Low-Dose Radiotherapy Reverses Tumor Immune Desertification and Resistance to Immunotherapy.

Developing strategies to inflame tumors is critical for increasing response to immunotherapy. Here, we report that low-dose radiotherapy (LDRT) of murine tumors promotes T-cell infiltration and enables responsiveness to combinatorial immunotherapy in an IFN-dependent manner. Treatment efficacy relied upon mobilizing both adaptive and innate immunity and depended on both cytotoxic CD4+ and CD8+ T cells. LDRT elicited predominantly CD4+ cells with features of exhausted effector cytotoxic cells, with a subset expressing NKG2D and exhibiting proliferative capacity, as well as a unique subset of activated dendritic cells expressing the NKG2D ligand RAE1. We translated these findings to a phase I clinical trial administering LDRT, low-dose cyclophosphamide, and immune checkpoint blockade to patients with immune-desert tumors. In responsive patients, the combinatorial treatment triggered T-cell infiltration, predominantly of CD4+ cells with Th1 signatures. Our data support the rational combination of LDRT with immunotherapy for effectively treating low T cell-infiltrated tumors. SIGNIFICANCE: Low-dose radiation reprogrammed the tumor microenvironment of tumors with scarce immune infiltration and together with immunotherapy induced simultaneous mobilization of innate and adaptive immunity, predominantly CD4+ effector T cells, to achieve tumor control dependent on NKG2D. The combination induced important responses in patients with metastatic immune-cold tumors.This article is highlighted in the In This Issue feature, p. 1.

Type VI choledochal cyst with gall bladder carcinoma.

An isolated dilatation of the cystic duct (type VI choledochal cyst (CDC)) is extremely rare with only 21 cases reported in the world literature until now. There is only one case of in situ gall bladder cancer (GBC) reported in association with type VI CDC in the literature. Here we are reporting a case of type VI CDC with papillary GBC.

Risk of second malignancies among survivors of pediatric thyroid cancer.

BACKGROUND: Thyroid carcinoma is a very rare tumor in the pediatric age group, accounting for only 1.5-3% of childhood carcinomas in the United States and Europe. We aimed to identify the risk of a second malignancy among pediatric thyroid cancer survivors. METHODS: The cohort analysis consisted of pediatric cancer patients aged less than 20 years, diagnosed with a primary thyroid cancer, identified by site code ICD-0-3: C739, and reported to the SEER 9 database between 1973 and 2013. They were followed up until December 31, 2013; the end of the study period, or up to death if earlier. RESULTS: Out of 1769 patients diagnosed primarily with thyroid carcinoma, 42 patients had a total of 45 incidences of subsequent malignancies. The mean age of patients at the initial diagnosis of thyroid cancer was 16 years. Females (90.5%) had a significantly higher incidence of second malignancies (SM) than males (9.5%). The overall Standardized Incidence Ratio (SIR) of SM in the study patients was higher than expected (SIR = 1.48). Some specific sites showed significantly higher incidences: the salivary glands (SIR = 33.95), the gum and other parts of the mouth [excluding the lips, tongue, salivary glands and floor of the mouth] (SIR = 24.53)*** and the kidneys (SIR = 5.72). The overall risk of SM in patients who had received radioactive iodine was higher than expected (SIR = 4.41). The cumulative incidence of SM after treatment of thyroid cancer in children increases steadily over 40 years (11.92%). CONCLUSIONS: Race, gender, histological subtypes, and radioactive iodine are potentially significant prognostic factors for the development of SM among pediatric thyroid cancer survivors. Identification of underlying mechanisms that raise the risk of SM is important for both treatment and follow-up strategies.

Role of Radiotherapy in Aggressive Digital Papillary Adenocarcinoma.

Aggressive digital papillary adenocarcinoma (ADPA) is a rare and often misdiagnosed malignant tumor of the sweat glands, most commonly encountered on the extremities. Due to the relatively high metastatic potential of the tumor, aggressive surgical treatment, including amputation, is generally recommended. We present a case of a 36-year-old male with an over 10-year history of a skin lesion on the right hand in the web space between the index and the middle finger. Histologically, the lesion revealed a malignant epithelioid neoplasm with features consistent with ADPA. The lesion was treated with 5-weeks preoperative radiation (total 5000 cGy) followed by surgical resection. There was no evidence of residual disease confirmed by pathological study of re-excision specimen as well as imaging studies. This is, to the best of knowledge, the first report of complete regression of an ADPA after radiotherapy.

[CME: Radioactive iodine therapy in thyroid cancer]. / CME: Radiojodbehandlung des Schilddrüsenkarzinoms.

Differentiated thyroid carcinomas represent about 90% of all thyroid tumors and are divided in papillary and follicular carcinomas. Their prognosis is good, however, recurrences are not rare. Their ability to accumulate iodine is used for the radioactive iodine treatment. The aim of the postoperative radioactive iodine ablation therapy is the complete elimination of remnant thyroid cells and sensitive staging (Fig. 1). The recurrence rate decreases after a complete thyroid ablation. Furthermore, thyroglobulin can be used as a sensitive tumor marker. Radioactive iodine treatment by itself describes the therapy of metastases. An exception is the papillary microcarcinoma, which in general is treated by a lobectomy alone.

Neoadjuvant radiotherapy with or without chemotherapy followed by extrafascial hysterectomy for locally advanced endometrial cancer clinically extending to the cervix or parametria.

PURPOSE: For locally-advanced uterine cancer clinically extending to the cervix, two treatment paradigms exist: surgical staging radical hysterectomy with tailored adjuvant therapy or neoadjuvant therapy followed by a less extensive simple hysterectomy. Currently, insufficient data exists to guide consensus guidelines and practical application of preoperative radiotherapy. MATERIALS AND METHODS: Retrospective IRB approved cohort study from 1999 to 2014 of 36 endometrial cancer patients with clinical involvement of cervix±parametria treated with neoadjuvant external beam radiotherapy (45-50.4Gy in 25-28 fractions) and image-based HDR brachytherapy (5-5.5Gy times 3-4 fractions)±chemotherapy followed by extrafascial hysterectomy performed at a median of 6weeks after radiotherapy. RESULTS: All patients had clinical cervical extension, 50% also had parametria extension, and 31% had nodal involvement. At the time of surgery 91% had no clinical cervical involvement, 58% had no pathologic cervical involvement, and all had margin negative resection. The pathologic complete response rate was 24%. Median follow-up from the time of surgery was 20months (range: 0-153). The 3-year local control, regional control, distant control, disease free survival and overall survival rates were 96%, 89%, 84%, 73%, and 100%. The 3-year rate of grade 3 complications was 11%, with no grade 4+ toxicity. CONCLUSIONS: Neoadjuvant radiation therapy±chemotherapy followed by extrafascial hysterectomy appears to be a viable option for patients with endometrial cancer clinically extending to the cervix and parametria. The HDR brachytherapy schema of 5-5.5Gy times 3-4 fractions, for a cumulative EQD2 of 60-70Gy, is well tolerated with high rates of clinical and pathological response.

Adjuvant radiation in early stage, unfavorable histology endometrial carcinoma is associated with improved local control and survival.

OBJECTIVE: Unfavorable histology endometrial carcinomas confer worse prognosis. We determined the association of adjuvant radiation on local recurrence and survival for unfavorable, early stage endometrial cancer. METHODS: We retrospectively identified 125 patients who had a hysterectomy for early stage (FIGO IA), unfavorable histology (clear cell, papillary serous or grade 3 endometrioid), endometrial carcinoma treated between 1992 and 2011. Patients were restaged according to current FIGO 2009 guidelines. Primary endpoint was local control and secondary endpoints were distant recurrence and overall survival. RESULTS: The median age of the cohort was 67 years old with a mean follow up 152 months. Adjuvant radiation was delivered in 60 patients (48%). There were a total of 24 recurrences; 5 had local-regional recurrences, 4 local and distant recurrence, 12 distant only recurrences, and 3 had unspecified recurrences. The 5-year local-regional control was 97.8% in patients who received radiation and 80.1% in patients who did not receive radiation (p=0.018). The 5-year overall survival rate was 68.1% if patients did not receive radiation and 84.9% if they did receive radiation (p=0.0062). On univariate analysis, only radiation (HR 0.12, 95% CI: 0.03 to 0.49, p-value=0.018) was associated with a significant increase in local relapse free survival. CONCLUSIONS: Adjuvant radiation therapy was significantly associated with an improvement in local-regional control and overall survival in patients with unfavorable histology, early stage endometrial cancer.

Predictive factors of recurrence following adjuvant vaginal cuff brachytherapy alone for stage I endometrial cancer.

PURPOSE: The purpose of this study is to identify risk factors for recurrence in a cohort of stage I endometrial cancer patients treated with vaginal cuff brachytherapy at a single academic institution. METHODS AND MATERIALS: From 1989 to 2011, 424 patients with stage I endometrial cancer underwent total hysterectomy and bilateral salpingo-oophorectomy, with or without lymphadenectomy (LND), followed by high-dose-rate vaginal cuff brachytherapy (VCB) to patients felt to be high or intermediate risk FIGO stage IA and IB disease. Covariates included: 2009 FIGO stage, age, grade, histology, presence of lymphovascular space invasion, LND, and receipt of chemotherapy. RESULTS: With a median follow-up of 3.7years, the 5 and 10-year disease free survival were 98.4% and 95.9%, respectively. A total of 30 patients developed recurrence, with the predominant pattern of isolated distant recurrence (57.0%). On multivariate analysis, grade 3 (p=0.039) and LND (p=0.048) independently predicted of increased recurrence risk. χ(2) analysis suggested that higher-risk patients were selected for LND, with significant differences in age, stage, and grade noted between cohorts. Distant metastatic rate was significantly higher for patients who qualified for GOG 0249 at 23.1% (95% CI 10.7-35.5%) compared to those who did not at 6.8% (95% CI 1.8-11.8%, p<0.001). CONCLUSION: Overall disease-free survival for this cohort of patients was >95% at 10years. Univariate analysis confirmed previously identified risk factors as predictors for recurrence. Multivariate analysis found that grade 3 and LND correlated with risk for recurrence. Of those that did recur, the initial site of relapse included distant metastasis in most cases.

Intrathoracic papillary thyroid carcinoma from occult primary disease.

A 42-year-old woman undertook a chest radiograph for a routine evaluation prior to surgery for pelvic endometrioma, which revealed a right paratracheal mass slightly displacing the trachea to the left. CT of the thorax disclosed a well demarcated, heterogeneous, lobular, right paratracheal mass, bearing punctate, coarse, and curvilinear calcifications. MRI further revealed two components within the lesion: a larger, cystic, exhibiting thin septations, and a solid component at the lower part exhibiting strong enhancement. No continuity of the mass with the thyroid gland was demonstrated, which had normal size and no focal lesion. Histological examination of the resected mass disclosed lymph node tissue infiltrated by papillary thyroid carcinoma; subsequent total thyroidectomy revealed small foci of papillary carcinoma within both lobes of the thyroid gland. Ablative dose I-131 was administered and the patient was put on daily thyroid supplements.

Disease-free survival in papillary and follicular thyroid carcinoma. Comparison between UICC 5th and 7th classifications of T stage, and the prognostic value of primary tumour size.

UNLABELLED: T stage was redefined for patients with differentiated thyroid carcinoma (DTC) between the 5th and 7th versions of the UICC tumour classification system. PATIENTS, METHODS: 636 patients (486 women, 150 men; mean age 49.1 ± 15.6 years, mean follow-up 4.6 years) who had been treated with ablative radioiodine therapy after thyroidectomy for papillary (PTC) or follicular thyroid carcinomas (FTC) were retrospectively assessed on occurrence of locoregional recurrent disease, or cervical lymph node or distant metastases. Disease-free survival was calculated from initial T stage, classified according to both versions of the UICC staging system and compared with the prognostic value of primary tumour size. Kaplan-Meier method and two measures of explained variation, (1) R2 based on the (partial) likelihood ratio statistic of the Cox proportional hazards model and (2) a model-free variant of a distance measure proposed by Schemper had the aim to detect the most advantageous classification. RESULTS: Of the 508 patients with PTC, 11 (2.2%) developed a local recurrence, 37 (7.3%) cervical lymph node and 23 (4.5%) distant metastases, 3 (2.3%), 8 (6.3%), and 18 (14.1%) were the numbers for the 128 FTC patients respectively. The two classification systems yielded an equal count of statistically significant differences regarding disease-free survival in patients with PTC while UICC 7th classification appeared slightly advantageous in patients with FTC. Regarding explained variation the UICC 7th classification tended to be superior to the UICC 5th classification, both in PTC and FTC, however statistical significance was not reached. CONCLUSION: The primary tumour size significantly added to the prognosis regarding local cervical and distant metastases.

Cerebral metastases from thyroid carcinoma: complete remission following radioiodine treatment.

BACKGROUND: Brain metastases arise in roughly 0.9% of all cases of differentiated thyroid cancer. The median survival of adult patients with thyroid carcinoma that has metastasized to the brain is less than one year. Radioactive iodine treatment is only rarely given because its efficacy is not documented. In children, the situation may be different. METHOD: In 2005, a 15-year-old girl underwent thyroidectomy, and an oxyphilic variant of papillary thyroid carcinoma was found in ectopic thyroid tissue. The patient underwent oral, high-dose radioactive iodine treatment. The post-therapeutic I-131 whole-body scan revealed multiple metastases in the skeleton, lungs, and the soft tissues, along with physiological uptake of the residual thyroid tissue. Magnetic resonance imaging of the head revealed two brain metastases. RESULTS: When the initial treatment was completed, additional age-adapted high-dose radioactive iodine treatment was given, up to a total activity level of 35 GBq. There followed a complete remission of all metastases in the brain, bones, lungs, and soft tissues. Computed tomography of the chest revealed stable residuals. Over the ensuing 7.5 years of follow-up, the thyroglobulin values steadily declined to less than 2 ng/mL. The patient was asymptomatic at her last follow-up in May 2013. She did not develop any delayed reaction to high-dose radioactive iodine treatment (in particular, she did not develop leukemia or any other secondary malignancy). She remained fertile: after completion of the treatment, she had two healthy children. CONCLUSION: In this patient with multifocal thyroid carcinoma, a rare entity, radioactive iodine treatment was successful as the single treatment. This case illustrates the point that a given therapeutic modality might succeed in an individual case despite a total or near-total lack of efficacy for most patients in the same situation.

[Long-term survival of a patient with extrahepatic cholangiocarcinoma treated with adjuvant radiotherapy for positive ductal margins after surgical resection].

A 57-year-old man with abdominal discomfort visited our hospital. Abdominal computed tomography (CT) revealed no tumorous lesions. Endoscopic retrograde cholangiography (ERC) revealed a tumorous lesion in the middle bile duct. Peroral cholangioscopy-assisted biopsy was performed, and the lesion was diagnosed as a papillary adenocarcinoma. Extra bile duct resection and regional lymph node dissection were performed; however, residual carcinoma in situ was detected at the ductal margins by intraoperative frozen section analysis. Therefore, external radiation therapy at a dose 50.4 Gy/28 Fr was administered after the operation. No complication due to radiotherapy occurred. The patient remains alive and recurrence -free for more than 7 years after the operation. We report the long-term disease-free survival of a patient with extrahepatic cholangiocarcinoma who was treated with external radiation therapy for positive ductal margins after surgical resection.

Randomized controlled trial of a computerized decision aid on adjuvant radioactive iodine treatment for patients with early-stage papillary thyroid cancer.

PURPOSE: Decision-making on adjuvant radioactive iodine (RAI) treatment for early-stage papillary thyroid cancer (PTC) is complex because of uncertainties in medical evidence. Using a parallel, two-arm, randomized, controlled trial design, we examined the impact of a patient-directed computerized decision aid (DA) on the medical knowledge and decisional conflict in patients with early-stage PTC considering the choice of being treated with adjuvant RAI or not. The DA describes the rationale, possible risks and benefits, and the medical evidence uncertainty relating to the choice. PATIENTS AND METHODS: We recruited 74 patients with early-stage PTC after thyroidectomy. Participants were assigned by using 1:1 central computerized randomization to either the DA group with usual care (intervention) or usual care alone (control). Medical knowledge about PTC and RAI treatment (the primary outcome), as well as decisional conflict (a secondary outcome), were measured by using validated questionnaires, and the respective scores were compared between groups. RESULTS: Consistent with PTC epidemiology, 83.8% (62 of 74) of the participants were women, and the mean age was 45.8 years (range, 19 to 79 years). Medical knowledge about PTC and RAI treatment was significantly greater and decisional conflict was significantly reduced in the DA group compared with the control group (respective P values < .001). The use of adjuvant RAI treatment was not significantly different between groups (DA group, 11 of 37 [29.7%]; controls, seven of 37 [18.9%]; P = .278). CONCLUSION: A computerized DA improves informed decision making in patients with early-stage PTC who are considering adjuvant RAI treatment. DAs are useful for patients facing decisions subject to medical evidence uncertainty.

The therapeutic and adverse effects of modified radiation fields for patients with rectal cancer.

PURPOSE: To compare the therapeutic effect and complications of modified radiation fields (MRFs) with those of conventional pelvic radiation fields (CPRFs) for rectal cancer. METHODS AND MATERIALS: From December 1996 to October 2009, a total of 160 patients with rectal carcinoma who received total mesorectal excision and postoperative radiotherapy were examined. Ninety-four patients were in the CPRFs group, and 66 were in the MRFs group. The dose was 50 Gy per 25 fractions in the initial plan. RESULTS: The treatment volume and the volume of small bowel that received more than 15 Gy of the MRFs was smaller than that of the CPRFs (P < .001). The rates of local recurrence, overall survival, and disease-free survival were not statistically significant between the MRFs and CPRFs groups (P > .05). There was a statistical difference (P < .05) in the incidence of acute toxicity, which included serious complications in the lower digestive tract (grade ≥3). The completion rate for the initial radiotherapy plan was higher in the MRFs group than in the CPRFs group (P = .027). CONCLUSIONS: Compared with CPRFs, MRFs manifested a lower incidence of complications and the same therapeutic effects. This finding will facilitate the clinical application of MRFs for patients with rectal cancer.

The utility of I-123 pretherapy scan in I-131 radioiodine therapy for thyroid cancer.

BACKGROUND: There is a growing belief that a pretherapy scan yields little or no additional information that would impact on radioiodine ablation dosing. In addition, there is some concern regarding on the stunning effect of a pretherapy scan, especially when I-131 radioisotope is used for imaging. We hypothesized that a pretherapy scan provides invaluable information on the amount of thyroid remnant, sometimes indicating the need for two-step I-131 ablation. It may also detect unsuspected local lymph node involvement or distant metastases, indicating the requirement for a higher I-131 dose after thyroidectomy. The aim of this study was to evaluate how effective pretherapy scans are for guiding I-131 therapy planning and augmenting information provided in the pathology reports for thyroidectomy specimens. METHODS: We reviewed 122 patients who underwent I-123 pretherapy scan and I-131 radioablation at Yale New Haven Hospital between January 2006 and August 2007. The percentage of neck uptake and whole-body images were acquired 24 hours following the administration of 51.8 MBq (1.4 mCi) of I-123 NaI. A 24-hour uptake of >3% was used as the cutoff to determine whether there was a greater than desired quantity of thyroid remnant, which would require a two-step treatment protocol. Furthermore, attention was paid to identifying cervical lymph nodes, which may not have presented themselves in the euthyroid state at the time of thyroidectomy. Additional clinical information provided by pretherapy scans was computed as percentages with 95% confidence intervals by using adjusted Wald intervals. RESULTS: Overall, the pretherapy scans provided additional critical information in 25% of the cases (31/122; 95% CI: 18%-34%). For cases demonstrating >3% uptake with midline lymph nodes, the pretherapy scan provided additional information in 50% of the cases (8/16; 95% CI: 28%-72%). CONCLUSIONS: Our study demonstrated that I-123 pretherapy scans provide valuable information with regard to unsuspected lymph nodes or distant metastases, indicating the requirement for a significantly higher I-131 dose, and unexpected large thyroid remnants, suggesting the need for two-step ablation. We should take advantage of stimulated pretherapy scans and adjust the treatment dosing accordingly.

Outpatient thyroid remnant ablation using repeated low 131-iodine activities (740 MBq/20 mCix2) in patients with low-risk differentiated thyroid cancer.

CONTEXT: In low-risk differentiated thyroid cancer (DTC), postoperative (131)I remnant ablation should employ a minimum effective activity; reports increasingly suggest efficacy of low activities, e.g. 1110 MBq/30 mCi. OBJECTIVES, DESIGN, PATIENTS, AND INTERVENTIONS: We retrospectively studied the ablation capability and diagnostic utility of the Minidose protocol, two 740-MBq/20 mCi outpatient administrations, 6-18 months apart, plus related diagnostic procedures, in 160 consecutive (near-) totally thyroidectomized low-risk DTC (pT1/N0-Nx) patients. Successful ablation comprised negative 740-MBq whole-body scintigraphy with cervical uptake below 0.1%, negative stimulated thyroglobulin (STg) (<1 ng/ml, negative thyroglobulin antibodies), and negative Doppler ultrasonography (performed around Minidose 2). SETTING: The study took place at a referral center. RESULTS: Minidose imaging found unsuspected nodal or distant metastases in nine of 160 patients (5.6%). Ablation success rates after one (two) 740-MBq activity (activites) were 75.9% (90.2%) in 145 (132) evaluable imaging-negative patients. Compared with thyroid hormone withdrawal, recombinant human TSH stimulation was associated with higher urinary iodine excretion/creatinine, lower cervical uptake, and more frequent ablation success after the first 740 MBq; success rates no longer differed significantly after both administrations. Patients with STg below 10 ng/ml at Minidose 1 were oftener ablated at Minidose 2 (odds ratio=13.9, 95% confidence interval=2.5-76.4, P<0.003), attaining 92.0% final ablation success after recombinant human TSH preparation, suggesting that one 740-MBq activity should suffice in this subgroup. All 81 evaluable patients with prolonged follow-up (mean 41.8±21.9 months after Minidose 1) had no evidence of disease at the last visit. CONCLUSIONS: The Minidose outpatient ablation protocol is effective and diagnostically useful in low-risk DTC.

Clinical outcome of low-risk differentiated thyroid cancer patients after radioiodine remnant ablation and recombinant human thyroid-stimulating hormone preparation.

AIM: Recombinant human thyroid-stimulating hormone (rhTSH) has been approved in Europe as a preparation tool for radioiodine ablation of post-surgical thyroid remnants in patients with low-risk differentiated thyroid cancer (DTC). Published studies report that, both thyroid hormone withdrawal and rhTSH preparation result in similar rates of successful remnant ablation, but few studies have determined the effectiveness of rhTSH preparation on disease recurrence. We sought to determine the clinical outcome, considering both ablation success and disease recurrence, of low-risk DTC patients who underwent (131)I ablation. MATERIALS AND METHODS: This retrospective study describes the clinical outcome of 100 patients treated with (131)I remnant ablation after preparation with rhTSH. After ablation, patients were classified as in complete remission, as having no evidence of persistent disease, or as having clinical recurrence on the basis of a subsequent diagnostic whole body scan with (131)I, stimulated thyroglobulin and cross-sectional imaging studies. RESULTS: Overall assessment of ablation success was verified and obtained in 75% of patients (75/100). Considering only patients who underwent a diagnostic whole body scan and stimulated thyroglobulin without interfering anti-thyroglobulin antibody, complete ablation was obtained in 96% of patients (75/78). After a follow-up of about 4 years, 78 patients are in complete remission: 75 with initial ablation success and three who achieved a complete remission during subsequent follow-up. Among the remaining 22 patients, 21 have no clinical evidence of disease (NCED), indicating the inability to verify the complete remission or to detect residual disease, as in patients with positive thyroglobulin antibody, whereas one has persistent disease demonstrated only by stimulated thyroglobulin. No recurrences were observed. Of four patients initially classified as having persistent disease, one obtained a complete remission and two are now considered NCED. CONCLUSION: Our data confirm the favourable outcome, with low rates of recurrence and persistent disease, of patients with low-risk DTC who underwent (131)I ablation after rhTSH. Moreover, our results compare favourably with those reported in the literature in patients prepared with rhTSH, but also in patients prepared with hormone withdrawal.

[Vacuum assisted closure (VAC) of pyothorax with bronchial fistula following radiotherapy, pneumonectomy and thoraco-myoplasty]. / Irradiatiót és pneumonectomiát követo hörgosipolyos empyema thoracis nyitott, vákuumtámogatott (VAC) kezelése thoraco-myoplastica után.

Pulmonary fibrosis and impeding gangrene as complications of radiotherapy and chemotherapy developed in a patient who previously underwent right upper lobectomy. Following completion pneumonectomy, bronchopleural fistula and consecutive thoracic empyema formed. This case presentation is to demonstrate the vicious circle of severe complications following oncological treatment. The role of vacuum assisted closure and other management options are discussed which resulted in full recovery of the patient after three years finally.