the advanced stage of technology readiness level (TRL), and with advances in lasers and miniature spectroscopy systems, probe-based Raman devices are also coming up.

Sonographic Estimation of the Fetal Head Circumference: Accuracy and Factors Affecting the Error.

Background: Sonographic measurement of fetal head circumference (HC) is an essential parameter for the estimation of fetal weight as well as in cases with abnormal fetal head size. Since there is a lack of data, the present study was to assess the accuracy of ultrasonographic estimation of fetal HC and to identify factors that affect the accuracy of fetal HC estimation. Material and Methods: A prospective cohort observational study was conducted for a year. Sonographic fetal biometry including HC was performed, and fetal HC was measured postnatally. Measures of accuracy and various factors which affect the accuracy are analyzed. Results: Ultrasonographic HC underestimated actual postnatal HC in 87.5% and overestimated actual HC in 12.5%. Sonographic underestimation of HC persisted throughout gestation and became more pronounced as gestational age increased. Error in HC was statistically significant in those with low liquor and anterior placenta and in those who had instrumental delivery. Parity, fetal presentation, and maternal diabetes did not affect the error in ultrasonographic measurement of head circumference. When the HC was beyond 95th centile on ultrasound, the error detected postnatally was significant (- 14 mm vs. - 8 mm), though not statistically significant (p value 0.82). The difference between the sonographic and postnatal HC was also related to the mode of delivery with the highest error seen in those who had instrumental vaginal delivery (p value 0.031). Conclusion: The ultrasound estimation of fetal HC is associated with significant underestimation of the actual HC measured postnatally. The error in measuring fetal HC increased in those with advanced gestational age, low liquor, and anterior location of the placenta and in those who had instrumental vaginal delivery. The measurement error may have important implications in specific clinical scenarios like monitoring pregnancy with fetal growth restriction, suspected fetal head growth abnormalities, and labor outcome.

A micro-Raman spectroscopy study of inflammatory condition of human cervix: Probing of tissues and blood plasma samples.

The present study explores the application of the micro-Raman spectroscopy technique to discriminate normal and cervicitis condition from cervical malignancy by analyzing the Raman signatures of tissues and plasma samples of the same subjects. The Raman peaks from tissue samples at 1026 cm-1,1298 cm-1 and 1243 cm-1 are attributed to glycogen, fatty acids and collagen and are found to be reliable signatures capable of identifying cervicitis and normal condition from cervical cancer. The Raman signatures from plasma samples belonging to carbohydrates (578 cm-1), lipids (1059 cm-1) and nucleic acids (1077 cm-1,1341 cm-1 and 1357 cm-1) are quite useful to classify various pathological conditions of cervix at par with tissue based diagnosis. The PCA-SVM based classification of the spectral data indicates the potential of Raman spectroscopy based liquid biopsy to rule out false diagnosis of cervicitis as cervical malignancy.

We Need to Improve Prenatal Screening Practices in Primary Obstetric Care: A Representative Data from a Fetal Medicine Unit in Coastal Karnataka.

BACKGROUND: The present observational data from the fetal medicine unit aim to identify gaps in prenatal screening modalities employed in the primary obstetric care population in coastal Karnataka. METHODS: A retrospective observational study of all referrals to Fetal Medicine unit is over 2 years. For each fetal abnormality, we reviewed the literature to note the range of gestational age at which the abnormality should almost always be diagnosed. Taking this as standard, the gestational age at which each of these problems was diagnosed and referred was noted down. They were compared and analysed to understand the efficiency of prenatal screening practices in the referral population. The final perinatal outcome was also noted down in order to assess the impact on perinatal mortality/morbidity. RESULTS: A total of 277 cases were referred to fetal medicine unit. Two hundred twenty-eight cases (82.31%) were low risk pregnancies. Among 277 cases, 200 (72.2%) had structural abnormalities, 7 (2.5%) chromosomal/ genetic abnormalities, 61 (22.02%) isolated soft markers, and 9 (3.2%) twin-related problems. Detection rate of structural abnormalities was 33% at 14 weeks and 52.22% at 20 weeks, considering those anomalies usually diagnosed by these gestational age windows. The primary reason for delayed diagnosis was non-performance of ultrasound "on time", rather than missed diagnosis. Fifty-three per cent (106 out of 200) of all the fetal structural abnormalities were diagnosed beyond 20 weeks. Average gestational age at mid-trimester anomaly scan in this group was between 20 and 24 weeks. Sixty-one patients were referred due to isolated soft markers, 30 beyond 20 weeks. Eighty per cent of them did not have any aneuploidy screening in pregnancy. CONCLUSION: Practice of fetal medicine hugely depends upon appropriate prenatal screening practices in the referral population. There is an urgent need to bring in standard protocols for Prenatal Screening across all the primary obstetric care providers, both in the public and private sectors. Considering the huge burden of delayed prenatal diagnosis in our country, the proposed revision of MTP bill is a welcome change in fast-growing field of fetal diagnosis and therapy.

A Randomized Controlled Trial on the Efficacy of Integrated Yoga on Pregnancy Outcome.

Physiological and biochemical changes occur in pregnancy to nurture the developing fetus. Pregnancy-related experience is unique to every woman. Pregnancy symptoms and complications can range from mild to severe. Many women can lower their risk by performing different therapies. In this context, the present study targets to evaluate the efficacy of integrated yoga consisting of (asanas and pranayama) on pregnancy to reduce the risk of complications. This study is a prospective randomized controlled single-blinded trial with parallel arms: the intervention arm received specific integrated yoga therapy; the control arm received routine standard care from 18 to 22 weeks of gestation until delivery. The incidence of preeclampsia and preterm delivery was lower in the intervention arm. Women in the intervention arm delivered at higher gestational age. Apgar scores and birth weights of neonates were significantly higher in the intervention arm. The findings suggest that yoga is a safe and effective intervention during pregnancy to reduce or prevent pregnancy-related complications. However, further randomized controlled trials are needed to provide firmer evidence regarding the utility and validity of yoga intervention during pregnancy.

A Novel Risk-Scoring Model for Prediction of Premalignant and Malignant Lesions of Uterine Endometrium Among Symptomatic Premenopausal Women.

PURPOSE: Uterine cancer is the second most prevalent cancer of the female genital tract, with 90% of it being of endometrial origin. The aim of this research was to create and validate a risk-scoring model using patients' clinical variables in predicting premalignant and malignant lesions of the uterine endometrium among premenopausal women with abnormal uterine bleeding (AUB). METHODS: This is a retrospective cohort study conducted at a tertiary hospital of Southern India for a period of 5 years from July 2014 to August 2019, including women aged ≤55 years who had AUB and underwent endometrial biopsy. The incidence of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC) was determined, and clinical and demographic variables were compared among cases (AEH/EC) and controls (no AEH/EC) using simple logistic regression. A risk-scoring model was derived and validated with a split-sample internal validation method. RESULTS: A total of 472 premenopausal women presenting with AUB were included in the study. There were 20 women (4.2%) with AEH and eight (1.7%) with EC. We found a statistically significant positive correlation of an anovulatory pattern of bleeding (odds ratio [OR]=3.4; p=0.009), age ≥45 years (OR=1.12; p=0.01), body mass index (BMI) ≥30 kg/m2 (OR=2.46; p=0.04) and diabetes mellitus (OR=3.00; p=0.02) with a higher risk of AEH/EC diagnosis upon histopathological examination of endometrial biopsy specimens of the study population. A risk-scoring model (PAD30) was created using these variables to predict premalignant and malignant endometrial lesions. The best cutoff score derived by the receiver operating characteristics (ROC) curve, of ≥5, had a sensitivity of 85.7% and specificity of 87.6% with an area under the curve (AUC) of 0.84 (95% CI 0.75-0.93; p=0.04). With a positive likelihood ratio of 6.91, our prediction model increases the post-test probability of AEH/EC to 30.6% from 6% of the pre-test probability. CONCLUSION: The proposed model demonstrated a moderate diagnostic accuracy in predicting premalignant and malignant lesions of the uterine endometrium among symptomatic premenopausal women.

Xanthomatous hypophysitis: A rare case report with review of literature.

Hypophysitis is classified into primary and secondary. Xanthomatous hypophysitis is one of the rare types of primary hypophysitis. A 55-year-old female presented with headache, vomiting, and blurring of vision. She also had endocrine dysfunction in the form of low serum T3, T4, and low cortisol levels. MRI scan showed a sellar expansile lesion suggestive of pituitary macroadenoma. Microscopy showed pituitary tissue replaced by inflammatory infiltrate made up of foamy histiocytes arranged in sheets along with lymphoplasmacytic infiltrate. Interspersed areas of fibrosis, hyalinization, few congested and sclerosed blood vessels were seen. Compressed residual pituitary tissue was identified at the periphery. Xanthomatous hypophysitis is a rare entity which can mimic as pituitary adenoma both clinically and radiologically. Accurate diagnosis at an early stage with postsurgical steroid therapy may help to prevent permanent pituitary damage.

Blooming in the Hypothalamus.

Cavernomas are vascular malformations which are collections of endothelium-lined sinusoids without intervening cerebral parenchyma. Hypothalamic location of cavernoma is extremely rare. We present a case of a 34-year-old male who presented with complaints of recent memory loss and vomiting. On magnetic resonance imaging with gradient sequences and contrast, a diagnosis of hypothalamic cavernoma was suggested. Excision of lesion was performed by a right parasagittal pericoronal craniotomy via transcallosal approach. Intraoperative findings and histopathology examination corroborated the diagnosis. The uniqueness of this case report is in the susceptibility-weighted sequence which led to the radiological diagnosis.

Occurrence of Synpolydactyly and Omphalocele in a Fetus with a HOXD13 Mutation.

Synpolydactyly (SPD) is an autosomal dominant congenital limb disorder due to mutations in HOXD13 . It is a phenotypically heterogeneous condition characterized by syndactyly of the third finger (F3), fourth finger (F4) and/or fourth toe (T4), and fifth toe (T5) with variably associated polydactyly. We report on a mother and fetus with SPD. The mother has a novel mutation (c.708_708delC) in the HOXD13 gene that was also seen in the fetus. However, the fetus had congenital omphalocele in addition to SPD that is an association not reported to date. A chromosomal microarray in the fetus was normal. We report a novel mutation in HOXD13 and document co-occurrence of an omphalocele and SPD in a fetus.

Osteoporosis Prevention and Management.

Osteoporosis, defined by BMD at the hip or lumbar spine that is less than or equal to 2.5 standard deviations below the mean BMD of a young-adult reference population, is the most common bone disease in humans affecting both sexes and all races. It's a silent killer affecting the quality of life due to fractures and postural changes. In osteoporosis there is an imbalance between bone formation and bone resorption in favor of latter. Preventive measures and treatments are available to combat this evil. Counseling is the integral part of prevention as well as treatment of osteoporosis. Preventive strategy includes life style changes, exercise, intake of calcium and vitamin D, avoiding alcohol, smoking and excessive intake of salt. Estrogen therapy/estrogen+progesterone therapy (ET/EPT) is no longer recommended as a first-line therapy for the prevention of osteoporosis. They may be used in the therapy for osteoporosis in women under 60. Diagnosis and classification are made by assessment of BMD using DEXA or ultrasound and laboratory investigations. Management includes estimation of 10-year fracture risk using FRAX, life style and diet modification and pharmacological therapy. The drugs used in osteoporosis may be those that inhibit bone resorption-bisphosphonates, denosumab, calcitonin, SERMs, estrogen and progesterone-or that stimulate bone formation-PTH, Teriparatide. Combination therapies are not recommended as they do not have proven additional BMD/fracture benefits. No therapy should be indefinite in duration. There are no uniform recommendations to all patients. Duration decisions need to be individualized. While on treatment monitoring should be done with BMD assessment by DEXA/ultrasound and bone turnover markers.

Cystic Sertoli-Leydig Cell Tumour in a Postmenopausal Woman with Absent Virilising Symptoms: A Diagnostic Challenge.

A 60-year-old postmenopausal woman, presented with a left ovarian cystic mass with mildly elevated CA125 levels. An intraoperative frozen section showed oedematous ovarian stroma with interspersed large aggregates of spindle shaped stromal cells. Subsequently, the excised specimen was reported as Sertoli-Leydig Cell Tumour (SLCT) of intermediate differentiation. The leydig cells were identified in the imprint smears, but were misinterpreted as luteinized cells. The lack of tubular differentiated cells in frozen section had contributed to the misdiagnosis. Immunohistochemistry (IHC) played an important diagnostic role in the absence of clinical suspicion and lack of virilising features that are classically described in association with SLCTs. This case is unusual, as the tumour was seen in a postmenopausal woman in the absence of virilising symptoms. The cytomorphological features, IHC findings and the reasons for misdiagnosis are discussed in this case report.

Can Transabdominal Scan Predict a Short Cervix by Transvaginal Scan?

Background. To determine whether transabdominal screening can be used to screen women with short cervix on transvaginal scan. Methods. The study was done between 18 and 20 weeks of gestation. Transabdominal scan was done and cervical length was measured. Transvaginal scan was also done and cervical length was measured. An attempt was made to find out whether transabdominal scan be used to predict a cervical length of 25 mm by transvaginal scan. Results. In our study the cut-off for transabdominal scan for detecting a short cervix of 25 mm by transvaginal scan was 29 mm. A transabdominal cervical length of 29 mm could predict a short cervix of 25 mm by transvaginal scan by 100% sensitivity and 92.4% sensitivity. Conclusion. A cut-off of 29 mm by transabdominal scan is very accurate in predicting a short cervix of 25 mm by transvaginal scan.

Quantifying proteinuria in hypertensive disorders of pregnancy.

Background. Progressive proteinuria indicates worsening of the condition in hypertensive disorders of pregnancy and hence its quantification guides clinician in decision making and treatment planning. Objective. To evaluate the efficacy of spot dipstick analysis and urinary protein-creatinine ratio (UPCR) in hypertensive disease of pregnancy for predicting 24-hour proteinuria. Subjects and Methods. A total of 102 patients qualifying inclusion criteria were evaluated with preadmission urine dipstick test and UPCR performed on spot voided sample. After admission, the entire 24-hour urine sample was collected and analysed for daily protein excretion. Dipstick estimation and UPCR were compared to the 24-hour results. Results. Seventy-eight patients (76.5%) had significant proteinuria of more than 300 mg/24 h. Dipstick method showed 59% sensitivity and 67% specificity for prediction of significant proteinuria. Area under curve for UPCR was 0.89 (95% CI: 0.83 to 0.95, P < 0.001) showing 82% sensitivity and 12.5% false positive rate for cutoff value of 0.45. Higher cutoff values (1.46 and 1.83) predicted heavy proteinuria (2 g and 3 g/24 h, resp.). Conclusion. This study suggests that random urinary protein : creatine ratio is a reliable investigation compared to dipstick method to assess proteinuria in hypertensive pregnant women. However, clinical laboratories should standardize the reference values for their setup.

A blast from the past!: The value of adding single slice magnetic resonance myelography sequence to magnetic resonance imaging of the spine; a flashback to the conventional myelography of the past.

BACKGROUND: The study was undertaken to determine whether a single slice magnetic resonance (MR) myelogram sequence improves the interpretation and diagnostic yield for magnetic resonance imaging (MRI) of the spine. METHODS: A total of 100 cases with positive findings were retrospectively reviewed. All patients had initial imaging with sagittal T1-weighted (T1-W) and T2-weighted (T2-W) scans, followed by axial T2-W images. Subsequently, a heavily T2-W single slice MR myelogram sequence was acquired in coronal and sagittal planes. The MR myelogram images were evaluated initially by a radiologist, and, further independently reviewed, by a neurologist, neurosurgeon, and spine surgeon. The utility of the MR myelogram in establishing the diagnosis was graded on a 4-point scale. RESULTS: Out of 100 cases, 53% showed degenerative spine or disc disease, 14% space occupying lesions, 13%, congenital lesions, 7% infection, and 7% other conditions. The MR myelogram contributed additional information in 50-74% cases. The intraclass correlation coefficient showed overall good agreement between observers in grading the utility of MR myelogram. CONCLUSION: Single slice MR myelography is noninvasive avoiding the complications associated with lumbar punctures/intrathecal contrast injections, while image acquisition takes only an added 6-8 s. Although MR myelogram has no value as a stand-alone sequence, its inherent advantage is that it completes the overview of the spinal pathology in entirety, and adds vital three-dimensional information in 50-74% of cases.

MRI sequence and characteristic features in 'giant cell tumor' of clivus.

Giant cell tumours of the clivus are rare. These tumours present in the second and third decades of life and they are slightly more frequent in women than in men. We are presenting a case of a 20 years young patient who came with the complaints of headache, retro-orbital pain and recurrent transient bleeding from the nose since two and half months. MRI of the brain with contrast was done and its features were suggestive of a Giant cell tumour of the clivus. A transnasal endoscopic biopsy was done under general anaesthesia and the histopathology report suggested that the features were of a giant cell tumour. Excision of the mass was done by Transnasal endoscopy. Post operatively, the patient did not recover from the lateral rectus palsy which was there on the right side. The patient was discharged with an advice of a follow up and radiotherapy. Radiation therapy and chemotherapy may be effective as adjuvant treatments. Even though a recurrence usually occurs within 4 years of the initial treatment, these patients will need to be carefully followed for the remainder of their lives.