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Results for “Neoadjuvant therapy”

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PubMed1998

Cervical cancer response to neoadjuvant therapy: MR imaging assessment.

PURPOSE: To determine the accuracy of magnetic resonance (MR) imaging in evaluating the invasive cervical carcinoma response to concurrent chemotherapy and radiation therapy. MATERIALS AND METHODS: MR imaging was performed before and after concurrent chemotherapy and radiation therapy in 18 patients with locally invasive cervical carcinoma. Surgery followed neoadjuvant therapy in all patients. The presence of a lesion, signal intensity, zonal anatomy integrity, vaginal and parametrial invasion, and lymph node enlargement was determined. Posttreatment MR and histopathologic findings were correlated. RESULTS: Fourteen patients had histopathologic confirmation of MR findings: Twelve had true-negative and two had true-positive findings. (Two had microscopic neoplastic foci beyond the spatial resolution of MR images; these foci do not change surgical treatment planning and probably do not influence prognosis. Therefore, these two patients were considered to have complete response). Four patients had false-positive findings; the hyperintense lesion on posttreatment MR images was due to a tunnel cluster pattern (focal hyperplasia of the endocervical glands with inflammation) in three patients and necrosis in one patient, without any evidence of neoplastic tissue. Thirty-three of 36 parametrial halves and 67 of 72 vaginal fornices were correctly interpreted on posttreatment images. Involvement of three parametrial halves and five fornices was overestimated at MR, because edema or inflammation was not distinguishable from tumor. CONCLUSION: MR imaging is 78% accurate in evaluation of tumor response; in 22% of patients, however, benign conditions were not distinguishable from tumor.

Adult↗

PubMed2005

Effect of a pT0 cystectomy specimen without neoadjuvant therapy on survival.

BACKGROUND: In some cases of radical cystectomy for bladder cancer, no residual tumor is found in the cystectomy specimen (the pT0 classification). The aim of this study was to evaluate the outcome of such patients in a large cystectomy series. METHODS: All 900 patients with radical cystectomy and pelvic lymphadenectomy for TCC of the bladder in the period January 1986 to September 2003 who received no neoadjuvant therapy were included. Cystectomy specimens from 181 (20.1%) patients were graded as pT0. Complete follow-up was obtained in all cases. Tumor-specific survival (pT0 vs. pT+) was calculated with the Kaplan-Meier method and compared with the log-rank test. RESULTS: The rate of lymph node metastases in the pT0 group was 6.6%. pT0 status was found with Ta/is/1 in 36.8%, T2a in 41.8%, and T2b in 10.9%. The 169 patients with pT0pN0 tumors had 10-year tumor-specific survival rates of 91.0. There was no statistically significant survival benefit for pT0pN0 tumors compared with pT+pN0 tumors for maximal tumor classifications of pTa/pTis/pT1 and pT2b, but patients with a pT0T2apN0 tumor had a statistically significantly better tumor-specific survival than those with a pT2apN0 tumor (P = 0.002). No patient with a pT0pN0 tumor had a local recurrence. The rate of incidental second primary malignancies in a specimen was 15.5%. CONCLUSIONS: A pT0pN0 cystectomy specimen indicates a curative therapy, but there is a substantial risk of tumor recurrence. In the group of tumors with a maximal classification of pT2a, the pT0 tumors constitute a subgroup with a significantly higher likelihood of survival.

Combined Modality Therapy↗

PubMed2005

[Neoadjuvant therapy for resectable esophageal cancer].

BACKGROUND: Surgical excision remains the only therapeutic approach with curative potential in patients with localized esophageal cancer. Due to the presence of lymph node metastases upon diagnosis in a large percentage of patients with locally advanced tumors and/or the presence of considerable co-morbidity, only a limited number of patients are amenable to surgery. These facts have prompted us to evaluate approaches including perioperative therapy modalities. METHODS: By means of a computer-supported search (MEDLINE, ASCO Proceedings) as well as a manual literature search, randomized clinical trials and meta-analyses evaluating preoperative therapy plus surgery in patients with resectable esophageal cancer were identified. RESULTS: Twenty-three randomized clinical studies and five meta-analyses were identified. Interpretation--especially of the older studies--however, is hampered by the lack of a stringent application of modern examination techniques allowing for exact specification of tumor stage (resectable/locally advanced) as well as the inclusion of patients with different histological entities (squamous cell/adenocarcinoma), different surgical techniques and the low number of patients. There were no significant differences for the following perioperative therapy modalities regarding tumor-related mortality: preoperative radiotherapy versus postoperative radiotherapy, preoperative and postoperative radiotherapy versus postoperative radiotherapy (higher mortality in preoperative and postoperative radiotherapy arm), preoperative radiotherapy versus surgery, preoperative chemotherapy versus surgery, preoperative and postoperative chemotherapy versus surgery. In terms of 3-year mortality, statistically significant differences could be found for the following therapy modalities: preoperative radiochemotherapy versus surgery (preoperative therapy superior), preoperative chemotherapy versus preoperative radiotherapy (preoperative radiotherapy superior). CONCLUSION: Judging from these data, no clear recommendation for a standard multimodality approach outside clinical studies can be given for patients with resectable esophageal cancer. Neoadjuvant therapy, therefore, can only be recommended in centers with a maximum surgical expertise and in the context of multidisciplinary study protocols.

Antibiotics, Antineoplastic↗

PubMed2001

Adjuvant and Neoadjuvant Therapies of Pancreatic Cancer: A Review.

The survival of patients diagnosed with pancreatic cancer is dismal. Few patients on initial presentation aresuitable for surgical resection. This has prompted clinical studies with chemotherapy and/or radiotherapydesigned either to increase the number of patients eligible for surgery (neoadjuvant therapy) or to prolong thesurvival of patients who had undergone surgery (adjuvant therapy). None of these studies may at this time beconsidered definitive. Wherever possible, patients felt eligible for neoadjuvant or adjuvant therapy should beentered on clinical trials. Where this is not possible, clinicians should exercise their best judgment in offeringthis type of treatment to pancreatic cancer patients under their care.

Journal Article↗

PubMed2000

[Neoadjuvant therapy in breast carcinoma].

The preoperative or neoadjuvant chemo- or endocrine therapy in the treatment of locally advanced breast cancer is a new therapy option. Clinical Studies could show, that there is no difference in overall survival between patients, who received a preoperative chemotherapy and patients, treated with the conventionally postoperative, adjuvant chemotherapy. There is an increased rate of breast conserving therapy for the locally advanced breast cancer because of tumor shrinking. Neoadjuvant chemotherapy is also a good in-vivo-model for chemosensitivity-testing. For elderly patients with comorbidity, the primary treatment with endocrine therapy with tamoxifen or aromatase inhibitors could even avoid an operation in some cases. The most effective drugs for preoperative chemotherapy are anthracyclines and taxanes. The assessment of predictive factors like S-phase, Ki67, ploidy, c-erb-B2, in-vitro-chemosensitivity-testing results and others could help to differentiate patients who will have a benefit from chemotherapy. It is important to have more results from studies with a long term follow-up, before we declare primary systemic chemo- or hormone therapy as standard therapy for breast cancer patients with locally advanced breast cancer.

Adult↗

PubMed2026

HIF1A+CSF3R+ neutrophils-dominated hypoxic niche induced metabolic reprogramming for neoadjuvant therapy resistance in NSCLC.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the frequently occurring cancers characterized by molecular heterogeneity and multiple immune cell infiltration patterns, which are associated with treatment sensitivity and resistance. However, the specific microenvironmental cells and their mechanisms that lead to treatment resistance in patients need to be explored in greater depth. METHODS: On the basis of patients receiving neoadjuvant therapy in our center, a multicenter, multicohort NSCLC spatial transcriptome, single-cell transcriptome, T-cell receptor repertoire sequencing, bulk RNA transcriptome, phosphorylated proteome, genome mutation, and clinical data were included for a comprehensive assessment of the therapeutic and prognostic impact of HIF1A+ CSF3R+ neutrophils in NSCLC. In vitro experiments validated the functional phenotype of HIF1A+ CSF3R+ neutrophils and co-localization interactions with other cellular subpopulations. Gradient boosting machine (GBM) constructed region of interest (ROI) models for evaluation. Computer-aided drug design (CADD) was used to predict targeted small molecule drugs, and in vivo mouse models were constructed to assess the effectiveness of the combination treatment regimen. RESULTS: Centered on HIF1A+ CSF3R+ neutrophils, recruited exhausted T cells and stromal cells form a hypoxic niche within the tumor region, which was enriched in non-response patients. ROI composed of these specific cellular subpopulations, associated with senescence and glycolysis, accurately predicting NSCLC progression, prognosis, and microenvironment composition. CADD analysis identified that platycodin-D2 specifically targeted CSF3R, reducing HIF1A expression and inhibiting neutrophil activity. Combining navitoclax, platycodin-D2 with anti-programmed cell death protein 1 (PD-1) significantly suppressed tumor proliferation and improved the immunosuppressive microenvironment. CONCLUSION: Our study emphasized the role of HIF1A+ CSF3R+ neutrophils in immunotherapeutic resistance of NSCLC, constructed a microenvironmental immune dysregulation network in a hypoxic ecological niche with HIF1A+ CSF3R+ neutrophils as the center. Platycodin-D2 specifically targeted HIF1A+ CSF3R+ neutrophils, enhancing the efficacy of anti-PD-1 therapy in NSCLC.

Humans↗

PubMed2005

Controversies in breast cancer: adjuvant and neoadjuvant therapy.

Initial randomised studies of chemotherapy and endocrine therapy showed that systemic treatments had a substantial impact on the survival of women with early breast cancer. The original assumption was that the efficacy of these treatments was limited to those patients presenting with more adverse prognostic features. Subsequently, meta-analyses of randomised trials revealed that the benefits of chemotherapy and endocrine therapy are not mutually exclusive and extend to all the prognostic subgroups. However, the absolute benefit varies according to baseline characteristics such as tumour stage and other biological factors. Over the last 10 years, considerable progress has been made with the introduction of new drugs into the adjuvant and neoadjuvant treatment of women with breast cancer. Taxanes and third-generation aromatase inhibitors are providing proof of additional benefits compared with standard reference treatments. In parallel, research on the biology of breast cancer is establishing novel prognostic and predictive factors, which may allow better treatment tailoring. Currently, however, women with early breast cancer and their doctors face the difficult task of making therapeutic decisions often based on early results from positive studies. In a disease where follow up is crucial to fully assess the benefit and long-term toxicities of an intervention, current knowledge leaves unanswered questions that generate debate and controversy. This review will summarise recent results from randomised trials of adjuvant and neoadjuvant therapy in women with early breast cancer and focus on the current controversies.

Age Factors↗

PubMed2001

[A survey of radical surgery without neoadjuvant therapy for patients with stage B and C prostatic carcinoma].

There has been much controversy regarding radical surgery for both localized and locally extensive carcinoma of the prostate. We analyzed the outcome of radical prostatectomy and the preoperative evaluation in order to assess the indication of radical prostatectomy. Fifty-six patients with clinical stage B or C prostate cancer were treated by radical prostatectomy without neoadjuvant therapy. Endocrine therapy was added to the non-curative cases postoperatively. Preoperative evaluation was compared with pathological results and survival, and furthermore the usefulness of the preoperative PSA and PSA half-life were investigated. The mean follow-up period was 44.5 months. The accuracy of the grade and the clinical stage were 58.9% and 23.2%, respectively. Organ-confined disease was seen in patients with an initial PSA level less than 30 ng/ml. Postoperative PSA half-life is significantly prolonged in cases with poorly differentiated adenocarcinoma or lymph node involvement and may be a predictor of PSA failure. The cause-specific 5-year survival rates were 92.7% on the whole, 92.9% for well differentiated, 96.7% for moderately differentiated, 85.7% for poorly differentiated, 100% for stage B1, 95.0% for stage B2 and 86.8% for stage C. These results indicated that patients with an initial PSA level of less than 30 ng/ml will benefit from radical prostatectomy.

Aged↗

PubMed2003

Neoadjuvant Therapy for Prostate Cancer: An Oncologist's Perspective.

With increasing use of prostate-specific antigen as a screening tool, diagnosis of prostate cancer has undergone a stage migration toward early-stage disease. Although this has increased the proportion of men who are candidates for definitive, potentially curative therapy, it has also made clear the limitations of our current standard of care. Specifically, despite adequate local therapy, a significant proportion of men go on to develop progressive disease. Neoadjuvant systemic therapy is one approach that continues to be studied as a way to maximize cure rates in the setting of early-stage disease. This article reviews the current data regarding neoadjuvant therapy, both hormonal and chemotherapy, and discusses which men are appropriate candidates for this option.

Journal Article↗

PubMed2006

[Neoadjuvant therapy with imatinib mesilate for gastrointestinal stromal tumor of the stomach before subsequent successful surgical resection].

A 65-year-old man is presented here with a huge mass of 13 cm in diameter in the left upper abdomen. Histopathologic assessment of endoscopic forceps biopsy revealed a c-kit positive gastrointestinal storomal tumor (GIST) of the stomach. Abdominal computed tomography (CT) showed a direct invasion to the pancreas. Imatinib mesilate was administered as neoadjuvant therapy according to the NCCN Guidelines. Imatinib mesilate therapy was stopped within 2 weeks because of adverse events such as Grade 2 of facial edema and dizziness. However, no hematological adverse event was shown. After three months of treatment (relative dose intensity was 87.5%), CT revealed a reduction in tumor diameter of 35.6% and showed no longer a direct invasion to the pancreas. The radical operation was considered feasible and partial gastrectomy was performed. The tumor was well encapsulated and radical surgery was possible without rupture. Adjuvant therapy was not performed. The patient has now been in good health without a recurrence for three months after the surgery.

Aged↗

PubMed2003

Current status of neoadjuvant therapy for adenocarcinoma of the distal esophagus.

Prospective studies dealing with preoperative therapy in adenocarcinoma of the esophagus alone are rare. The interpretation of the preferential phase II trials and a few phase III trials is complicated, as most studies include adenocarcinoma of the esophagus (i.e., Barrett's carcinoma), adenocarcinoma of the esophagogastric junction (including cardia carcinoma and subcardia carcinoma), or squamous cell carcinoma. Preoperative chemotherapy, generally well tolerated, cannot decrease the incidence of local failure beyond the level achieved with surgery alone, but it might delay systemic relapse. Preoperative radiotherapy can enhance local control, but it fails to improve overall survival. Neoadjuvant chemoradiation was demonstrated in only one randomized trail to have a survival benefit, but survival in the surgery-alone group was unusually low. Generally, survival was ameliorated in patients responding to neoadjuvant treatment. However, preoperative chemoradiation was often accompanied by a remarkable increase in postoperative morbidity and mortality. Nonresponding patients have, in this respect, a worse prognosis than responders after resection. The prediction of responding patients to neoadjuvant therapy as well as the early identification of patients who will not respond is of utmost clinical importance. Today, there is no absolute evidence that neoadjuvant treatment for patients with potentially resectable Barrett's cancer prolongs survival. In patients with locally advanced, presumably not completely resectable adenocarcinoma of the esophagus, preoperative treatment appears to increase the chance for a curative resection and enhance survival in responding patients. Neoadjuvant treatment of adenocarcinoma of the esophagus, as a consequence, is currently not the standard treatment and should be performed only within controlled clinical trials.

Adenocarcinoma↗

PubMed2002

Histopathologic effects of neoadjuvant therapies for advanced squamous cell carcinoma of the esophagus: multivariate analysis of predictive factors and p53 overexpression.

In 97 patients (60, chemotherapy; 22, chemoradiotherapy; 15, radiotherapy), histopathologic effects were evaluated microscopically, and histologic response rates were compared among three neoadjuvant treatment modalities. Predictive factors for neoadjuvant therapies were analyzed by logistic regression, including the results of p53 immunohistochemical staining. In the chemoradiotherapy group, the pathologic response rate was 86.4%, and was significantly higher than that for chemotherapy (P < 0.0001) or for radiotherapy (P = 0.0031). In patients with normal p53 protein expression, the histopathologic response rate to chemotherapy was 20.0%, a higher rate than that for patients with abnormal p53 overexpression. In the chemoradiotherapy or radiotherapy group, however, the response rates were almost the same, irrespective of p53 oncoprotein status. From multivariate analysis, the neoadjuvant treatment modality itself was identified as the most powerful predictive factor for the effect. Chemoradiotherapy had the most powerful effect on advanced esophageal cancer, and p53 status did not influence the clinical outcome in this group.

Adult↗

PubMed2003

Adenocarcinoma of the pancreas: the rationale for neoadjuvant therapy.

The survival of patients with pancreatic cancer is dismal: tumor's resection is possible in only 10-20% of patients. This has prompted clinical studies with chemotherapy and/or radiotherapy designed to increase the number of patients eligible for surgery, to maximize local tumor control and to improve the length of survival. Since postoperative chemoradiation is often delayed in these patients due to morbidity and prolonged recovery time associated with surgery, investigators are assessing the efficacy of chemoradiation before pancreatic resection in patients with potentially resectable pancreatic carcinoma or the potential to downstage locally advanced pancreatic cancer to resectable tumor. The analysis of several clinical trials published so far shows that results are conflicting and not definitive. No randomized clinical studies have been reported. Moreover, neoadjuvant therapy rarely leads to surgical downstaging allowing for potentially curative pancreatic resections. Novel multimodality approaches are required, and patients should be entered on clinical, controlled trials.

Adenocarcinoma↗

PubMed2001

[Therapeutic strategies in neoadjuvant therapy of non-small cell lung cancer: benefits of gemcitabine].

Stages of non-small cell lung cancer (NSCLC) that are potential candidates for surgical resection have been treated in several ways: surgery alone is curative in only two-thirds of cases and post-operative radiotherapy (RT) provides only weak control of advanced-stage disease. Since metastatic recurrence is due to the presence of micrometastases, chemotherapy (CT) can be envisaged, even at an early stage of the disease--first with the CT/RT induction combination, which improves survival (median survival: 15 months) and the resection rate (70%). Recent studies on neoadjuvant therapy have evaluated the usefulness of different induction CT regimens. Among these, the gemcitabine/cisplatin study protocol (GC), set up in a phase II study for patients with stage IIIA N2 NSCLC, was very effective [objective response (OR): 70.2%; median survival: 19 months] and should be promising for stages IB and II. Other studies involving platinum analogs have shown good OR rates inducing a high resection rate and a reduction in the spread to mediastinal lymph nodes. Major studies are ongoing, one of which compares GC + surgery versus surgery alone (stages IB-IIIA); the other regimen aims to evaluate GC versus paclitaxel/carboplatin as well as two induction strategies.

Antimetabolites, Antineoplastic↗

PubMed2004

Neoadjuvant therapy with gemcitabine in breast cancer.

Primary systemic therapy (ie, preoperative or neoadjuvant) increases the possibility for breast-conserving surgery in patients with primary breast cancer. Patients with pathologic complete response to primary systemic therapy have improved survival compared with those with persistent tumors. Several phase II trials have evaluated gemcitabine-containing doublet or triplet regimens as primary systemic therapy for breast cancer, results of which have shown promising clinical and pathologic response rates with manageable toxicity. Results of a phase I/II study of gemcitabine (Gemzar)/epirubicin (Ellence)/docetaxel (Taxotere), or GEDoc, with prophylactic filgrastim (Neupogen), as primary systemic therapy in 77 evaluable patients with primary breast cancer are reported herein. Dose-limiting toxicities were grade 3 febrile neutropenia (n = 1) and grade 3 diarrhea (n = 2) at the fourth dose level of GEDoc tested (gemcitabine at 800 mg/m2 days 1 and 8, epirubicin at 90 mg/m2 day 1, and docetaxel at 75 mg/m2 day 1). As assessed by ultrasound, 92% of patients responded overall (22% complete response), and 79% of patients could undergo breast-conserving surgery. The pathologic complete response rate in resected breast tissue was 26%.

Adult↗

PubMed2001

[Staging and neoadjuvant therapy of squamous cell carcinoma of esophagus].

Once the diagnosis of esophageal cancer is established, the decision on treatment will depend on the stage of the disease. Since improvement of prognosis can only be expected in patients with complete removal of their tumor, preoperative staging plays a pivotal role in the decision-making process. Preoperative diagnostic procedures should define the tumor in its relation to the tracheal bifurcation (site), determine the depth of tumor invasion (T status), evaluate regional lymph node metastases (N1 disease) and exclude distant metastases (M1 disease). Endosonography represents currently the most accurate imaging technique for detecting the correct T stage over the correct N stage. A higher accuracy rate may be achieved by combining endosonography with other staging modalities such as computed tomography. Chest x-ray, and percutaneous ultrasonography (abdominal, neck) form the diagnostic basis in staging M1 disease. Computed tomography (neck, chest and abdomen) is currently the best method to detect metastases in the liver and in celiac nodes. Staging laparoscopy when combined with laparoscopic ultrasonography shows a higher sensitivity than ultrasonography and computed tomography in the diagnosis of smaller metastases and peritoneal seedings. En bloc esophagectomy together with the regional lymph nodes remains the treatment of choice in medically fit patients with localized esophageal carcinoma (Stage I-IIB, T1-T2/N0-N1/M0). Due to early involvement of mediastinal structures, curative resection is unlikely to be achieved in patients with locally advanced esophageal carcinoma (Stage III, T3-T4/N0-N1/M0). Most available data indicate that neoadjuvant radiochemotherapy leads in a significant number of patients to downstaging of the tumor, increases the rate of R0 resection, improves local tumor control, and prolongs the recurrence free interval. However, neoadjuvant radiochemotherapy resulted in a marked increase of morbidity and postoperative mortality without improvement of survival. At present, neoadjuvant therapy is still experimental and there is no consensus for an optimal treatment regimen. Its use outside of an investigational setting can not be recommended. Future research must focus on more effective and less toxic neoadjuvant modalities (e.g. new chemotherapy agents, hyperthermia).

Carcinoma, Squamous Cell↗

PubMed2006

[Neoadjuvant therapy for operable breast-cancer].

Preoperative or neoadjuvant systemic treatment refers to either the first postdiagnosis systemic treatment that a patient receives or indicates that additional subsequent therapy is intended. Randomized controlled clinical trials have shown that preoperative systemic treatment offers the same disease free survival and overall survival benefits as does adjuvant systemic treatment. Neoadjuvant therapy has been found to increase the breast-conserving surgery rate. This therapy also allows to evaluate the primary tumor response to chemotherapy. Additionally, on the basis of the biologic characteristics of a tumor and differences in the response to systemic treatment, primary systemic treatment should be regarded as a tool that can be used to individualize systemic treatment for patients with breast cancer. However, some issues remain to be resolved, such as the markers that should be assessed before this therapy, as well as the optimal surgical and radiotherapy treatment.

Breast Neoplasms↗

PubMed2001

Estrogen-receptor-directed neoadjuvant therapy for breast cancer: results of a randomised trial using formestane and methotrexate, mitozantrone and mitomycin C (MMM) chemotherapy.

BACKGROUND: We wanted to determine whether neoadjuvant systemic chemoendocrine therapy guided by the estrogen receptor (ER) status of the primary breast cancer, followed by conventional surgery and/or radiotherapy, reduces local and distant recurrence and improves survival compared with adjuvant treatment given conventionally postoperatively. PATIENTS AND METHODS: Two hundred ten patients with primary breast cancer (T1-T4, N0, N1-2) were randomised to receive treatment with neoadjuvant chemoendocrine therapy or conventional post-operative chemoendocrine therapy. Systemic therapy was based on the estrogen receptor (ER) status of the primary tumour obtained by trucut core biopsy. ER-negative patients received MMM chemotherapy (methotrexate (30 mg/m2), mitozantrone (7 mg/m2) and mitomycin (7 mg/m2) three-weekly for three months and ER-positive patients who were premenopausal received goserelin (3.75 mg monthly), and post menopausal women formestane (250 mg every two weeks) over three months. RESULTS: With a minimum of five years follow-up, there is no evidence of any survival benefit from the pretreatment neoadjuvant therapy regimen, with five year overall survival being 79% +/- 4.7% (neoadjuvant) and 87% +/- 3.4% (adjuvant). Similarly, there was no apparent benefit in terms of disease-free survival. There was, however, a significant reduction in the incidence of distant metastases in responders (4 of 51; 8%) compared with non-responders (17 of 49; 35%) (P < 0.01). There was a reduction in the need for surgery in responding patients with T1 and T2 tumours, since 10 of 74 (14%) had no detectable residual tumour, without any apparent increase in the risk of local or distant recurrence. CONCLUSION: In this study neoadjuvant treatment with endocrine or chemotherapy provided no obvious survival benefit to women with breast cancer. However, it does allow avoidance of surgery in some cases. Also, the patients whose tumours respond to neoadjuvant systemic therapy have a lower incidence of distant metastases after five year follow-up compared to those whose tumours fail to respond.

Adult↗