The preventive effect of weekly high-dose 5-FU infusion (WHF) after resection of hepatic metastasis from colorectal cancer

Hepatic metastasis is often found even after resection of hepatic metastases from colorectal cancer. This implies that the micrometastasis already existed in residual liver when the resection was performed, and so complete recovery with resection alone is rare. We have been using a weekly high-dose 5-FU HAI (WHF = 5-FU 1,000 mg/m2/5 hrs/qw) since 1991, which has preventive effects for metastasis in residual liver as compared to a group treated without infusion chemotherapy. Hepatectomy was performed in 30 of 113 cases of hepatic metastasis from colorectal cancer during the past 16 years. For comparison, we divided the 30 cases into group A1 (16 cases H1:12, H2:4), which received hepatectomy only, and group A2 (14 cases H1:8, H2:4, H3:2), which additionally received infusion chemotherapy. The 1- and 3-year (cumulative) survival rates were 64.6% and 32.3% in group A1, and 100% and 75.3% in group A2 respectively in which the treatment outcome was significantly higher. The 1- and 3-year recurrence rates were 41.7 and 66.3 in group A1, and 8.3% each in group A2, respectively, which reveals that metastasis in residual liver was controlled in group A2. Other metastases were seen in lung (6 cases), bone (2 cases), hepatic hilar lymph node (3 cases), brain (1 case) and local (3 cases) in group A1, while only one metastasis in each brain and locally was seen in group A2 so far. WHF after resection of hepatic metastasis from colorectal cancer has a preventive effect not only for the recurrence in residual liver but also for other metastases. Therefore, as improvement in the survival rate is expected.     

Hepatic arterial chemotherapy for liver cancer over a period of 8 years

Hepatic arterial chemotherapy was performed for 27 patients with primary (3), metastatic liver cancer (21), and 3 other cases, over a period of 8 years. Chemotherapy was performed by intermittent hepatic arterial infusion of 5-FU or FAM (in case of metastatic tumor from colorectal cancer), FAM (from gastric cancer), and CDDP or Farmorubicin (HCC). Hepatic resection was performed in 10 cases of metastatic tumor from colorectal cancer, and 8 cases of 10 were curative operation. The 5-year survival rates of curative liver resection group, and non-curative liver resection or non-resection group were 57.1% and 12.5%, respectively. As is the case with metastatic cancer from gastric cancer, pancreatic cancer, and hepatocellular carcinoma (HCC), the prognosis was poor except for one CR case of HCC. We concluded that hepatic arterial chemotherapy may be recommended for a curative resected case of liver metastasis from colorectal cancer.     

Efficacy of combination therapy (hepatectomy and prophylactic arterial chemoinfusion) for liver metastases of colorectal cancer

From 1979 to 1997, 146 patients had hepatectomy for metastases of colorectal cancer (curative B: 122; curative C: 24). We categorized the severity of liver metastases as follows, H1: one lobe; H2: bilateral but less than five, and H3: bilateral with five or more lesions. In H1 and H2 patients, we compared the survival rate after resection alone (including repeat hepatectomy) with that after combination therapy (resection and prophylactic arterial chemoinfusion of 12-24 g of 5-FU). In H1 patients, the 3-year survival rate of the resected group (n = 74) and combination group (n = 6) was 47.2 and 53.3, respectively. In H2 patients, the resected group (n = 16) and combination group (n = 7) had survival rates of 34.5 and 100%, respectively. In H1 cases, the 3-year recurrence rate in the remnant liver was 63.4 versus 16.7% and in H2 cases it was 58.0 versus 0%. H3 patients received one week of continuous prophylactic arterial chemoinfusion [total dose of 5-FU = 6 g]. All four patients in the H3 combination group are alive at 20, 13, 13, and 12 months after resection, while the median survival of the resection only group (n = 4) was 12.5 months. We suggest that our combination therapy may be applicable to all patients with liver metastases of colorectal cancer.     

Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases

BACKGROUND: Although the survival benefit of hepatic resection for colorectal metastasis has been established, some controversy remains regarding the significance of adjuvant chemotherapy after hepatic resection. METHODS: One hundred thirty-two consecutive patients who had liver resection for colorectal metastasis at our hospital between 1980 and 1997 were studied. After curative hepatic resection, 37 patients underwent systemic chemotherapy, administered orally or intravenously, and 38 patients underwent regional chemotherapy, given intra-arterially or intraportally. Forty patients had no adjuvant chemotherapy. The chemotherapeutic agents used for oral administration were uracil and Tegafur or Tegafur alone. Mitomycin C (MMC) or 5-FU was used for IV chemotherapy. Combinations of 5-FU/leucovorin or MMC/5-FU (doxorubicin) were used for regional chemotherapy. Univariate and multivariate analyses were applied to test the significance of adjuvant chemotherapy for patient survival or disease-free survival. RESULTS: Overall 5-year survival was 42.2% (95% CL: 31.2%, 53.2%). Among the possible prognostic factors studied, univariate analysis showed a significant difference in survival based on the number of tumors and lymph node metastases in the hepatic hilum. There was a significant difference in disease-free survival based on adjuvant chemotherapy and lymph node metastasis. The multivariate analysis for patient survival selected four prognostic factors (P < .05), including adjuvant chemotherapy, lymph node metastasis, disease-free interval, and tumor size. The multivariate analysis for disease-free survival selected adjuvant chemotherapy, lymph node metastasis, and disease-free interval as significant factors. The most common recurrence site was remnant liver, regardless of adjuvant chemotherapy. CONCLUSIONS: Adjuvant chemotherapy significantly improved survival and disease-free survival after hepatic resection for colorectal metastases. It did not decrease recurrence rate in the remnant liver.     

Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen)

OBJECTIVE: To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA: Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. METHODS: Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only. RESULTS: The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. CONCLUSION: According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.     

Adjuvant intra-arterial chemotherapy with gastrin receptor antagonist after hepatic resection in colorectal cancer metastasis

The aim of this study was to determine whether chemo-endocrine therapy after the resection of liver metastasis from colorectal cancer would prevent recurrence in the remnant liver and prolong survival. Eleven colorectal cancer patients underwent hepatic resection for liver metastasis. Subsequently, they were administered Proglumide gastrin antagonist 1,200 mg/day + 5'-DFUR 800 mg/day for 2 years. In seven of them, MMC 6-10 mg and ADM 20 mg were infused intra-arterially every two weeks alternately for one year. In four of them, 5-FU 250 mg/day was infused for seven days continuously intra-arterially every two weeks for one year. Recurrence in the remnant liver occurred in four of 11 patients. All of these patients underwent repeated hepatectomy. The mean disease-free survival in the remnant liver was 37 months and the five-year survival rate was 91%. These results indicate that intra-arterial chemotherapy with gastrin receptor antagonist might be effective for adjuvant therapy in patients with resectable liver metastasis from colorectal cancer.     

Evaluation of intra-arterial infusion chemotherapy for advanced gastric cancer

We evaluated the therapeutic efficacy of intraarterial infusion chemotherapy in advanced gastric cancer, its side effect and patient prognosis, in comparison with systemic infusion. Of 125 cases of advanced gastric cancer, 41 cases received intraarterial chemotherapy (A group) and the rest were given systemic infusion (S group). Protocols of chemotherapy were 5-FU + MTX in 49 cases, 5-FU + cisplatin in 62, and 5-FU + MMC in 14. Location of the disease was the peritoneum in 69 cases, nodes in 59, liver in 38, and other sites, 33. The response rate of A group was significantly higher than that of S group, at 31% and 13% respectively. Although 41% of cases showed side effects (> or = grade 2), there was no significant difference between the 2 groups. The median survival period and 1-year survival rate were 8.4 months and 35%, respectively, and there was no significant difference between the 2 groups. In cases with liver metastasis, the prognosis of A group was better than that of S group. The results suggest that intra-arterial infusion chemotherapy is an effective treatment for liver metastasis from gastric cancer.     

Value of oncologic follow-up of patients operated for colorectal cancer. A prospective study of 1000 patients

OBJECTIVE: The purpose of our prospective study was to evaluate the contribution of follow-up in resected colorectal cancer. METHODS: One-thousand patients with colorectal adenocarcinoma who underwent radial resection from January 1975 to January 1990 were prospectively divided into two groups: the first group (n = 442, 42%) entered a 5-year follow-up protocol and the second group (n = 558, 56%) was free to make unscheduled visits in case of symptoms. RESULTS: Recurrence was found in 31.5% of the patients in the first group compared with 33% in the second group. Chorioembryonic antigen was the most accurate test detecting recurrence: 77% of the cases (97% for hepatic metastasis). Surgical resection of recurrent tumors was performed in 37% of the group 1 patients (curative resection in 15%) and in 9% (curative resection in 1.5%) of the group 2 patients (p < 0.001). 5-year survival after recurrence in group 1 was 11.5% versus 1% in group 2 (p < 0.01). CONCLUSION: These results emphasize the rational for a follow-up program in patients undergoing surgery for colorectal cancer.     

Transcatheter arterial chemoembolization to hepatic metastases from colorectal cancer

Response of transcatheter arterial chemoembolization (TAE) and transcatheter arterial infusion chemotherapy to hepatic metastases was reported in 25 cases of colorectal cancer. The severity of liver metastases was H1 in 12 cases, H2 in 9 cases, and H3 in 4 cases. Liver metastases were found during surgery in 12 of these patients, and 13 showed metastases or recurrence in the liver after resections of primary lesions. Catheters were inserted selectively to the proper hepatic artery by Seldinger's method, followed by injection of embolizing agents (gelfoam particles of Lipiodol) with adriamycin or 5-FU + leucovorin in most cases. Response was assessed by blood CEA levels, diagnostic imaging, and period of survival. In 5 cases in whom liver resections were performed following TAE, response was assessed by histopathological findings of the resected specimens. Two patients showed partial response (PR), 12 no change (NC) and 11 progressive disease (PD) by diagnostic imaging. Blood CEA levels fell to less than 50% of pre-treatment levels in 26% of cases. Histological changes by TAE were confirmed in 4 of 5 cases after liver resections, but viable cancer cells were observed in all cases. A case of mucinous cancer showed no change histologically. As the other case of mucinous cancer showed PD by diagnostic imaging, TAE was not suggested to be suitable to treat cases of mucinous cancer. More improvements in the dosage, drugs and times of treatment were suggested to yield a better response rate in TAE therapy for liver metastases from colorectal cancer.     

Clinical evaluation of postoperative adjuvant arterial infusion chemotherapy in resected hepatoma patients

Eighty surgically treated patients with advanced hepatocellular carcinoma (HCC) were divided into two groups. In group I, twenty patients whose mean diameter of tumors was 56 mm, prophylactically underwent hepatic arterial infusion chemotherapy after liver resection. Chemotherapeutic agents (5-FU, ADM, MMC, CDDP, Lipiodol) were administered 4 times a year via Infuse A port. The remaining 60 patients, whose mean diameter of tumors was 57 mm, served as the control without prophylactic infusion (group II). The 2-year cumulative survival rate was higher in the prophylactic group (71%) than the control (48%, p = 0.040). The two-year disease-free survival rate was improved in group I (38%) compared with that in group II (27%, p = 0.021). Intrahepatic multiple recurrence within 1 year after surgery was recognized in four out of 18 patients of group I (22%) and in thirty-three out of 60 patients of group II (55%, p = 0.029). In group I, two cases who died of hepatic failure with no recurrence, had lower functional reverse and a larger amount of Lipiodol than the remaining 18 patients. Adjuvant arterial infusion chemotherapy can thus be be efficacious in alleviating hepatoma recurrence after liver resection. For patients with poor liver function, a smaller volume of chemotherapeutic agents might be feasible.     

Arterial infusion chemotherapy of 5-FU and leucovorin for patients with liver metastases from colorectal cancer

Fifteen patients with liver metastases from colorectal cancer were treated by arterial infusion of 5-FU and leucovorin. Two regimens were performed. One was weekly bolus infusion of leucovorin following bolus infusion of 5-FU (bolus group), the other was 5 days continuous infusion of 5-FU and leucovorin in 3 weeks (continuous group). One PR was obtained both in the bolus group and in the continuous groups. The objective response rate was 11% in the bolus group and 20% in the continuous group. The one- and 2-year survival rates for these patients were 40% and 0% in the bolus group, and 80% and 60% in the continuous group, respectively. These results suggest that continuous arterial infusion of 5-FU and leucovorin was more effective than individual bolus arterial infusion of leucovorin and 5-FU for patients with liver metastases from colorectal cancer.     

Identification of autolysosomes directly associated with proteolysis on the density gradients in isolated rat hepatocytes

BACKGROUND: More than 40% of patients who undergo curative resection of advanced colorectal carcinoma can be expected to have recurrence of the disease. The most frequent sites of recurrence are the liver (33% of patients) and lung (22%). Interest has therefore focused on treating hepatic or pulmonary metastases, or both, to improve the outcomes of these patients. Although surgical resection has become an increasingly accepted treatment for resectable localized hepatic or localized pulmonary metastases from colorectal carcinoma, the value of aggressive surgery for the removal of both hepatic and pulmonary metastases from patients with primary colorectal carcinoma remains to be clarified. METHODS: Data on 30 patients who had undergone resection of both hepatic and pulmonary metastases from colorectal carcinoma were included in the study. RESULTS: Independent, significant prognostic features were found to be the time that hepatic or pulmonary metastases occurred and the distribution of pulmonary metastases. Median survival times were 30 months (range, 7-108 months) after resection of both hepatic and pulmonary metastases and 48.5 months (range, 11-149 months) after excision of the primary colorectal tumor. Actuarial 1-, 3-, and 5-year survival after resection of both hepatic and pulmonary metastases was 86.7%, 49.3%, and 43.8%, respectively. No perioperative mortality occurred. There were three cases of minor morbidity, which the authors considered acceptable. CONCLUSIONS: Resection of both hepatic and pulmonary metastases from colorectal carcinoma may help to prolong the survival of a small group of patients with these metastases.     

Combination hepatic intra-arterial 5-fluorouracil and CDDP administration with oral regimen in patients with colorectal cancer metastasis to the liver

We investigated therapeutic effectiveness and side effects of a combination weekly high-dose 5-FU plus one shot CDDP HAI (WHF + CDDP method) with oral regimen in patients with colorectal cancer metastasis to the liver. All 24 patients enrolled in this study showed 54% efficacy whereas patients combined HAI with oral regimen over one week obtained 83% efficacy for multiple liver metastasis. They showed good quality of the life during combination chemotherapy without any symptoms of metastatic lesions. The WHF + CDDP method combined with oral regimen is a promising treatment for colorectal cancer metastasis to the liver as well as extrahepatic distant organs, and this protocol may be satisfactorily accepted by most colorectal cancer laden patients because of negligible side effects.     

Evaluation of prophylactic hepatic arterial infusion chemotherapy after hepatectomy for metastases from colorectal cancer--the second report

We followed 18 patients who underwent curative hepatectomy for metastatic carcinoma of the colon from March 1993 to March 1995, and investigated their survival and the effect of treatment on recurrence. The patients were randomly divided into two groups. Group A (n = 9) was given continuous 5-FU (500 mg x 4 days/week) for six weeks from 2 weeks after surgery via the hepatic artery and Group B (n = 9) was given 5-FU orally from 2 weeks after surgery. The cumulative one-, two-, and three-year survival was 88.9, 88.9, and 76.2% in Group A, while the one- and two-year survival was 100 and 80% in Group B. The one-, two-, and three-year disease-free survival was 77.8% in Group A, while the one- and two-year disease-free survival was 55.6 and 29.6% in Group B (p = 0.0369: Mantel-Cox). These findings suggest that continuous hepatic artery infusion of 5-FU is effective against post-hepatectomy recurrence of metastatic carcinoma of the colon.     

G proteins in carotid body chemoreception

This study explored the efficacy of hepatic arterial therapy, comparing both injection and infusion of 5-fluorouracil (5-FU) in prolonging the survival of 92 patients with recurrent unresectable hepatic metastasis from colorectal cancer. With respect to pretreatment carcinoembryonic antigen doubling time (CEA-DT), 56 patients were treated with intra-arterial injection, and 36 with intra-arterial infusion. In 21 patients with a CEA-DT of less than 40 days, the cumulative survival of patients treated with arterial injection was significantly longer than that of patients treated with arterial infusion. In 45 patients with a CEA-DT of 40-80 days, the survival curves of patients did not differ from each other. Of the remaining 26 patients with a CEA-DT of more than 80 days, those treated using arterial infusion had an excellent prognosis, in contrast to those treated using arterial injection, with statistical significance. CEA-DT may be useful when choosing a chemotherapy regimen, and may help to accurately establish the prognosis of patients with unresectable hepatic metastasis from colorectal cancer.     

Prognosis of hepatic metastasis from colorectal cancer following hepatic resection and arterial infusion chemotherapy--assessment from the percentage of tumor involved area

Prognosis of hepatic metastasis from colorectal cancer following hepatic resection and arterial infusion chemotherapy was studied from the percentage of tumor involved area (PTIA). The PTIA was calculated by the following formula: sigma S'/sigma S, with S' as the tumor area and S as the liver area on each CT slice. The subjects were 25 cases of hepatic resection (HR), and 31 cases of hepatic arterial infusion chemotherapy (HAI). The PTIA of the cases of HR and that of HAI was 1.5 to 25.9% and 0.8 to 31.3%, respectively. For comparison, all cases were divided into group A, which was not more than 10% of the PTIA, and group B, which was more than 10% of the PTIA. In the cases of HR, the prognosis of group A was significantly better than that of group B (p < 0.05). In the cases of HAI, the prognosis of group A was better than that of group B. Even in group A, the prognosis of the cases of HR was significantly better than that of HAI (p < 0.05). These results suggest that the PTIA in the cases of HR and HAI for metastasis from colorectal cancer is important factor which reflects the prognosis.     

Hepatic resection for colorectal liver metastases

The lack of other effective treatment for colorectal liver metastases makes hepatic resection a primary treatment consideration. Between January 1980 and December 1990, 26 selected patients with liver colorectal metastases who underwent hepatic resection were reviewed. The age, sex, site of primary lesion, histological grade, lymph node involvement, location, size, and number of hepatic metastases, type of hepatic resection, and preoperative CEA blood levels were documented. Complete removal with histologically negative resection margins were accomplished in 24 patients. The extent of resection performed was hepatic lobectomy in 12 patients. Segmentectomy in eight patients, and wedge resection in four patients. The 5-year survival rate was 30.5 per cent. Patients with metachronous metastases showed a better survival rate than those with synchronous lesions--46.6% versus 13.6% respectively (P = 0.08). None of the other factors studied showed a significant effect on survival. All patients were followed from the time of hepatic resection to the time of this study or death. During a median follow-up of 30.9 months, 20 patients developed recurrence of their disease (60 per cent in the liver). There was no perioperative mortality. Morbidity arose in 66.6 per cent of patients, with a majority of the complications being minor. We conclude that hepatic resection can be performed safely enough to be recommended in selected patients.     

Multidisciplinary treatment for colorectal liver metastases

The liver is an large immunologic organ with liver-associated macrophages (Kupffer cells) and natural killer-like primitive T cells. As these effectors are activated by interleukin-2 (IL-2), we have administered IL-2-based hepatic arterial infusion therapy in the treatment of patients with liver metastases of colorectal cancer. Patients with unresectable liver metastases were administered IL-2 7 x 10(5) U and 5-fluorouracil (5-FU) 250 mg/day as a continuous infusion, with a bolus injection of mitomycin C (MMC) 4 mg once weekly. Of 25 patients treated with this regimen, 19 achieved complete or partial responses (response rate: 76%). A multi-institutional randomized trial following the pilot study showed reproducible favorable results. For patients with resectable metastases, we have administered this infusion therapy for the prevention of cancer recurrence in the liver. Patients who had undergone curative hepatectomy received IL-2 1.4 to 2.1 x 10(6) U, 5-FU 250 mg and MMC 2 to 4 mg weekly for 6 months. Of 18 patients, 12 are alive disease-free, and the 5-year overall survival rate is 75%. Recurrent cancer has developed in 6 of the 18 patients; however, no patients had recurrence in the residual liver. We believe that liver metastases of colorectal can be controlled by this multimodal treatment.     

Risk factors for thrombotic events in giant cell arteritis and polymyalgia rheumatica

BACKGROUND: FOLFOX2, a bimonthly regimen of high-dose leucovorin (LV), 48-hour continuous infusion of 5-fluorouracil (5-FU) (LV-5-FU) and oxaliplatin (100 mg/m2) produced a high response rate (46%; 95% confidence interval (95% CI): 31%-60%) in 5-FU pre-treated patients with metastatic colorectal cancer. In this phase II study, pre-treated patients were given a lower dose of oxaliplatin to reduce the toxic effects of the regimen. PATIENTS AND METHODS: Thirty patients with advanced colorectal adenocarcinoma and progression while receiving bimonthly LV-5-FU (LV: 500 mg/m2, 5-FU: 1.5-2 g/m2/22 hours, days 1-2, every two weeks), were given the same LV-5-FU schedule with the addition of oxaliplatin (85 mg/m2) every two weeks (FOLFOX3). RESULTS: The main toxic effects were peripheral neuropathy (90%) with four severe sensitive neuropathies (WHO grade 2: 13%). The response rate was 20% (95% CI: 8%-39%). Median progression-free survival was 26 weeks, median survival was 57 weeks from the start of FOLFOX3 and median duration of the response was 37 weeks. CONCLUSIONS: Results obtained with FOLFOX3 confirmed the synergy between oxaliplatin and 5-FU in 5-FU-resistant metastatic colorectal cancer. However, the response rate seems to be lower than that obtained with FOLFOX2. Further studies to determine the best oxaliplatin dose intensity are in progress.     

Alpha and omega: studying resuscitation at the beginning and end stages of life

BACKGROUND: To clarify whether or not multiple pulmonary metastases from colorectal cancer are contraindicated for a surgical resection, we retrospectively evaluated the influence of the number of pulmonary metastases on both the postthoracotomy survival and the pattern of the first failure. METHODS: From 1981 to 1993, 36 patients underwent a complete resection for pulmonary metastases from colorectal cancer. RESULTS: Of the various factors investigated including gender, primary site, disease-free interval, tumor size, the number of metastases, type of resection, and the history of hepatic metastases, only the number of pulmonary metastases was found to be significantly related to postthoracotomy survival. The rate of disease-free survival at 5 years was 62% for solitary metastasis (n = 17), 35% for two metastases (n = 8), and 0% for four or more metastases (n = 11). The pattern of failure also differed according to the number of pulmonary metastases. In particular, the incidence of local recurrence at the primary site increased with the number of pulmonary metastases (ie, 1 of 17 patients with a solitary metastasis, 3 of 8 with two metastases, and 6 of 11 with four or more metastases). CONCLUSIONS: These results suggest that multiple metastases might indicate the presence of local recurrence at the primary site; therefore, in cases of multiple pulmonary metastases, the primary site should be thoroughly explored.