Novel staging protocol for non-small-cell lung cancers according to MRP-1/CD9 and KAI1/CD82 gene expression.

1998 ◽  
Vol 16 (4) ◽  
pp. 1397-1406 ◽  
Author(s):  
M Adachi ◽  
T Taki ◽  
T Konishi ◽  
C I Huang ◽  
M Higashiyama ◽  
...  
Keyword(s):  
Small Cell ◽  
Nodal Status ◽  
Pcr Analysis ◽  
Significant Prognostic Factor ◽  
Small Cell Lung ◽  
New Classification ◽  
Lung Cancers ◽  
Group A ◽  
Group B ◽  
Better Than

PURPOSE The transmembrane-4 superfamily (TM4SF) is a recently discovered family of genes. Of the TM4SF members, MRP-1/CD9, KAI1/CD82, and ME491/CD63 have been reported to modulate tumor progression or metastasis. In this study, we investigated the relationships between these three genes, MRP-1, KAI1, and ME491, in patients with non-small-cell lung cancers (NSCLCs). Moreover, we assessed the prognostic value of evaluating the expressions of MRP-1, KAI1, and ME491 simultaneously in NSCLCs. PATIENTS AND METHODS One hundred seventy-two patients up to stage IIIB NSCLC underwent radical surgery during the period of January 1991 through June 1994. Using a quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis, we studied the expression of MRP-1, KAI1, and ME491 genes in these patients. RESULTS We found that 109 patients (63.4%) had MRP-1-positive tumors and 42 patients (24.4%) had KAl1-positive tumors. Conversely, all 172 patients expressed ME491. No relationship was found between MRP-1 expression and KAI1 expression. We classified these patients into three groups. The 36 patients who were positive for both MRP-1 and KAI1 were defined as group A; the 79 patients with reduced expression of either MRP-1 or KAI1 were defined as group B, and the remaining 57 patients with reduced expression of both MRP-1 and KAI1 were defined as group C. This new classification was correlated with nodal status, tumor status, and pathologic stage (P = .0056, P = .0003, and P < .0001, respectively). In NSCLC patients, the 5-year survival rate of group A patients was significantly better than that of group B patients and much better than that of group C patients (86.8%, 53.9%, and 31.5%, respectively; P < .0001). Cox multivariate regression analysis showed that this new classification in NSCLCs was a significant prognostic factor, as was the nodal status (P < .0001). CONCLUSION Our results suggest that a low MRP-1 and KAI1 expression by tumors of the lung may be associated with poor prognosis. It is conceivable that the evaluation for MRP-1 and KAI1 expression may identify node-negative lung cancer patients who are at high risk for early disease recurrence, and thus need intensive adjuvant therapy.

Can patients with advanced malignancy and poor performance status benefit from nivolumab plus ipilimumab as a palliative treatment?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 12028-12028
Author(s):  
Omar Khaled Abughanimeh ◽  
Smriti Sharma ◽  
Robin High ◽  
Mridula Krishnan ◽  
Benjamin A. Teply
Keyword(s):  
Performance Status ◽  
Small Cell ◽  
Small Cell Lung ◽  
Predictive Tool ◽  
Lung Cancers ◽  
The Poor ◽  
Group A ◽  
Poor Outcomes ◽  
Group B ◽  
Ecog Ps

12028 Background: Performance status (e.g. Eastern Cooperative Oncology Group [ECOG] score) is a predictive tool used to determine whether a patient may benefit from cytotoxic chemotherapy. The toxicity profile of immunotherapy is different, and less is known about whether performance status (PS) is similarly associated with toxicity and benefit. Nonetheless, most clinical trials for immune checkpoint inhibitors have excluded patients with poor PS. Emerging data by our group and others has linked poor PS with lack of response and decreased survival with anti-PD-1/L1 agents, but whether combination therapy abrogates the poor outcomes of PD1 only therapy is unknown. Methods: We conducted a retrospective cohort study of patients with metastatic cancer who received ipilimumab plus nivolumab at our institution between January 2014-December 2020. We compared outcomes between those with good PS (Group A, ECOG PS 0-1) and poor PS (Group B, ECOG PS ≥ 2). Our primary outcomes were overall survival (OS) and incidence of grade 3-4 immune-related adverse events (irAEs). Other outcomes included objective response rates and need for hospitalization. We utilized the Kaplan-Meyer method for time to survival analysis and exact Pearson Chi-squared testing for response, toxicity, and hospitalization analysis. Results: A total of 129 patients were identified with a mean age of 59.9 years. Among them were 73 males (57%) and 56 females (43%). Malignant melanoma was the most common malignancy (39%) followed by renal cell carcinoma (27%), small cell lung cancers (10%), non-small cell lung cancers (9%), and the rest with other histologies. 113 patients (87.6%) were in group A and 16 (12.4%) in group B. Across all tumor types, patients in Group B had significantly worse OS compared to group A (HR 0.24 [0.13-0.48], P = < 0.0001). Group B similarly had higher rates of hospitalization compared to group A (94% vs 56%, P = 0.0048). Interestingly, irAEs were not driving these hospitalizations, with a trend toward lower rates of irAEs in the poor PS group (19% vs 46% in Group A, P = 0.057). The overall response rate in group B was numerically lower (6% vs 26% in group A, p = 0.1). Conclusions: Our study showed that using ipilimumab plus nivolumab in patients with poor PS was associated with significantly poorer OS and higher rates of hospitalizations. irAEs were not increased in the poor PS group, suggesting a lack of treatment efficacy seemed to driving these poor outcomes. Extrapolation of clinical trial data for ipilimumab-nivolumab to a broader population including those with poor PS should be done with caution. Unfortunately, our data showed that most patients with poor PS were not adequately palliated with ipilimumab-nivolumab.

scholarly journals Association between number of dissected lymph nodes and survival in stage IA non-small cell lung cancer: a propensity score matching analysis

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Lei-Lei Wu ◽  
Jia-Jian Lai ◽  
Xuan Liu ◽  
Yang-Yu Huang ◽  
Peng Lin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Propensity Score ◽  
Tumor Size ◽  
Wedge Resection ◽  
Small Cell ◽  
Matched Cohort ◽  
Small Cell Lung ◽  
Group A ◽  
Stage Ia ◽  
Group B

Abstract Background For patients with stage IA non-small cell lung cancer (NSCLC) with tumor size ≤ 2 cm, the prognostic significance of the number of removed lymph nodes (NLNs) through different surgical methods remains unclear. To determine the association of NLNs with cancer-specific survival (CSS) and overall survival (OS) in patients with stage IA NSCLC with tumor size ≤ 2 cm who underwent different lung surgeries. Methods We retrospectively enrolled 7293 patients from the Surveillance, Epidemiology and End Results database. Median NLNs was used to classify the patients into two groups: group A with NLNs ≤ 5 and group B with NLNs > 5. Propensity score matching (PSM) was performed to decrease selection bias. Kaplan–Meier analysis and Cox regression analysis were performed to identify the association between NLNs and survival outcomes. Results Group B had better survival than group A in the unmatched cohort and matched cohort (all P < 0.05). Multivariable analyses revealed that the NLNs significantly affected CSS and OS of eligible cases in the unmatched cohort and matched cohort. Additionally, we found that the NLNs was a protective prognostic predictor of OS for patients who underwent wedge resection, segmental resection, or lobectomy. Conclusion The NLNs was a protective prognostic factor in NSCLC patients with tumor size ≤ 2 cm. We demonstrated that patients with > 5 NLNs in the cohort of wedge resection, segmental resection, or lobectomy exhibited a significantly better OS.

scholarly journals Characteristics of non-small-cell lung cancer with interstitial pneumonia: variation in cancer location, histopathology, and frequency of postoperative acute exacerbations in interstitial pneumonia

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kazumasa Ogawa ◽  
Hironori Uruga ◽  
Takeshi Fujii ◽  
Sakashi Fujimori ◽  
Tadasu Kohno ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Interstitial Pneumonia ◽  
Squamous Cell ◽  
Small Cell ◽  
Normal Lung ◽  
Small Cell Lung ◽  
Acute Exacerbations ◽  
Group A ◽  
Group B

Abstract Background Non–small-cell lung cancer (NSCLC) has been reported to develop in patients with interstitial pneumonia (IP); however, clinical, radiological, and pathological features remain to be elucidated. Methods We retrieved the records of 120 consecutive NSCLC patients associated with IP who underwent surgery at Toranomon Hospital between June 2011 and May 2017. We classified the patients into three groups according to NSCLC location using high-resolution computed tomography: group A, within a fibrotic shadow and/or at the interface of a fibrotic shadow and normal lung; group B, within emphysematous tissue and/or at the interface of emphysematous tissue and normal lung; and group C, within normal lung. In 64 patients, programmed death ligand-1 (PD-L1) status was assessed with immunohistostaining. Results Most of the patients (89; 70%) were classified as group A. This group tended to have squamous cell carcinoma with the usual interstitial pneumonia (UIP). These cancers were located mainly in the lower lobes and seven of the eight postoperative acute exacerbations (pAE) of IP developed in this group. NSCLC in the group B were mainly squamous cell carcinomas located in the upper lobes. No patient with PD-L1 negative was classified into group B. None of the patients in group C showed UIP. and most of the cancers were adenocarcinoma. The frequency of epidermal growth factor receptor mutation-positive NSCLC was the highest in this group. Conclusions The three groups each showed characteristic features in terms of tumor location, histopathology, PD-L1 expression, and frequency of pAEof IP.

The effect of nivolumab treatment for central nervous system metastases in non-small cell lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20601-e20601 ◽  
Author(s):  
Hiromi Watanabe ◽  
Toshio Kubo ◽  
Takashi Ninomiya ◽  
Kadoaki Ohashi ◽  
Eiki Ichihara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Central Nervous System ◽  
Nervous System ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung ◽  
Group A ◽  
Group B ◽  
Nsclc Patients ◽  
Cns Lesions

e20601 Background: Central nervous system (CNS) metastases (mets) occur in 30% of patients with advanced non-small cell lung cancer (NSCLC) and are associated with poor overall survival (OS). Although nivolumab, a programmed death-1 immune checkpoint inhibitor antibody, has demonstrated a longer survival benefit compared with docetaxel in previously treated NSCLC patients (CheckMate 017 and 057; N Engl J Med, 2015), patients with symptomatic or untreated CNS mets were excluded in these trials. In CheckMate 012 Arm M, 2 of 12 patients (16.7%) with untreated CNS mets showed intracranial responses, but the effect of nivolumab treatment for CNS mets was not fully investigated. Methods: To investigate the effect and safety of nivolumab for CNS mets in NSCLC patients, we retrospectively analyzed 48 patients with NSCLC who were treated with nivolumab from February 2016 to December 2016 at Okayama University Hospital. Results: Twenty-nine patients (60%) had no CNS lesions (group A) and 19 patients (40%) had brain mets (BM) (group B). In group B, 15 patients (79%) received radiotherapy (RT) for BM, including 5 patients who received RT just before nivolumab treatment. The responses of extra-CNS lesions to nivolumab are shown in the table. The PFS was longer in group A than in group B (p=0.14). In group B, the PFS of patients who received prior RT tended to be longer than in those without RT (p=0.42); OS was not reached in either group. In group B, the effects of nivolumab treatment for CNS mets were evaluated in 12 patients: SD occurred in 3 patients (25%), PD in 4 patients (33%), and NE in 5 patients (42%). All 4 patients with PD in the CNS lesion also showed PD in the extra-CNS lesion. In group A, no patients showed progression only in the CNS lesion. Conclusions: In this retrospective study, there were no patients treated only with nivolumab who showed a response to CNS mets. RT prior to nivolumab might be more effective, so future investigations should involve additional cases and prospective studies. [Table: see text]

The association between STK11/LKB1 and/or KEAP1 mutations and response to PD-1/PD-L1 inhibitors in patients with advanced non-small cell lung cancer (NSCLC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21538-e21538
Author(s):  
Meagan Elizabeth Miller ◽  
Meera Patel ◽  
Sandra K. Althouse ◽  
Nasser H. Hanna ◽  
Hirva Mamdani
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Concurrent Chemotherapy ◽  
Small Cell ◽  
Small Cell Lung ◽  
Disease Characteristics ◽  
Clinical Databases ◽  
Group A ◽  
Group B

e21538 Background: Advanced non-small cell lung cancer (NSCLC) patients with tumors harboring STK11/LKB1 or KEAP1 mutations have inferior treatment outcomes when treated with PD-1/PD-L1 blockade, regardless of KRAS status, PD-L1 score, or TMB score (Skoulidis et al, Cancer Discovery 2018, ASCO abstract 102, 2019). Methods: Retrospective clinical databases from Indiana University and Karmanos Cancer Institute were queried to identify patients from 2008-2019 with advanced NSCLC treated with PD-1/PD-L1 monotherapy (group A) or concurrent chemotherapy + PD-1/PD-L1 inhibitors (group B) whose tumors harbored STK11/LKB1 and/or KEAP1 mutations. Patients were characterized by best response, progression of disease (PD) or non-PD (complete response (CR) + partial response (PR) + stable disease (SD)). Patient and disease characteristics, response, and duration of response (> vs. < 6 months) were recorded. Results: A total of 77 patients met the above criteria (55 in group A, 22 in group B). 52 of 55 patients in group A received prior chemo. Patient and disease characteristics and outcomes are summarized in the table. Conclusions: STK11/LKB1 and/or KEAP1 mutations are independent of PD-L1/TMB status, although most patients had PD-L1 of <1%. Nearly ½ of patients with STK11/LKB1 and/or KEAP1 mutations achieve at least SD with PD-1/PD-L1 inhibitor monotherapy and more than 50% of those with non-PD maintain that response status for > 6 mos. The frequency and duration of non-PD in this population is higher in patients receiving chemotherapy + PD-1/PD-L1 concomitantly. [Table: see text]

scholarly journals Predictive Factors of Lymph Node Status in Small Peripheral Non-small Cell Lung Cancers: Tumor Histology is Better Than Subcentimeter in Size

CHEST Journal ◽  
2012 ◽  
Vol 142 (4) ◽  
pp. 36A
Author(s):  
Yang Zhang ◽  
Haiquan Chen ◽  
Jiaqing Xiang ◽  
Yawei Zhang ◽  
Yihua Sun ◽  
...  
Keyword(s):  
Lymph Node ◽  
Predictive Factors ◽  
Small Cell ◽  
Lymph Node Status ◽  
Small Cell Lung ◽  
Lung Cancers ◽  
Tumor Histology ◽  
Node Status ◽  
Better Than

scholarly journals Sequential Treatment of Afatinib and Osimertinib in Patients with Advanced Non-small Cell Lung Cancer Harboring EGFR Mutations: Results from a Real-world Study in South Korea

2021 ◽  
Author(s):  
Taeyun Kim ◽  
Tae Won Jang ◽  
Chang Min Choi ◽  
Mi-Hyun Kim ◽  
Sung Yong Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
South Korea ◽  
Small Cell Lung Cancer ◽  
Survival Rates ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Group A ◽  
Group B ◽  
Egfr Mutated

Abstract The optimal sequence for administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for treating non-small cell lung cancer (NSCLC) is still unclear. This study aimed to evaluate the efficacy of sequential afatinib and osimertinib treatment in patients with NSCLC harboring EGFR mutations. Electronic records of patients with EGFR-mutated NSCLC, who were administered afatinib and osimertinib (group A) or other chemotherapy (group B) between October 2014 and October 2019, across 16 hospitals in South Korea were reviewed. The primary outcome, time on treatment (TOT), secondary outcome, and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test. Multivariate analyses were performed using the Cox proportional hazards model. Of the 737 patients who received frontline afatinib treatment, 360 with complete records were selected (group A:154, group B: 206). The median TOT was 33.9 months (95% confidence interval [CI]: 24.5−43.3) in group A and 21.3 months (95% CI: 19.4−23.1) in group B. The median TOT with afatinib was 12.9 months (95% CI: 11.8−14.0) overall, and 15.2 months (95% CI: 13.2−17.1) in group A. The 2- and 3-year survival rates were 86.0% and 69.3% in group A and 75.9% and 55.3% in group B, respectively. Sequential afatinib and osimertinib treatment resulted in better survival rates than treatment with afatinib followed by other chemotherapies. Therefore, this sequential treatment strategy may offer clinical benefits to patients with EGFR-mutated NSCLC.

Thymidylate synthase polymorphisms and immunohistochemistry in non-small cell lung cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11101-11101
Author(s):  
J. Stoehlmacher ◽  
E. Goekkurt ◽  
G. Hoeffken ◽  
R. Zinsky ◽  
F. Lynch ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Carcinoma ◽  
Cell Lung Cancer ◽  
Staining Intensity ◽  
Small Cell ◽  
Small Cell Lung ◽  
Histological Subtypes ◽  
Group A ◽  
Group B

11101 Background: Recently, pemetrexed has been introduced into the treatment of non-small cell lung cancer (NSCLC). There's evidence that pemetrexed appears to be more efficient in non squamous NSCLC including adenocarcinoma (AC) and large cell carcinoma (LCC). TS represents a major target enzyme of pemetrexed. We evaluated the expression of TS among different histological types of NSCLC and its association with functional genetic polymorphisms of the TS gene. Methods: Archived tumor samples from 312 individuals with NSCLC were analyzed. Immunohistochemistry (IHC) was performed using a mouse monoclonal antibody to TS. TS stained sections were scored for cytoplasmic and nuclear localization. For each compartment, the tumor was evaluated for the estimated percentage of positive cells with the greatest intensity within the tumor. Intensity was scored on a scale of 0–4. A score of 3–4 was classified as high expression. Genotyping of TS-VNTR including the G/C SNP and TS1394del6 was performed by PCR based RFLP techniques. Genotypes supposed to be associated with low expression were grouped (group A: 2R/2R or 2R/3RC or 3RC/3RC + -6/-6) and compared to genotype groups associated with high expression (group B: 2R/3RG or 3RC/3RG or 3RG/3RG + -6/+6 or +6/+6). Results: IHC and polymorphisms could be performed successfully in 312 (100%) and 287 (92%), respectively. Distribution of histology was as follows: 50% AC, 42% squamous cell carcinoma (SCC), 3% LCC and 5% mixed or other histological subtypes. Group B genotypes were significantly more present in SCC than in AC (49% vs 23%, p=.002). Tumors with group B genotypes were more likely to display high nuclear staining intensity than group A tumors (30% vs. 17%, p=.077). A similar but not significant trend was seen for cytoplasmic staining intensity. There was no significant difference between histological subtypes of NSCLC with respect to TS protein expression. AC were more common than SCC to show a G1 differentiated tumors (8% vs 1%, p<.001). No difference between genotype groups were observed with respect to grading. Conclusions: TS polymorphisms are significantly associated with histology subtypes in NSCLC. These results represent a potential explanation for efficacy differences of pemetrexed in NSCLC and warrants further investigations. [Table: see text]

scholarly journals Multiinstitutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases from non–small cell lung cancer (JLGK0901 study–NSCLC)

2018 ◽  
Vol 129 (Suppl1) ◽  
pp. 86-94 ◽  
Author(s):  
Takashi Shuto ◽  
Atsuya Akabane ◽  
Masaaki Yamamoto ◽  
Toru Serizawa ◽  
Yoshinori Higuchi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Prospective Observational Study ◽  
Incidence Rates ◽  
Small Cell ◽  
Leptomeningeal Dissemination ◽  
Small Cell Lung ◽  
Secondary Endpoints ◽  
Group A ◽  
Function Preservation ◽  
Group B

OBJECTIVEPrevious Japanese Leksell Gamma Knife Society studies (JLGK0901) demonstrated the noninferiority of stereotactic radiosurgery (SRS) alone as the initial treatment for patients with 5–10 brain metastases (BMs) compared with those with 2–4 BMs in terms of overall survival and most secondary endpoints. The authors studied the aforementioned treatment outcomes in a subset of patients with BMs from non–small cell lung cancer (NSCLC).METHODSPatients with initially diagnosed BMs treated with SRS alone were enrolled in this prospective observational study. Major inclusion criteria were the existence of up to 10 tumors with a maximum diameter of less than 3 cm each, a cumulative tumor volume of less than 15 cm3, and no leptomeningeal dissemination in patients with a Karnofsky Performance Scale score of 70% or better.RESULTSAmong 1194 eligible patients, 784 with NSCLC were categorized into 3 groups: group A (1 tumor, n = 299), group B (2–4 tumors, n = 342), and group C (5–10 tumors, n = 143). The median survival times were 13.9 months in group A, 12.3 months in group B, and 12.8 months in group C. The survival curves of groups B and C were very similar (hazard ratio [HR] 1.037; 95% CI 0.842–1.277; p < 0.0001, noninferiority test). The crude and cumulative incidence rates of neurological death, deterioration of neurological function, newly appearing lesions, and leptomeningeal dissemination did not differ significantly between groups B and C. SRS-induced complications occurred in 145 (12.1%) patients during the median post-SRS period of 9.3 months (IQR 4.1–17.4 months), including 46, 54, 29, 11, and 5 patients with a Common Terminology Criteria for Adverse Events v3.0 grade 1, 2, 3, 4, or 5 complication, respectively. The cumulative incidence rates of adverse effects in groups A, B, and C 60 months after SRS were 13.5%, 10.0%, and 12.6%, respectively (group B vs C: HR 1.344; 95% CI 0.768–2.352; p = 0.299). The 60-month post-SRS rates of neurocognitive function preservation were 85.7% or higher, and no significant differences among the 3 groups were found.CONCLUSIONSIn this subset analysis of patients with NSCLC, the noninferiority of SRS alone for the treatment of 5–10 versus 2–4 BMs was confirmed again in terms of overall survival and secondary endpoints. In particular, the incidence of neither post-SRS complications nor neurocognitive function preservation differed significantly between groups B and C. These findings further strengthen the already-reported noninferiority hypothesis of SRS alone for the treatment of patients with 5–10 BMs.

Survival outcome of tyrosine kinase inhibitors beyond progression in association to radiotherapy in oligoprogressive EGFR-mutant non-small-cell lung cancer

2019 ◽  
Vol 15 (33) ◽  
pp. 3775-3782 ◽  
Author(s):  
Sabrina Rossi ◽  
Giovanna Finocchiaro ◽  
Vincenzo Di Noia ◽  
Maria Bonomi ◽  
Eleonora Cerchiaro ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Small Cell ◽  
Small Cell Lung ◽  
Group A ◽  
Group B

Aim: The association of tyrosine kinase inhibitors (TKIs) and local radiotherapy in EGFR-mutated non-small-cell lung cancer patients experiencing disease progression under TKIs could be a valid an option. Patients & methods: We included 131 patients experiencing disease progression during first-line TKI. In group A, patients received TKI beyond progression and site(s) of progression were irradiated; in group B, patients remained on TKI alone beyond progression; and group C stopped TKI at first disease progression. Results: Median overall survival resulted longer in group A versus B and C (p < 0.0001). Group A had a trend toward a longer second progression-free survival (measured from the time of first progression until second progression) versus group B (p = 0.06). Conclusion: TKI beyond progression in association with local ablative treatment is a valid treatment option in oligoprogressive patients.

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