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Biomedical subjects

K H Link

Publications and source records attributed to K H Link.

At least 19 recordsLinked to original sources

Colon cancer: survival after curative surgery.

Several new aspects have evolved during the past years concerning factors that influence survival in surgically and medically treated colon cancer patients that are relevant to the treating team for the treatment strategy and patient's choice. The 5-year-survival rates dependent on UICC stages/substages (I: 68%-100%, II: 58%-90%, III: 33%-76%, IV: <5%-9%) show remarkable variations between published reports, surgical hospital units, individual surgeons, and continents (USA vs Europe). Those variations may be due to surgical techniques, training status, hospital and individual case volume, and, also, referral patterns and statistical evaluation methods. Survival times and cure rates are significantly improved by adjuvant chemotherapy in UICC III and in substages of UICC II (e.g. UICC II B) by 5%-12%, when compared with surgical controls. In three recently published trials standard adjuvant chemotherapy was further improved by increased survival rates, e.g. from 59% to 71% in stage III and IIB patients. Molecular and genetic factors, such as thymidylate synthase (TS), microsatellite instability (MSI) or loss of chromosome 18q/"DCC" might have an independent impact on prognosis in the spontaneous course, and TS could help to better select patients for adjuvant chemotherapy.

Colectomy↗

[Emergent surgery for body packing - what happens to the drugs?].

Body packing is a well recognized method of drug trafficking by smuggling drug containers in the gastrointestinal tract. Medical professionals might get involved with body packers after presentation by law enforcement or in case of medical emergencies such as drug overdose or mechanical intestinal obstruction due to the containers within the gastrointestinal tract. Besides the medical aspects in treating these patients, physicians must be aware of all the different legal specifics in dealing with body packers. In case of medical emergencies, drug traffickers have the legal status of regular patients with respect to professional medical discretion. The question remains of what physicians should do with the drugs after surgical removal? Even though the body packer remains the legal owner of the drugs, physicians may not return the drugs, since that constitutes the criminal offence of dealing in narcotics. Returning the drugs to law enforcement authorities is also prohibited because of professional medical discretion. The only way out of this predicament is for physicians to destroy the drugs under the observation of witnesses.

Abdomen, Acute↗

Intraperitoneal chemotherapy with mitoxantrone in malignant ascites.

A retrospective analysis of intraperitoneal mitoxantrone instillation therapy for malignant ascites in advanced breast and gynecologic pelvic cancers was performed to confirm the efficacy and safety of this therapy. Several smaller phase II trials had suggested good palliative effects. In 143 patients (37 breast cancer and 106 gynecologic cancers), 257 instillations were registered. Response in breast cancer was induced in 49% and in 63% with gynecologic cancer. Severe or life-threatening clinical or laboratory side effects related to intraperitoneal mitoxantrone occurred in 2.7% (clinical) or 1.9% (laboratory) of the 257 instillations. Induction of adverse side effect was dose dependent. Intraperitoneal chemotherapy with mitoxantrone for treatment of malignant ascites in breast cancer and gynecologic malignancy is effective and well tolerated. For this treatment 30 mg mitoxantrone in > or = 1000 mL carrier solution (e.g., saline) is recommended. A minimal concentration of at least 10 micrograms/mL should be achieved.

Adult↗

Conversion of locally inoperable primary rectal cancer with multiple liver metastases to an option for cure after local down-staging and hepatic arterial infusion chemotherapy.

AIMS: This case report presents a patient with local unresectable primary rectal cancer and multiple synchronous liver metastases. METHODS: The treatment consisted of primary tumor resection after down-staging by local irradiation followed by hepatic arterial infusion chemotherapy. RESULTS: The patient is now without any signs of tumor growth 44 months after beginning of treatment.

Antineoplastic Combined Chemotherapy Protocols↗

[Interferon-alpha in adjuvant treatment of colorectal carcinoma].

UNLABELLED: Based on preclinical and clinical studies, in this German three-arm adjuvant multicenter trial the FOGT (Forschungsgruppe Onkologie Gastrointestinale Tumoren) studied whether one of the 5-FU modulations with either folinic acid(FA) or Interferon alpha-2a (IFNa) is superior to the recommended standard of adjuvant treatment in R0-resected colon cancer, 5-fluorouracil (5-FU) plus levamisole (LEV) for 12 months, in terms of overall survival rates. PATIENTS/METHODS: From 7/92 to 10/99 813 patients with resected colon cancer stage II (only T4N0M0, 63 pts.) and stage III (750 pts.) were randomized into three treatment groups and stratified according to N-stage and participating centers (64 hospitals). The patients received a postoperative loading course with 5-FU [450 mg/m2 d1-5 (arms A and C)] or 5-FU [450 mg/m2 plus folinic acid (Rescuvolin, medac, Hamburg, Germany), 200 mg/m2 d1-5 (arm B)]. After completion of the first chemotherapy cycle LEV was administered orally at 150 mg/d d1-3, every 2 weeks. After a 4-week chemotherapy-free interval the treatment was continued weekly for up to 52 weeks. The standard group, arm A (279 pts.) was treated with 5-FU i.v. (450 mg/m2 at d 1, q 1 w) plus LEV. 5-FU plus LEV was modulated in arm B (283 pts.) with FA (200 mg/m2 d1, q 1 w), and in arm C (251 pts.) with IFNa at 6 million units 3x/week, q 1 w. Chemotherapy doses were adjusted to toxicity if toxic events > WHO 2 occurred. The patients were followed-up to determine relapse rates and--patterns and survival. Survival rates were calculated according to Kaplan-Meier, and treatment costs and immune effects were analysed. RESULTS: Toxic event(s) > WHO2, mainly leukopenia, diarrhea and nausea, occurred in 113 pts. (14%), in arms A (8%), B (13%) and C (32%). Discontinuance rates were 28% (all), 29% (A), 21% (B), 34% (C), but 80% of patients received > or = 6 months treatment. Overall relapse rates were 27% (all), 30% (A), 24% (B) and 28% (C). Tumors relapsed either locally (2% each) or distant (A: 22%, B: 20%, C: 22%). 4-year overall survival rates in arms A, B and C were 66%, 77%, 66%, respectively. The 4-year survival rate in arm B was significantly superior to arms A and C (p < 0.02, log-rank). There were no signs of a superior immune function in either treatment arm (skin test, proliferation, cytotoxicity, flow cytometry). Treatment costs per patient were 2,500 [symbol: see text](arm A), 3,500 [symbol: see text](arm B) or 10,850 [symbol: see text](arm C), respectively. CONCLUSION: Adjuvant therapy with 5-FU plus FA plus LEV for 12 months is superior to the recommended standard (5-FU + LEV, 12 m). IFNa-modulation of 5-FU (plus LEV) adds toxicity and high treatment costs without therapeutic benefit.

Antineoplastic Combined Chemotherapy Protocols↗

Regional chemotherapy of nonresectable colorectal liver metastases with mitoxantrone, 5-fluorouracil, folinic acid, and mitomycin C may prolong survival.

BACKGROUND: Regional chemotherapy of isolated, nonresectable colorectal liver metastases (CRLMs) by hepatic artery infusion (HAI) has the advantages of high response rates and the possibility of downstaging and resection of CRLMs. 5-Fluorodeoxyuridine (5-FUDR) has been the drug studied in most Phase II and III trials. The meta-analysis of the Phase III trials comparing HAI with systemic or supportive therapy confirmed an advantage for response and even survival for HAI. Hepatic artery infusion with 5-FUDR, however, is hepatotoxic, inducing sclerosing cholangitis (SC). The authors have introduced 5-fluorouracil (5-FU) with folinic acid for HAI and found equal effectivity but no SC when compared with HAI with 5-FUDR. Now, they report a new combination chemotherapy protocol based on HAI with 5-FU with FA and on in vitro Phase II studies suggesting mitoxantrone and mitomycin C as active drugs for HAI in CRLM. PATIENTS AND METHODS Between February 1993 and August 2000, 63 patients with CRLM were treated with HAI using mitoxantrone, 5-FU with FA, and mitomycin C (MFFM) via port catheters with a protocol planing up to 11 cycles of treatment. Toxicity and response were analyzed according to World Health Organization (WHO) criteria, and survival was analyzed according to Kaplan-Meier. All patients were treated with more than two HAI cycles. RESULTS: The objective response rate (complete remission and partial remission) was 54% and primary intrahepatic progression (progressive disease) occurred in 4.8%, whereas in 41.3% of the patients the intrahepatic disease was evaluated as no change. Median survival times from the first diagnosis of CRLM or start of HAI were 25.7 months and 23.7 months, respectively, and 7 patients lived longer than 40 months. Grade 3 toxicity according to WHO occurred in 34.9%, and Grade 4 occurred in 3.2%. No toxic death or SC occurred. CONCLUSIONS: Our new HAI protocol with MFFM seems to be superior to HAI with 5-FUDR, 5-FU with FA, and systemic chemotherapy with 5-FU and FA at acceptable toxicity. Currently, HAI with MFFM is compared with systemic chemotherapy using 5-FU and FA intravenously in a randomized Phase III trial.

Adult↗

Surgery, radio- and chemotherapy for multimodal treatment of rectal cancer.

The possibilities and results of multimodal treatment in rectal cancer were reviewed with respect to the results of surgical treatment only. Based on the results of 4 studies, reducing local relapse rates and increasing long term survival rates significantly, postoperative radiochemotherapy (RCT) + chemotherapy (CT) should remain the recommended standard for R0 resected UICC II and III rectal cancers. The addition of RT to adjuvant CT reduces local relapses without significant impact on survival (NSABP R-02). Vice versa, the addition of CT to RT or an improved CT in the RCT-concept prolongs survival. Preoperative neoadjuvant radiotherapy (RT) reduced local relapse rates in 9 studies, and extended survival in one study that evaluated all eligible patients. Preoperative RT reduced local relapse rates in addition to total mesorectal excision (TME) but did not extend survival. The preoperative RCT + CT downstages resectable and nonresectable tumors and induces a higher sphincter preservation rate. Phase III data justifying its routine use in all UICC II + III stages are not yet available. This treatment may be routinely applied in nonresectable primary tumors or local relapses. Preoperative RCT (or RT) may evolve as standard, if the patient selection is improved and postoperative morbidity and long term toxicity reduced. Intraoperative RT could be added to this concept or be used together with preoperative/postoperative RT at the same indications. Postoperative adjuvant RT reduced local relapses significantly in a single trial, and no impact on survival time is reported. Since postoperative RT is inferior to preoperative RT, this treatment cannot be recommended, if RT is chosen as a single treatment modality in adjunction to surgery. The results of local tumor excisions may be improved with pre- or postoperative RCT + CT. In the future, multimodal treatment of rectal cancer might be more effective, if individualized according to prognostic factors.

Chemotherapy, Adjuvant↗

Thymidylate synthase quantitation and in vitro chemosensitivity testing predicts responses and survival of patients with isolated nonresectable liver tumors receiving hepatic arterial infusion chemotherapy.

BACKGROUND: Patients with isolated, nonresectable liver tumors may receive regional hepatic arterial infusion (HAI) chemotherapy with response rates of about 50%. The objective of this study was to investigate the value of thymidylate synthase (TS) determination in combination with in vitro chemosensitivity testing to predict the responses and survival of patients receiving HAI. METHODS: TS mRNA expression was quantitated using a reverse transcription-polymerase chain reaction technique with beta-actin as the internal standard. In vitro chemosensitivity testing was performed with tumor cell suspensions using the human tumor colony-forming assay (HTCA). RESULTS: An analysis of the test combination in 24 consecutive patients revealed that 77% (10 of 13) of the sensitive and 9% (1 of 11) of the resistant patients had complete or partial clinical responses. Sensitive patients were 8.5-fold more likely to respond (P = 0.0036) and displayed with 32 months (range, 5-75 months) a longer median survival than resistant patients with 17 months (range, 3-28 months, P = 0.003). Analysis of the Kaplan-Meier curves revealed that sensitive patients had a higher overall survival probability, as determined by the log rank test (P = 0.044). CONCLUSIONS: These results suggest that the clinical outcomes of patients receiving HAI therapy may be predictable with TS quantitation and HTCA. It is possible, therefore, that this combination may be used in the future to select patients with liver tumors who will benefit from HAI before the start of regional chemotherapy.

Adult↗

Follow-up in colorectal cancer: cost-effectiveness analysis of established and novel concepts.

BACKGROUND: Follow-up programs in colorectal cancer have been under question recently due to their low efficacy. Some meta-analyses found a survival benefit and four randomized studies suggested the opposite. Therefore, this paper analyzes existing and proposed follow-up programs for costs and efficacy. METHODS: One thousand and fifty-four colorectal cancer patients intensively followed-up in Ulm (endoscopy, chest radiography, abdominal ultrasound, computed tomography (CT) pelvis) were prospectively evaluated for recurrence, salvage surgery rate, survival and costs. Costs were compared among existing and proposed international follow-up programs retrieved by a MedLine search. RESULTS: A total of 350/1,054 colorectal cancer patients (33.2%) relapsed asymptomatically, as detected by follow-up. 56/350 (local 47%, distant 53%) recurrences were resectable (16%), 21/350 patients survived (6%). The efficacy of follow-up was 21/1,054 patients (2%). Costs were, per patient, 2,220 euros (colon) or 4,851 euros (rectum). Costs in five randomized studies varied between 616 euros for minimal and 5,049 euros for intensive follow-up. Four proposed follow-up concepts include risk-adaption, which claim to reduce costs by 50-60% and range between 889 (colorectal) and 5,910 (high-risk, rectum) euros. The recommended German follow-up guideline costs 610 euros (low-risk, colorectal), 1,120 euros (high-risk, colon) or 2,252 euros (high-risk, rectum). CONCLUSION: Follow-up concepts for colorectal cancer should aim at the identification of curable patients with recurrence. Evidence-based concepts, including life quality tests, remain to be defined, but currently abdominal ultrasound, endoscopy and carcino-embryonic antigen (CEA) determination at 6-month intervals for 2 years and annual intervals for 3 years seem to identify this patient sub-group.

Carcinoembryonic Antigen↗

Pre-clinical evaluation of the activity of gemcitabine as a basis for regional chemotherapy of pancreatic and colorectal cancer.

AIMS: To estimate the potential activity of gemcitabine for hepatic arterial infusion (HAI) chemotherapy in pancreatic and colorectal cancer. METHODS: The anti-proliferative effects of gemcitabine were determined in MIA PaCa-2 and PMH2/89 pancreatic and HT29 and NMG64/84 colon cancer cell lines and in fresh tumours from patients with liver metastases of colon, rectal and pancreatic cancer in vitro using the human tumour colony forming assay. RESULTS: Gemcitabine showed concentration and time-dependent cytotoxic effects in all tested cell lines. The IC(50)of gemcitabine in MIA PaCa-2, PMH2/89, HT29 and NMG64/84 cells at 2 h exposure time were >100, 18, 100 and 2.5 microg/ml, respectively, at 4 h 15, 1.2, 45 and 0.5 microg/ml, respectively, and at 24 h 0.2, 0.1, 1.8 and 0.1 microg/ml, respectively. All tumours displayed concentration dependent inhibition of colony formation after exposure to gemcitabine for 2 h. The IC(50)values of gemcitabine in six of the 10 metastases were </=100 microg/ml. CONCLUSIONS: Based on our results and theoretical considerations regarding hepatic arterial infusion therapy gemcitabine seems to be suitable for HAI therapy phase II studies. Moreover, patients with colorectal or pancreatic tumours that demonstrated in vivo sensitivity may benefit from regional chemotherapy with gemcitabine.

Aged↗

Theoretical considerations and in vitro concentration response studies with two human colorectal carcinoma cell lines. The rational experimental base for clinical studies in regional chemotherapy.

The theoretical advantage of regional vs. systemic chemotherapy was calculated, based on pharmacokinetic considerations. The relevance of exposure time and high local concentrations of chemotherapeutic drugs for regional chemotherapy was elucidated in time dependent concentration response curves with two human cell lines. The theoretical pharmacological advantage of regional vs. systemic chemotherapy was defined by the formula Rd = (AUCi. a. 1 + AUCi. a. 2)/(AUCi. v.) and in hepatic artery infusion is for adriamycin (ADM) 5.8-.6, cis-platinum (CDDP) 8, epirubicine (EPI) 6.3, 5-fluorouracil (5-FU) 22-58, mitomycin C (MMC) 4.6, mitoxantrone (NOV) 6.3. All drugs but 5-FUDR exerted concentration response behaviour in the cell line-experiments. In the cell lines cytotoxicity depended on exposure time so that concentration chi time products at (IC50), (c chi t (IC50)), were calculated to determine an optimal in vitro exposure time. Based on these results and clinical considerations, optimal clinical exposure times could be defined for regional chemotherapy. The results may be of high relevance for e.g. hepatic artery infusion at the lower and chemoembolization or intraperitoneal instillation at the higher test concentration, respectively.

Antibiotics, Antineoplastic↗

p53 in relation to therapeutic outcome of locoregional chemotherapy in pancreatic cancer.

Since celiac artery infusion (CAI) led to an increase in survival in palliative chemotherapy in pancreatic cancer, we treated 26 patients with adjuvant CAI following resection for advanced pancreatic cancer. Catheters were placed angiographically into the celiac artery and remained there for five consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-fluorouracil (5-FU), folinic acid, and cis-platinum. This treatment was repeated five times in monthly intervals. Median survival times in patients who received CAI are 21 months for all patients, whereas in patients who did not receive adjuvant treatment median survival is 10.5 months. In all patients p53 expression of the carcinomas was determined by immunohistochemistry. In 11/26 patients a p53 overexpression was observed. Although p53 overexpression turned out to be associated with poor prognosis in the patients who underwent adjuvant regional cancer treatment, p53 is not a sufficient prognostic parameter in pancreatic carcinoma, since p53 overexpression was more frequent in undifferentiated tumors and in palliative resected tumors.

Adult↗

[Effect of therapy on survival of patients with pancreatic carcinoma].

PURPOSE: To identify the impact of treatment factors on overall survival in patients with pancreatic carcinoma. PATIENTS AND METHODS: We performed a follow-up study on 38 patients with adenocarcinoma of the pancreas treated from 1984 to 1998. 18/38 patients were resected. Irradiated volume included the primary tumor (or tumor bed) and regional lymph nodes. Thirty-seven patients received in addition chemotherapy consisting of mitoxantrone, 5-fluorouracil and cis-platin, either i.v. (14/38) or i.a. (23/38). The influence of treatment related factors on the overall survival was tested. Biologically effective dose was calculated by the linear-quadratic model (alpha/beta = 25 Gy) and by losing 0.85 Gy per day starting accelerated repopulation at day 28. RESULTS: Treatment factors influencing overall survival were resection (p = 0.02), overall treatment time (p = 0.03) and biologically effective dose (p < 0.002). Total dose and kind of chemotherapy had no significant influence. Treatment volume had a negative correlation (r = -0.5, p = 0.06) with overall survival, without any correlation between tumor size, tumor stage, and treatment volume. In multivariate analysis only biologically effective dose remained significant (p = 0.02). CONCLUSIONS: Among with surgery, biologically effective dose strongly influences overall survival in patients treated for pancreatic carcinoma. Treatment volume should be kept as small as possible and all efforts should be made to avoid treatment splits in radiation therapy.

Adenocarcinoma↗

Intraarterial adjuvant chemotherapy after pancreaticoduodenectomy for pancreatic cancer: significant reduction in occurrence of liver metastasis.

The clinical benefit of adjuvant chemotherapy in pancreatic cancer patients is still questionable. Phase II studies using radiochemotherapy based on 5-fluorouracil (5-FU) provided evidence of an increase in median survival times. Because palliative chemotherapy by celiac artery infusion (CAI) led to an increase in survival in pancreatic cancer, we treated 24 patients with adjuvant CAI following resection of the head of the pancreas for pancreatic cancer (21 patients with Union Internationale contre le Cancer (UICC) stage III, 2 with UICC stage II, 1 with UICC stage I). Catheters were placed angiographically into the celiac artery and remained there for 5 consecutive days. One cycle of chemotherapy consisted of mitoxantrone, 5-FU, folinic acid, and cisplatinum. This treatment was repeated five times at monthly intervals. CAI was well tolerated, and World Health Organization (WHO) grade III toxicities were observed in 8%; WHO grade IV was seen in none of the treatment cycles. Furthermore, we observed pain reduction in nearly all patients under CAI. Median survival times in patients who received CAI were 23 months for all patients, whereas in patients who did not receive adjuvant treatment the median survival was 10.5 months. With Kaplan-Meier regression analysis of the patients who were curatively resected (R0 resection) and received CAI, the overall 4-year survival was 54%, whereas in patients without CAI the 4-year survival was 9.5%. The occurrence of liver metastases in the CAI group went down to 17%. These results demonstrate that CAI is well tolerated, reduces the risk of liver metastasis, and increases the survival time of pancreatic cancer patients.

Adult↗

Regional chemotherapy of non-resectable liver metastases from colorectal cancer - literature and institutional review.

BACKGROUND: Cure is possible by resecting colorectal isolated liver metastases. In non-resectable isolated colorectal liver metastases (CRLM), regional chemotherapy has been advocated to optimize the disease control in the liver in order to improve the results of the alternative, systemic chemotherapy. The drugs are delivered by means of hepatic artery infusion (HAI) via ports or pumps; pharmacological modifications of the hepatic arterial blood-flow-like HAI with starch microspheres or stop-flow and perfusion techniques were applied to improve HAI. METHODS: We reviewed the literature and report our progress, up to May 1999, in analyzing the validity of HAI for CRLM therapy. RESULTS: In the majority of phase-II and -III trials, the response rates to HAI were significantly higher than those from systemic chemotherapy, and local disease control could be achieved even when HAI was used second line to systemic chemotherapy. The meta-analysis of randomized trials comparing HAI with either systemic chemotherapy (five trials) or, optionally, either 5-fluorouracil (FU) or symptomatic treatment (two trials) showed a significant advantage of HAI in response (41% vs 14%, P<10(-10)) and median survival time (15 months vs 11 months, P<0.0009). The active anabolite of 5-FU, 5-fluordeoxyuridine (5-FUDR), the drug of choice for HAI in those trials, may cause severe hepatotoxicity. To avoid this toxicity, we developed a HAI protocol using mitoxantrone, 5-FU plus folinic acid (FA) and mitomycin C (MFFM). The response rates of HAI with 5-FU plus FA or MFFM were 45% and 66%, the interim median survival times 19.8 months and 27.4 months. 5-Year survivors were observed in all our protocols. Since no severe hepatotoxicity occurred, 9 of 74 patients were resected after response to HAI with 5-FU plus FA or MFFM, without surgical mortality and with survival times from 2+ months to 58+ months. CONCLUSION: The high response rates, the long survival times, the possibility of achieving 5-year-survival either by HAI alone or by resection after down staging with HAI all sum up to the evidence that HAI could be the primary choice of treatment for CRLM. Phase-III trials are conducted to compare the protocols with optimal regional versus systemic chemotherapy.

Adenocarcinoma↗

Immunotherapy in pancreatic cancer - current status and future.

BACKGROUND: In pancreatic cancer, multimodal protocols, involving chemotherapy, radiation, or regional treatment, are initiated to improve oncological outcome. Since pancreatic adenocarcinoma has been shown to be susceptible to immune stimulation, several immunotherapy approaches have been investigated to define the role of immunotherapy in pancreatic cancer. METHOD: A review of current and past data concerning experimental and clinical immunotherapy in pancreatic cancer is presented in the context of basic immunotherapeutic principles. Past pitfalls and future developments are analyzed and a synthesis of immune stimulation and immune suppression is deduced on the basis of published data. RESULTS: Preclinical and initial clinical studies with monoclonal antibodies CO17-1A, BW494/32 and anti-epidermal growth factor receptor (EGFR) have been conducted, and various targets suitable for immunotherapy have been identified involving new molecular and gene technology. Targets on pancreatic cancer cells currently under investigation are mucins (MUC-1), glycoproteins (GA733), ras peptides and EGFRs. Side effects are minor and rarely auto-immune reactive. Another approach combines randomized regional with systemic chemoimmunotherapy (mitomycin C, 5-fluorouracil, folinic acid, carboplatin, epirubicin; interferon-gamma, interleukin-2) in nonresectable pancreatic cancer and obtains significant differences in median survival rates (14 months vs 4.5 months in controls) and quality of life. CONCLUSION: Although single remarkable improvements in the immunological approach to treatment of pancreatic cancer have been made, immunotherapy in pancreatic cancer is still experimental. On the basis of reliable preclinical data, new immunotherapy protocols will have to be evaluated clinically. Careful monitoring of immune responses and side effects, and assessment of quality of life will ensure identification of effective immunotherapy protocols for human pancreatic cancer in the near future.

Animals↗