Safety of nivolumab monotherapy in five cancer types: pooled analysis of post-marketing surveillance in Japan.

BACKGROUND: Nivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan. METHODS: We performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years]). RESULTS: The overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7%. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), and interstitial lung disease (7.0%) were the three most common categories (any grade). The incidences of rare TRAEs with high risk of becoming serious, which occurred in < 1% of patients, were consistent with those in previous reports. The frequencies of TRAEs were not markedly increased in the specified patient groups relative to the overall population. CONCLUSION: To our knowledge, this is the largest study examining the safety of nivolumab-treated patients in real-world clinical practice including rare but potentially serious TRAEs. We found no new signals in the safety of nivolumab among the patient groups relative to the overall population, and no additional safety measures are required in these groups. Trial registration UMIN000048892 (overall analysis), JapicCTI-163272 (melanoma), Japic-163271 (non-small cell lung cancer), JapicCTI-184071 (head and neck cancer), JapicCTI-184070 (gastric cancer), and JapicCTI-184069 (renal cell cancer).

Real-world safety of nivolumab in patients with non-small-cell lung cancer in Japan: Postmarketing surveillance.

Postmarketing surveillance of Japanese patients with unresectable, previously treated, advanced or recurrent non-small-cell lung cancer treated with nivolumab was undertaken during the conditional approval period. The study aim was to evaluate the occurrence of treatment-related adverse events of nivolumab in the real world. Patients were registered between December 2015 and March 2016 at 536 sites. Nivolumab was given intravenously (3 mg/kg every 2 weeks); the observation period was 12 months after the first dose of nivolumab. Patients were evaluated for safety (n = 3601; 18.2% ≥75 years, 22.4% ECOG performance status ≥2) and effectiveness (n = 3570). The frequencies of any grade and grade 3 or higher treatment-related adverse events were 47.1% and 15.9%, respectively. The most frequent treatment-related adverse events (any grade) were interstitial lung disease (6.4%), hypothyroidism (5.7%), and diarrhea (4.4%). Treatment-related adverse events of special interest (priority items) occurring at a frequency of 5% or more were adverse events related to interstitial lung disease, thyroid dysfunction, liver dysfunction, colitis/severe diarrhea, infusion reaction, and infusion reaction within 24 hours. Significant risk factors for these priority items were identified by competing risk analysis: interstitial lung disease (previous/comorbid interstitial lung disease, abnormal findings on chest imaging, and smoking history); liver dysfunction (previous/comorbid liver disease, smoking history, and metastasis); thyroid dysfunction (previous/comorbid thyroid disease and performance status); and colitis/severe diarrhea (treatment line 2 vs ≥3). The 12-month survival rate was 40.7%. In conclusion, the safety profile of nivolumab in this postmarketing surveillance was similar to that in clinical trials, and no new safety signals were identified. The study was registered with the Japan Pharmaceutical Information Center (clinicaltrials.jp: Japic-163271).

Radiographic features and poor prognostic factors of interstitial lung disease with nivolumab for non-small cell lung cancer.

Nivolumab can cause interstitial lung disease (ILD), which may be fatal; however, mortality risk factors have not been identified. This postmarketing study evaluated the poor prognostic factors of ILD in nivolumab-treated patients with non-small cell lung cancer (NSCLC) in Japan. Clinical and chest imaging findings for each ILD case were assessed by an expert central review committee, and prognosis was evaluated by radiographic findings, including the presence/absence of peritumoral ground-glass opacity (peritumoral-GGO). Poor prognostic factors were identified by univariate and multivariate Cox regression analysis. Of the 238 patients with nivolumab-induced ILD, 37 died. The main radiographic patterns of ILD were cryptogenic organizing pneumonia/chronic eosinophilic pneumonia-like (53.4%), faint infiltration pattern/acute hypersensitivity pneumonia-like (20.2%), diffuse alveolar damage (DAD)-like (10.9%), and nonspecific interstitial pneumonia-like (6.3%). The main poor prognostic factors identified were DAD-like pattern (highest hazard ratio: 10.72), ≤60 days from the start of nivolumab treatment to the onset of ILD, pleural effusion before treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal change in C-reactive protein (CRP) levels. Of the 37 deaths due to ILD, 17 had DAD-like radiographic pattern, three had peritumoral-GGO, and five had a change in radiographic pattern from non-DAD at the onset to DAD-like. Patients with NSCLC who develop ILD during nivolumab treatment should be managed carefully if they have poor prognostic factors such as DAD-like radiographic pattern, onset of ILD ≤60 days from nivolumab initiation, pleural effusion before nivolumab treatment, lesion distribution contralateral or bilateral to the tumor, and abnormal changes in CRP levels.

Treatment and relapse of interstitial lung disease in nivolumab-treated patients with non-small cell lung cancer.

Nivolumab, a human monoclonal antibody against programmed death-1, is approved for the treatment of non-small cell lung cancer (NSCLC). Although nivolumab is generally well tolerated, it can cause interstitial lung disease (ILD), a rare but potentially fatal immune-related adverse event. Currently, there are limited data available on the treatment of nivolumab-induced ILD and its outcome. This retrospective cohort study based on a post-marketing study described the treatment of nivolumab-induced ILD and its outcome in NSCLC patients in Japan through the assessment of clinical and chest imaging findings by an expert central review committee. Treatment details for patients who experienced a relapse of ILD were also analyzed. Of the 238 patients identified as having nivolumab-induced ILD, 37 patients died of ILD. Corticosteroids were used in 207 (87.0%) patients. Of those, 172 (83.1%) patients responded well and survived and 35 (16.9%) died (most died during corticosteroid treatment). A total of nine patients experienced a relapse; at the time of relapse, four patients were taking nivolumab. Of those who were receiving corticosteroids at the time of relapse, three of four patients were taking low doses or had nearly completed dose tapering. All patients (except one, whose treatment was unknown) received corticosteroids for the treatment of relapse, but one patient died. Patients with NSCLC who experience nivolumab-induced ILD are treated effectively with corticosteroids, and providing extra care when ceasing or reducing the corticosteroid dose may prevent relapse of ILD.

Radiologic features of pneumonitis associated with nivolumab in non-small-cell lung cancer and malignant melanoma.

Aim: To assess the clinical features/imaging characteristics of pneumonitis reported during nationwide nivolumab postmarketing surveillance in Japan. Patients & methods: Clinical and radiological data were collected from pneumonitis cases reported during/after nivolumab treatment for melanoma or non-small-cell lung cancer. The expert central review committee evaluated each case. Results: Among 144 cases analyzed, 91 (63.2%) had radiological patterns considered typical for drug-induced pneumonitis and 53 (36.8%) patients had previously unobserved patterns with one or more atypical features, including 23 cases (16.0%) with ground glass opacity confined to the area around the tumor (peritumoral infiltration). A higher proportion of patients with (vs without) peritumoral infiltration had an antitumor response to nivolumab. Conclusion: Images of nivolumab-induced pneumonitis showed previously unobserved radiological patterns.

Neo-aortic insufficiency late after staged reconstruction for hypoplastic left heart syndrome: impact of differences in initial palliative procedures.

The neo-aortic insufficiency in patients with hypoplastic left heart syndrome is an important sequela. We assessed the risks of the neo-aortic valve deterioration by the difference of initial palliations: Group I underwent primary Norwood (Nw) with systemic-to-pulmonary artery shunt (SPS), Group II underwent bilateral pulmonary artery banding (bPAB) and subsequent Nw with SPS (bPAB-Nw/SPS), Group III underwent bPAB and subsequent Nw with bidirectional Glenn (BDG) procedure (bPAB-Nw/BDG). The neo-aortic valve z score changes over time did not reach statistical significance in all groups (p = 0.43 for Group I, 0.20 for Group II, and 0.30 for Group III). The degree of neo-aortic valve insufficiency did not change significantly over time during this period except for Group III (p = 0.34 for Group I, 0.20 for Group II, and 0.02 for Group III). On the other hand, dimensions of the neo-aortic annulus and degrees of neo-aortic insufficiency did not differ significantly among the 3 groups at any pre-determined time. The presence or absence of incision into the sino-tubular junction at Nw did not affect the late neo-aortic valve z score or insufficiency. These data indicate that the difference of initial palliative procedures does not affect late neo-aortic valve insufficiency in Nw survivors. Because valve failure may develop in longer follow-up, further observation should be conducted.

[Atrial Septal Hematoma after Repair of Ventricular Septal Defect;Report of a Case].

A 3-month-old female with ventricular septal defect underwent definitive repair. In the operation, a venting tube was inserted through the incised patent foramen ovale. The ventricular septal defect was closed using a patch and the incised patent foramen ovale was directly closed. A transesophageal echography showed no abnormal findings in the operating room. On 1st postoperative day, the patient's heart rate and pressure of the superior vena cava increased while blood pressure decreased. A transthoracic echocardiography revealed an atrial septal hematoma. After conservative therapy, the heart rate and pressure of the superior vena cava gradually decreased while blood pressure increased. The atrial septal hematoma disappeared spontaneously. The patient was discharged on 16th postoperative day. The atrial septal hematoma appears to have a good prognosis, but sometimes can be poor resulting and death. Meticulous and constant observation is required to detect an atrial septal hematoma.

Feasibility study of docetaxel plus bevacizumab as first line therapy for elderly patients with advanced non-small-cell lung cancer: Thoracic Oncology Research Group (TORG) 1014.

BACKGROUND: Docetaxel monotherapy is one of the standard treatments for non-small-cell lung cancer in elderly patients. The addition of bevacizumab to docetaxel seems promising; however, the feasibility of this combination has not been investigated in such patients. METHODS: Patients with advanced non-squamous non-small-cell lung cancer aged 70 years or older who had not previously received cytotoxic chemotherapy were enrolled. Patients in the Level 0 cohort received docetaxel 60 mg/m(2) and bevacizumab 15 mg/kg, whereas those in the Level-1 cohort received docetaxel 50 mg/m(2) and bevacizumab 15 mg/kg. Chemotherapy was repeated 3 weekly for six cycles. The primary endpoint was toxicity and the secondary endpoints were response rate, progression-free survival, overall survival, and proportion of patients who underwent three or more cycles of chemotherapy. RESULTS: Twenty-one patients were enrolled from December 2010 to September 2012 at six institutes. Of the nine patients enrolled in Level 0, two experienced dose-limiting toxicity (febrile neutropenia and prolonged Grade 4 neutropenia in one patient, and Grade 3 infection in another patient) during the first cycle. Enrollment to the Level 0 cohort was terminated because two patients developed Grade 4 sepsis during later cycles. The remaining 12 patients were enrolled in the Level-1 cohort, in which two dose-limiting toxicities (prolonged Grade 4 neutropenia and Grade 3 increased aminotransferase level) were observed. No patient in the Level-1 cohort experienced Grade 4 nonhematologic toxicity. Grade 4 neutropenia occurred in 89 % of Level 0 patients and 50 % of Level-1 patients. The proportion of patients who experienced Grade 3/4 infection, febrile neutropenia or sepsis was 44 % in the Level 0 cohort, and 8 % in the Level-1 cohort. The overall response rate to chemotherapy and progression-free survival were 29 % (95 % CI, 11-52 %) and 5.9 months (95 % CI, 3.6-9.1 months), respectively. Efficacy outcomes did not differ significantly between the cohorts. CONCLUSIONS: Toxicities were tolerable in level-1 cohort. The recommended dose of combination chemotherapy with docetaxel and bevacizumab for elderly patients was determined as 50 mg/m(2) of docetaxel and 15 mg/kg of bevacizumab and toxicities were tolerable. Further studies are warranted. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004240 .

[Impacts of bilateral pulmonary artery banding on the surgical and long-term outcomes in hypoplastic left heart syndrome( HLHS) and its variants].

Although Norwood-type operation is a fundamental procedure for hypoplastic left heart syndrome and its variants, the surgical risk is still high even in the high volume center. Bilateral pulmonary artery (PA) banding( BPAB) is an alternative procedure to avoid the risk in the neonatal period. We clarified the impacts of BPAB on the surgical and long-term outcomes in HLHS and its variants. Consecutive 85 patients( classical HLHS:52, variant:33) who underwent surgical intervention between July, 1993 and December, 2012 were evaluated. Fetal diagnosis was done in 37 patients (44%). Forty-two patients underwent primary Norwood operation[ Gp N, Blalock-Taussig( BT):29, right-ventricle( RV)-PA conduit:13] and the remaining 43 patients underwent BPAB followed by Norwood operation. Among them, 4 patients did not reach Norwood [9%, atrioventricular valve regurgitation (AVVR):1, infection:1, preoperative shock:2). The survived 39 patients were divided into 2 groups;Gp BN (BPAB → Norwood+BT/RV-PA conduit, n=22), Gp BG [BPAB → Norwood+bidirectional Glenn procedure(BDG), n=17]. BPAB for HLHS and its variants is useful in terms of lower mortality. The 2nd stage palliation is so important that modified Norwood procedure with BT shunt or RV-PA conduit contribute to the lower morbidity including neurological outcome. Norwood+BDG strategy might be beneficial for the high risk patients such as with poor cardiac function or low body weight.

Predictors of central line-associated bloodstream infections in cancer patients undergoing chemotherapy through implanted venous access ports: a retrospective, observational study.

Background: Central venous catheters (CVCs) are sometimes superior to peripheral vascular access for chemotherapy. Central line-associated bloodstream infections (CLABSIs) are an important complication of CVCs in chemotherapy. Methods: A retrospective, observational study was conducted to investigate patients with implanted venous access ports (PORTs) from July 2010 to June 2021 in a teaching hospital. General conditions of the PORTs, backgrounds, and characteristics of patients were compared between CLABSI cases and uninfected cases to identify predictors of CLABSI. Results: A total of 566 patients with PORTs who underwent chemotherapy were enrolled in this study, with CLABSI identified in 41 patients, for a total of 436,597 catheter-days. The median duration of PORT use was 26 vs. 494 days (P<0.001) in the CLABSI and uninfected groups, respectively. There were no significant differences in tumor classification, staging, white blood cell (WBC) count, neutrophil proportion, lymphocyte proportion, albumin, C-reactive protein (CRP), and performance status between the CLABSI and uninfected groups. Multivariable analysis showed that antibiotic usage within the previous week, total protein (TP), and immediate PORT use were independently associated with CLABSI, and their odds ratios (ORs) were 4.89 [95% confidence interval (CI): 1.67, 14.35], 1.95 (95% CI: 1.14, 3.53), and 3.13 (95% CI: 1.18, 8.30), respectively. The area under the curve (AUC) of the receiver-operating characteristic curve for TP was 0.63, and the cutoff value was 5.9 g/dL. Conclusions: PORT implantation should be avoided in patients who had antibiotic treatment episodes within 1 week, especially for those with low serum TP levels.

[Ventricular septation using two-patch technique for total inlet-trabecular septal defect].

A 3-year-old girl underwent ventriclar septation using 2 patch technique. Echocardiography at birth revealed single left ventricle with pulmonary hypertension. Pulmonary artery banding was performed at the age of 1 month. Echocardiography at the age of 3 years showed total inlet-trabecular septal defect. Ventricular septation was performed through the right atrium. The tendon of Todaro and the coronary sinus were in normal positions. Almost all of the inlet septum and trabecular septum were deficit, although the posterior median ridge was present. It was considered that the atrio-ventricular node was shifted inferiorly and the conduction system ran down the inlet septum as in the case of atrioventricular septal defect, since this patient had concordant atrioventricular( AV) connection. It was difficult to form the septum using a single patch because of complicated anatomy. Thus we decided to divide the patch in order to make smooth surface avoiding conduction injury. One patch was used for the trabecular defect using running sutures and another patch was used for the inlet defect using pledgeted mattress sutures. Eventually both patches were sutured together to close the defect. Regular sinus rhythm resumed, although 2:1 AV block appeared temporally. The patient was discharged at postoperative day 30 without any complication.

[Successful application of cholangioscope as an intravascular endoscope in hybrid operation for a child].

We performed hybrid operation on a 3-year-old boy with thrombosis in the pulmonary arterial conduit which had been implanted concomitantly at the time of Fontan operation. We used a cholangioscope as a substitute of intravascular endoscope. It visualized the organized thrombus and the suture line in the conduit. Hybrid operation was successfully performed based on the detailed findings gained by cholangioscopy.

[Persistent fifth aortic arch with coarctation of aorta; report of a case].

Persistent 5th aortic arch (PFA) is a rare congenital cardiac anomaly that was firstly reported by Van Praagh et al, in 1969. A 3-month-old boy was referred to us with no symptom but heart murmur. Cardiac echocardiography and the following 3-dimensional computed tomography (3D-CT) scan revealed PFA with coarctation of aorta. There was pressure gradient of 50 mmHg between upper and lower limbs. He was carefully observed at the outpatient clinic because of no afterload mismatch. At the age of 9 months, coarctectomy and end-to-end anastomosis was performed between the PFA and distal arch below left vertebral artery. A histological examination of resected tissue revealed the thickened intima and rough elastic fiber that is absolutely different from normal aorta. Careful observation is necessary with the possibility of future aneurysmal change or re-coarctation, although the postoperative course has been so far uneventful.

Biventricular Repair Conversion After Temporary One and a Half Ventricular Repair for Hypoplastic Right Ventricle.

This case was an infant with critical pulmonary stenosis at birth. A temporary one and a half ventricular repair was performed to increase right ventricular end-diastolic volume and the size of the tricuspid valve annulus before biventricular repair conversion. The one and a half ventricular repair was performed using a unidirectional bicaval Glenn anastomosis. The right ventricular end-diastolic volume at 3 years was 73.2% of normal value but with a 64/36 right/left lung perfusion ratio. An anatomic biventricular correction included removal of the bicaval Glenn shunt and reconstruction of the continuity between the right and main pulmonary arteries. The one and a half ventricular repair made the reconstruction feasible.

Safety and effectiveness of nivolumab in Japanese patients with malignant melanoma: Final analysis of a post-marketing surveillance.

Nivolumab, a monoclonal antibody against human programmed death 1, was approved for the treatment of melanoma in July 2014 in Japan. Because the Japanese phase II studies (ONO-4538-02, ONO-4538-08) enrolled small numbers of melanoma patients, post-marketing surveillance (PMS; JapicCTI-163 272) was conducted to collect safety data in a larger patient population. We report data for melanoma patients who received nivolumab between July 4, 2014 and February 28, 2017. Data collected included baseline characteristics, laboratory tests, treatment-related adverse events (TRAE), and overall survival (OS). Of 2069 enrolled patients, 2008 patients were included in the safety analysis population. There were 1030 (51.3%) males, the median age was 69 years, and 269 patients (13.4%) had a performance status of ≥2. The primary tumor sites were cutaneous (34.4%), mucosal (34.2%), acral lentiginous (18.6%), others (6.8%), and unknown (6.3%). TRAE occurred in 62.1% of patients, the most common being hypothyroidism (14.0%), increased aspartate aminotransferase (8.5%), and increased alanine aminotransferase (6.9%). TRAE of special interest in ≥5% of patients were thyroid dysfunction (24.9%), hepatic dysfunction (20.6%), infusion reactions (11.4%), colitis/severe diarrhea (6.3%), and interstitial lung disease (ILD; 5.0%). Several types of TRAE of special interest, which included myasthenia gravis/myocarditis/myositis/rhabdomyolysis (0.9%), venous thromboembolism (0.2%), immune thrombocytopenic purpura (0.1%), and encephalitis (0.0%), were observed in this PMS. Although these TRAE were not reported in previous studies (ONO-4538-02, ONO-4538-08, CheckMate 066, and CheckMate 037), they have been listed in the current Risk Management Plan. History of ILD and male sex were risk factors for ILD in a multivariable analysis. Age <75 years was a risk factor for hepatic dysfunction. At 12 months, median OS was not reached. In conclusion, these results suggested that there was no concern requiring additional precautions for the safety of nivolumab in Japanese patients with melanoma other than the safety information in the Risk Management Plan.

[Acute coronary syndrome due to abnormal fibrous tissue growth after Aubert-Imai modification for transposition of the great arteries].

We report a female infant with acute coronary syndrome after Aubert-Imai modification for transposition of the great arteries. Two months postoperatively, she visited the emergency room because of perspiration and tachypnea. She was diagnosed with acute coronary syndrome by blood chemistry examination. Cardiac catheterization revealed Aubert route stenosis, and emergency operation was performed. The lumen around the aortopulmonary window was almost totally occluded by fibrous tissue extending from the equine pericardial patch. This fibrous tissue was completely resected and the aortopulmonary window was deepened to enlarge the coronary ostium. We recommend a close follow-up including angiography after these procedures.

[Pulmonary valve replacement due to ectopic ossification on expanded polytetrafluoroethylene cusp after tetralogy of Fallot repair; report of a case].

Operative correction of tetralogy of Fallot has been performed for more than 50 years and well established. To date, the literature on reoperation has focused and indications and the long-term outcome have not been well defined. We herein report a case of pulmonary valve replacement due to ectopic ossification on expanded polytetrafluoroethylene (ePTFE) cusp in a female child who had undergone right ventricular outflow tract reconstruction for tetralogy of Fallot with pulmonary atresia. Because of severe right ventricular dilatation with end diastolic volume of 186 ml/m2 on cardiac catheterization, redo operation was planned for functional recovery of the right ventricle. Previous transannlar patch was removed and pulmonary valve replacement was performed using CEP 23 mm. A hard calcification was observed around the cusp of transannular patch. Pathological findings revealed ectopic ossification with osteoblast colonization around the ePTFE cusp. This is the 1st report of ectopic ossification on ePTFE.

[Results of Norwood type operation for interrupted aortic arch complex; surgical decision making].

BACKGROUND: Interrupted aortic arch (IAA) is associated with a multitude of lesions ranging from isolated ventricular septal defect to hypoplastic left ventricle or severe subaortic stenosis (SAS). Left ventricular outflow obstruction such as SAS continues to be an important factor for deciding the surgical procedure between univentricular and biventricular repairs. METHODS: A retrospective study was conducted in 8 consecutive infants aged 14 to 117 days and operated on between 2004 and 2009. Seven patients had undergone bilateral pulmonary artery banding for pulmonary high flow regulation. All patients underwent Norwood-type operation (4 with systemic to pulmonary artery shunt, 3 with right ventricle to pulmonary artery shunt, and 1 with bidirectional Glenn shunt). RESULTS: One patient died 2 months after surgery due to respiratory failure. The others were discharged in a good condition. One patient underwent Rastelli-type operation and biventricular circulation was achieved. The other 6 patients were all Fontan candidates. CONCLUSION: Satisfactory initial palliation can be achieved by Norwood-type operation for IAA with severe SAS or hypoplastic left ventricular-aortic complex.

[Long-term outcome of aortic valve replacement with annular enlargement].

BACKGROUND: The choice of appropriate treatment in children with aortic valvular lesions remains controversial. The purpose of this study is to assess early and late outcomes of aortic valve replacement with annular enlargement in children. METHODS: A retrospective study was conducted in 16 consecutive patients aged 0.26 to 15.9 years operated on between 1993 and 2008. Thirteen children underwent aortic valve replacement with Konno procedure (mechanical valve: 12, homograft: 1), 2 children underwent Ross procedure, and the last child underwent Nicks procedure with mechanical valve replacement. All patients undergoing mechanical valve replacement were given warfarin with a monthly international normalized ratio (INR) control. RESULTS: Overall early mortality was 12.5% (2 cases). Emergency operation was performed in these cases because of infectious endocarditis and acute cardiac failure. However, cardiopulmonary bypass (CPB) weaning could not be obtained. There was 1 late death 5 months after mechanical valve replacement. The patient developed methicillin-resistant Staphylococcus aureus (MRSA) sepsis after cleft palate repair. Reoperation was needed in 1 case. CONCLUSION: We conclude that mechanical valve replacement with aortic annular enlargement is an acceptable treatment in children. It is associated with acceptable mortality and low incidence of late events, and provides long-term survival.