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Biomedical subjects

Allan J Pantuck

Publications and source records attributed to Allan J Pantuck.

At least 19 recordsLinked to original sources
PubMed2006

Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer.

PURPOSE: Phytochemicals in plants may have cancer preventive benefits through antioxidation and via gene-nutrient interactions. We sought to determine the effects of pomegranate juice (a major source of antioxidants) consumption on prostate-specific antigen (PSA) progression in men with a rising PSA following primary therapy. EXPERIMENTAL DESIGN: A phase II, Simon two-stage clinical trial for men with rising PSA after surgery or radiotherapy was conducted. Eligible patients had a detectable PSA > 0.2 and < 5 ng/mL and Gleason score < or = 7. Patients were treated with 8 ounces of pomegranate juice daily (Wonderful variety, 570 mg total polyphenol gallic acid equivalents) until disease progression. Clinical end points included safety and effect on serum PSA, serum-induced proliferation and apoptosis of LNCaP cells, serum lipid peroxidation, and serum nitric oxide levels. RESULTS: The study was fully accrued after efficacy criteria were met. There were no serious adverse events reported and the treatment was well tolerated. Mean PSA doubling time significantly increased with treatment from a mean of 15 months at baseline to 54 months posttreatment (P < 0.001). In vitro assays comparing pretreatment and posttreatment patient serum on the growth of LNCaP showed a 12% decrease in cell proliferation and a 17% increase in apoptosis (P = 0.0048 and 0.0004, respectively), a 23% increase in serum nitric oxide (P = 0.0085), and significant (P < 0.02) reductions in oxidative state and sensitivity to oxidation of serum lipids after versus before pomegranate juice consumption. CONCLUSIONS: We report the first clinical trial of pomegranate juice in patients with prostate cancer. The statistically significant prolongation of PSA doubling time, coupled with corresponding laboratory effects on prostate cancer in vitro cell proliferation and apoptosis as well as oxidative stress, warrant further testing in a placebo-controlled study.

Administration, Oral↗
PubMed2006

Long-term outcomes of the surgical management of renal cell carcinoma.

It has been 35 years since the radical nephrectomy was standardized by the work of Robson et al. (J Urol 101:297-301, 1969). Despite being based on a retrospective review of only 88 cases operated upon over a span of 15 years, this publication was an important milestone in the attempt to create uniformity in the staging of Renal cell carcinoma (RCC), and the measurement of surgical outcomes for RCC. Although this manuscript forms the basis for our contemporary measurement of the long-term results of RCC surgery and set the standard to which the entire subsequent literature was compared, contemporary research subsequently has questioned many of Robson's conclusions regarding RCC. In Robson's era, the majority of patients presented with large, symptomatic tumors, pre-operative staging was imprecise, and many patients had locally advanced disease at the time of surgery: of the 88 patients in Robson's series, 75% were managed through a thoracoabdominal incision. Since that time, advances in renal imaging and clinical staging have led to the increased detection of incidental, lower stage, organ-confined tumors more amendable to expanded surgical options. Surgical techniques have evolved and technological advances have made possible new methods of managing renal tumors in situ that have emphasized a transition from radical to less extirpative approaches. In addition, understanding of the basic biology and genetics of kidney cancer has led to improved prognostication and the development of effective immunotherapies for advanced disease. The current concepts and long-term outcomes of the surgical management of RCC will be reviewed to help elucidate some of these changes, from the evolution of open to laparoscopic to percutaneous, from radical to partial to ablative approaches.

Adrenalectomy↗
PubMed2006

Mammalian target of rapamycin inhibitors in renal cell carcinoma: current status and future applications.

Significant achievements in the basic sciences have led to a greater knowledge of the underlying signaling pathways in renal cell cancer (RCC), including the mammalian target of rapamycin (mTOR) pathway (phosphoinositide 3-kinase/Akt pathway). The mTOR pathway has a central role in the regulation of cell growth and increasing evidence suggests its dysregulation in cancer. Receiving input from multiple signals, including growth factors, hormones, nutrients, and other stimulants or mitogens, the pathway stimulates protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase. The mTOR pathway also contributes to many other critical cellular functions, including protein degradation and angiogenesis. Hence, use of inhibitors of the pathway represents a new strategy for the targeted treatment of RCC, and mTOR inhibitors have already shown promising clinical efficacy and low toxicity profiles in unselected patients with metastatic RCC. As with other new, targeted cancer agents, the future use of mTOR inhibitors will benefit from reproducible biomarkers that can be used in the clinic to identify patients most likely to respond and to document modulation of the drug target in addition to clinical response.

Carcinoma, Renal Cell↗
PubMed2006

Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score.

OBJECTIVE: To investigate the expression and potential clinical usefulness of structure-specific flap endonuclease 1 (FEN-1) in human primary prostate cancer using tissue microarray technology, as FEN-1 was recently identified to be overexpressed in CL1.1, the most aggressive clone generated from the hormone-refractory prostate cancer cell line CL1. MATERIALS AND METHODS: Immunohistochemistry was performed on tissue microarrays constructed from paraffin-embedded specimens of primary prostate cancer from 246 patients who had had a radical prostatectomy. Prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH) and normal prostate epithelium were represented on the array. FEN-1 nuclear expression was scored based on the percentage of target cells staining positively, and correlated with Gleason score, preoperative prostate-specific antigen (PSA) level and pathological stage. The time to PSA recurrence was also analysed. RESULTS: The mean expression of FEN-1 was significantly higher in cancer (36.7%) than in normal (13.2%), BPH (4.5%) and PIN (15.4%) specimens (P < 0.001). FEN-1 expression was significantly correlated with Gleason score (ó = 0.23, P = 0.002). A higher preoperative serum PSA level (P = 0.015), Gleason score > or = 7 (P < 0.001), seminal vesicle invasion (P < 0.001) and capsular involvement (P = 0.004) were associated with PSA recurrence, whereas FEN-1 expression was not. In a multivariate analysis, only Gleason score > or = 7 (P < 0.001), seminal vesicle invasion (P = 0.005) and capsular involvement (P = 0.009) were retained as independent predictors for PSA recurrence. CONCLUSIONS: FEN-1 is overexpressed in prostate cancer compared with matched normal prostate, and its expression increases with tumour dedifferentiation, as shown by increasing Gleason score. These results suggest that FEN-1 might be a potential marker for selecting patients at high risk, and a potential target for prostate cancer diagnosis and therapy.

Aged↗
PubMed2006

Significance of gene expression analysis of renal cell carcinoma.

Renal cell carcinoma (RCC) describes a family of epithelial tumors arising from within the kidney. Each subtype of RCC presents a unique clinical picture with varied tumor biology, patient prognosis and response to treatment. Gene expression profiling offers the ability to analyze thousands of candidate genes in high-throughput arrays and has led to a greater knowledge of the molecular genetics of RCC. This powerful technology can identify RCC subtypes, recapitulating and refining the current histological classifications. Gene expression data also promise to advance current staging systems and improve prognostic information for patients and clinicians. Understanding the genetic signature of RCC tumors will allow for sophisticated application of systemic and targeted therapies, improving patient response and minimizing unnecessary exposure of patients to treatment toxicities. This article reviews the significance of gene expression analysis in the understanding of tumor biology and RCC treatment.

Carcinoma, Renal Cell↗
PubMed2005

Prevention of bladder cancer: a review.

INTRODUCTION: Bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies. In addition to reviewing the epidemiology of transitional cell carcinoma (TCC), we review the current status and the future directions of bladder cancer prevention. MATERIALS AND METHODS: A literature review of peer-reviewed articles which address bladder cancer prevention was performed. RESULTS: Pre-clinical and limited clinical data suggest that bladder cancer is responsive to efforts to delay or prevent its development in at-risk patients, and in reducing the risk of recurrence in patients with established disease. Many epidemiologic studies, however, investigating natural products, such as vitamins and herbal compounds, lack conclusive evidence of their chemopreventive effects. CONCLUSIONS: While many agents hold promise in the prevention of bladder cancer, none currently can be recommended as proven chemoprevention strategies. Improving the accuracy of patient risk assessment and identification of surrogate endpoint biomarkers are crucial to the testing of these strategies. Efficient study design will ensure rapid and substantial advances in the chemoprevention of bladder cancer.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Gene signatures of progression and metastasis in renal cell cancer.

PURPOSE: To address the progression, metastasis, and clinical heterogeneity of renal cell cancer (RCC). EXPERIMENTAL DESIGN: Transcriptional profiling with oligonucleotide microarrays (22,283 genes) was done on 49 RCC tumors, 20 non-RCC renal tumors, and 23 normal kidney samples. Samples were clustered based on gene expression profiles and specific gene sets for each renal tumor type were identified. Gene expression was correlated to disease progression and a metastasis gene signature was derived. RESULTS: Gene signatures were identified for each tumor type with 100% accuracy. Differentially expressed genes during early tumor formation and tumor progression to metastatic RCC were found. Subsets of these genes code for secreted proteins and membrane receptors and are both potential therapeutic or diagnostic targets. A gene pattern ("metastatic signature") derived from primary tumor was very accurate in classifying tumors with and without metastases at the time of surgery. A previously described "global" metastatic signature derived by another group from various non-RCC tumors was validated in RCC. CONCLUSION: Unlike previous studies, we describe highly accurate and externally validated gene signatures for RCC subtypes and other renal tumors. Interestingly, the gene expression of primary tumors provides us information about the metastatic status in the respective patients and has the potential, if prospectively validated, to enrich the armamentarium of diagnostic tests in RCC. We validated in RCC, for the first time, a previously described metastatic signature and further showed the feasibility of applying a gene signature across different microarray platforms. Transcriptional profiling allows a better appreciation of the molecular and clinical heterogeneity in RCC.

Adult↗
PubMed2005

Clinicopathologic and molecular correlations of necrosis in the primary tumor of patients with renal cell carcinoma.

BACKGROUND: The presence of histologic necrosis in the primary tumor of patients with renal cell carcinoma (RCC) has been suggested to be an important predictor of survival. The authors investigated the relation of tumor necrosis to other clinicopathologic factors known to be important prognostic indicators for patients with RCC. METHODS: The records of 311 patients undergoing treatment for RCC were evaluated for basic clinicopathologic information including TNM classification, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease recurrence, and survival. The presence and extent of histologic necrosis of the primary tumors was recorded and correlated with clinicopathologic factors, carbonic anhydrase IX and Ki-67 expression, disease recurrence, and survival. RESULTS: The presence of necrosis in the primary tumor of patients with RCC compared with patients with RCC without necrosis was associated with higher T classification (P < 0.0001), the presence of lymph node disease (P = 0.009), the presence of metastases (P < 0.0001), higher grade (P < 0.0001), greater mean tumor size (P < 0.0001), an ECOG PS score > or = 1 (P = 0.007), higher University of California-Los Angeles Integrated Staging System (UISS) category (P < 0.0001), and higher Ki-67 expression (P < 0.0001). The extent of necrosis in the primary tumor was associated with the presence of lymph node disease (P = 0.009) and the presence of metastases (P < 0.0001), and correlated with higher T classification (sigma = 0.31, P < 0.0001), poorer ECOG PS (sigma = 0.18, P = 0.002), higher grade (sigma = 0.33, P < 0.0001), greater tumor size (sigma = 0.40, P < 0.0001), higher UISS category (sigma = 0.37, P < 0.0001), and higher Ki-67 staining (sigma = 0.32, P < 0.0001). Patients with the presence of necrosis in the primary tumor demonstrated a lower 5-year disease-specific survival compared with patients without necrosis in the primary tumor (36% vs. 75%; P < 0.0001). Multivariate analysis demonstrated that T classification (P < 0.0001), distant metastases (P < 0.0001), and ECOG PS (P < 0.0001) were independent predictors of DSS, whereas the presence of necrosis was not (P = 0.1100). Substratification into localized and metastatic disease demonstrated that the presence of necrosis was an independent predictor of survival in patients with localized (P = 0.025), but not metastatic (P = 0.44), disease. The extent of necrosis was not an independent predictor of survival (P > 0.05). Patients with the presence of necrosis in the primary tumor had a lower 5-year disease recurrence-free rate compared with patients without the presence of necrosis (62% vs. 92%, P < 0.0001). CONCLUSIONS: The presence of necrosis in the primary tumor was associated with adverse prognostic factors such as high T classification, presence of lymph node disease and metastases, high grade, large tumor size, and poor ECOG PS. The extent of necrosis was found to be associated with the presence of lymph node disease and metastases and correlated with higher T classification, higher grade, greater tumor size, poorer ECOG PS, and higher UISS category. The presence of this histologic variant was an independent predictor of poor survival in patients with localized, but not metastatic, disease. In addition, Ki-67 expression served as a valuable surrogate marker for the presence of histologic tumor necrosis.

Adenocarcinoma, Clear Cell↗
PubMed2005

Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience.

PURPOSE: To analyze to what extent histologic subtype is of prognostic importance in renal cell carcinoma based on a large, international, multicenter experience. PATIENTS AND METHODS: Four thousand sixty-three patients from eight international centers were included in this retrospective study. Histologic subtype (1997 International Union Against Cancer [UICC] criteria of tumor response), age, sex, TNM stage, Fuhrman grade, tumor size, Eastern Cooperative Oncology Goup performance status (ECOG PS), and overall survival were determined in all cases. The prognostic values of clear cell, papillary, and chromophobe histologic features were assessed by uni- and multivariate analysis using the Kaplan-Meier method and Cox model, respectively. RESULTS: Clear cell, papillary, and chromophobe carcinomas accounted for 3,564 (87.7%), 396 (9.7%) and 103 (2.5%) cases, respectively. In univariate analysis, a trend toward a better survival was observed when clear cell, papillary, and chromophobe histologies were considered prognostic categories (log-rank P = .0007). However, in multivariate analysis, TNM stage, Fuhrman grade and ECOG PS, but not histology, were retained as independent prognostic variables (P < .001). CONCLUSION: The stratification in three main renal cell carcinoma histologic subtypes as defined by the 1997 UICC-American Joint Committee on Cancer consensus should not be considered a major prognostic variable comparable to TNM stage, Fuhrman grade and ECOG PS.

Adolescent↗
PubMed2005

Dominant B cell epitope from NY-ESO-1 recognized by sera from a wide spectrum of cancer patients: implications as a potential biomarker.

Monitoring the spontaneous antibody (Ab) response against a panel of relevant tumor-associated antigens (TAA) in cancer patients may provide useful information regarding the clinical status of cancer. However, current Ab detection approaches require the purification of recombinant proteins, which is often difficult to achieve. In order to bypass the purification of recombinant proteins, we identified a dominant B-cell epitope from a shared tumor antigen NY-ESO-1. A synthetic peptide of the epitope, ESO:1-40, was as sensitive as the recombinant protein for detecting Ab against NY-ESO-1 in most patients. NY-ESO-1 specific Ab present in the sera of patients with melanoma, prostate cancer, nonsmall cell lung cancer, esophageal cancer, gastric cancer and hepatocellular carcinoma reacted with the dominant peptide at a similar frequency as the recombinant protein. To our knowledge, ESO:1-40 is the first peptide epitope recognized by sera from a wide spectrum of cancer patients but not healthy donors. This simple and straightforward approach may allow the investigation of the clinical significance of spontaneous Ab responses against multiple TAA and their correlation with the clinical course of malignant diseases in the future.

Amino Acid Sequence↗
PubMed2005

G250: a carbonic anhydrase IX monoclonal antibody.

G250 or carbonic anhydrase IX (CA IX) is a membrane-associated carbonic anhydrase (CA) thought to play a role in the regulation of cell proliferation in response to hypoxic conditions and may be involved in oncogenesis and tumor progression. G250 refers to a monoclonal antibody (mAb) that was raised by immunization of mice with human renal cell carcinoma (RCC) homogenates. The RCC-associated transmembrane protein designated G250 has since proven to be identical to tumor-associated protein MN or CA IX. Previous studies using a mAb against CA IX have shown that CA IX is induced constitutively in certain tumor types, but is absent in most normal tissues with the exception of epithelial cells of the gastric mucosa. Furthermore, previous immunobiochemical studies of malignant and benign renal tissues revealed that CA IX was also highly expressed in RCC. Studies on tumor-bearing kidneys demonstrate selective uptake of mAb CA IX in antigen-positive cells versus antigen-negative cells. Furthermore, extraordinarily high uptake and the requirement of a low protein dose to obtain tumor saturation with respect to tumor targeting occur with mAb CA IX. These studies formed the basis of numerous clinical trials aimed at mAb-guided therapy in patients with metastatic RCC.

Animals↗
PubMed2005

p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized renal cell carcinoma.

PURPOSE: We determined which clinical and molecular variables can predict cancer recurrence in patients following surgical management for localized renal cell carcinoma (RCC). MATERIALS AND METHODS: From a custom kidney cancer tissue microarray containing tumors specimens from 350 patients 193 undergoing nephrectomy for localized RCC at our institution between 1989 and 2000 were identified. The array was then analyzed by immunohistochemistry for certain molecular markers, namely CA9, CA12, Ki67, gelsolin, p53, EpCAM, pTEN and vimentin. The medical records of these patients were then reviewed for age, sex, TNM stage, tumor size, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status, recurrence status and, when applicable, time to recurrence. Cox regression analyses were done to determine clinical and molecular predictors of time to tumor recurrence. RESULTS: Of the patients 15% demonstrated evidence of tumor recurrence following nephrectomy (29 of 193). Univariate Cox regression demonstrated that tumor size, T stage, grade, ECOG performance status, Ki67, EpCAM and p53 were significantly associated with recurrence (p <0.05). A multivariate Cox regression model showed that T stage (p = 0.018), ECOG (p = 0.004) and p53 (p = 0.003) were the 3 most significant predictors. p53 expression correlated significantly with nuclear grade (Pearson correlation 0.22, p = 0.023) but not with any other clinical factors. Patients with localized tumors demonstrating mean p53 staining values above and below 20% of cells had recurrence rates of 37.7% and 14.4%, respectively (RR = 3.28, p = 0.018). CONCLUSIONS: p53 is a significant molecular predictor of tumor recurrence, as identified in patients undergoing treatment for localized RCC.

Adult↗
PubMed2005

Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system.

PURPOSE: We created an evidence based postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma (RCC) based on a risk group stratification system. MATERIALS AND METHODS: 559 patients undergoing surgery for localized and ocally advanced RCC were stratified into low risk (LR), intermediate risk (IR) and high risk (HR) groups based on the University of California-Los Angeles Integrated Staging System (UISS). Tumor recurrences were identified and categorized according to time and location. RESULTS: Patients with localized disease had a lower 5-year recurrence rate than patients with locally advanced (nodal) disease (27.6% vs 64%, p <0.0001). Patients in the LR, IR, and HR groups following nephrectomy demonstrated 5-year recurrence-free rates of 90.4%, 61.8%, and 41.9%, respectively (p <0.0001), and median times to recurrence of 28.9, 17.8 and 9.5 months, respectively (p <0.0001). Chest and abdomen recurrences comprised of 75% and 37.5%, 77.4% and 58.1%, and 45.2% and 67.7% of recurrences in the LR, IR and HR groups, respectively. In patients with node positive disease, chest and abdomen comprised of 58.8% and 76.5% of recurrences, respectively. Patients undergoing partial nephrectomy did not demonstrate a greater rate of local or distant recurrence compared with patients undergoing radical nephrectomy. CONCLUSIONS: Significant differences in incidence and time to recurrence following surgical resection for RCC mandates unique surveillance protocols for patients in each of the UISS risk groups. LR group patients should be followed for at least 5 years, whereas IR and HR group patients require longer surveillance. HR group patients require more stringent abdominal surveillance, whereas LR group patients should emphasize the chest. Patients with nodal disease also require stringent followup. Patients undergoing partial nephrectomy for localized disease can be followed according to the same UISS risk group based protocol.

Adult↗
PubMed2005

Carbonic anhydrase IX and the future of molecular markers in renal cell carcinoma.

The use of carbonic anhydrase IX as a promising molecular marker in RCC is described by authors from Los Angeles, who discuss the promise that molecular markers hold to improve diagnosis, staging, treatment, surveillance and survival of patients with RCC. There is a whole range of new treatments being introduced in the management of metastatic renal cancer. The use of VEGF-targeted therapy has particular importance, especially as it has a strong genetically linked rationale for its potential success in this area. Authors from the USA show that substantial clinical activity has been reported in initial clinical trials. In prostate cancer, drugs targeting microtubules, such as taxanes, have already been introduced clinically, and their success has received widespread attention. A new group of drugs, the epothilones, have similar but not identical binding properties to microtubules, and authors from the USA describe how they have shown activity in hormone-refractory prostate cancer, and are moving to phase III testing.

Antigens, Neoplasm↗
PubMed2004

Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.

PURPOSE: To evaluate ability of the University of California Los Angeles Integrated Staging System (UISS) to stratify patients with localized and metastatic renal cell carcinoma (RCC) into risk groups in an international multicenter study. PATIENTS AND METHODS: 4,202 patients from eight international academic centers were classified according to the UISS, which combines TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status. Distribution of the UISS categories was assessed in the overall population and in each center. RESULTS: The UISS stratified both localized and metastatic RCC into three different risk groups (P <.001). For localized RCC, the 5-year survival rates were 92%, 67%, and 44% for low-, intermediate-, and high-risk groups, respectively. A trend toward a higher risk of death was observed in all centers for increasing UISS risk category. For metastatic RCC, the 3-year survival rates were 37%, 23%, and 12% for low-, intermediate-, and high-risk groups, respectively; in 6 of 8 centers, a trend toward a higher risk of death was observed for increasing UISS risk category. A greater variability in survival rates among centers was observed for high-risk patients. CONCLUSION: This study defines the general applicability of the UISS for predicting survival in patients with RCC. The UISS is an accurate predictor of survival for patients with localized RCC applicable to external databases. Although the UISS may be useful for patients with metastatic RCC, it may be less accurate in this subset of patients due to the heterogeneity of patients and treatments.

Adult↗
PubMed2004

Epithelial cell adhesion molecule (KSA) expression: pathobiology and its role as an independent predictor of survival in renal cell carcinoma.

PURPOSE: Epithelial cell adhesion molecule (EpCAM) is a widely expressed adhesion molecule in epithelial cancers. The purpose of this study is to determine the protein expression patterns of EpCAM in renal cell carcinoma (RCC) using tissue arrays linked to a clinicopathological database to evaluate both its predictive power in patient stratification and its suitability as a potential target for immunotherapeutic treatment strategies. EXPERIMENTAL DESIGN: The University of California, Los Angeles kidney cancer tissue microarray contains specimens from 417 patients treated with nephrectomy. EpCAM protein expression in tumors and matched morphologically normal renal tissues was evaluated using anti-EpCAM immunohistochemistry. The resultant expression reactivity was correlated with clinicopathological variables. RESULTS: EpCAM is consistently expressed in the distal nephron on normal renal epithelium. Clear cell RCCs show minimal and infrequent EpCAM expression, whereas chromophobe and collecting duct RCCs both demonstrate intense and frequent expression. Of 318 clear cell carcinomas used in the analysis, 10% were EpCAM positive in > or = 50% of cells, and 8% of patients would be considered candidates for EpCAM-based therapy, based on high expression [> or = moderate intensity and frequent (> or = 50%) expression] and the need for systemic treatment. EpCAM expression was an independent prognostic factor for improved disease-specific survival, with a multivariate hazard ratio of 0.63 (P = 0.017; 95% confidence interval, 0.43-0.92). CONCLUSIONS: EpCAM is a novel prognostic molecular marker in RCC patients, and its positive expression is an independent predictor associated with improved survival. However, high expression in morphologically normal renal tissues and minimal or absent expression in clear cell carcinomas will likely limit the utility of this epithelial marker in targeted treatments of this most common RCC type.

Adenocarcinoma, Clear Cell↗