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Biomedical subjects

R E Clark

Publications and source records attributed to R E Clark.

At least 73 records · Page 4Linked to original sources
PubMed1998

Immunohistochemical staining for desmogleins 1 and 2 in keratinocytic neoplasms with squamous phenotype: actinic keratosis, keratoacanthoma and squamous cell carcinoma of the skin.

Desmosomes are intercellular junctions that have been shown to be down-regulated in certain types of carcinoma and that may play a role in suppression of invasion and metastasis. This paper describes an immunohistochemical study of three types of epidermal neoplasms with monoclonal antibody to desmoglein in order to determine how desmosomal staining correlates with the clinical, biological and histopathological features of these neoplasms. Actinic keratosis (AK) is the most common keratinocytic premalignant neoplasm that was reported to have a 10-20% rate of malignant transformation into squamous cell carcinoma (SCC). Keratoacanthoma (KA) is a benign neoplasm that involutes spontaneously after a few months of rapid growth. SCC is a malignant tumour capable of metastasis. Electron microscope studies of KA and SCC showed significantly reduced staining for desmosomes in SCC but not in KA. We have examined staining for desmoglein using the monoclonal antibody 33-3D, a mouse IgM monoclonal antibody, that recognizes the cytoplasmic domains of desmoglein (Dsg)1 and Dsg2 on frozen sections. Immunohistochemical staining of normal skin with this antibody revealed strong pericellular localization of the antigen, outlining the cell membranes of the keratinocytes. A series of 30 AKs, 12 KAs and 24 SCCs was stained immunohistochemically with 33-3D monoclonal antibody. All examined KAs showed extensive pericellular staining for Dsg. By contrast, juxtanuclear staining for Dsg was noted in 12 SCCs, and completely negative staining in seven SCCs. The five remaining SCCs showed focal pericellular staining for the Dsg marker. The most common finding in AK was focal pericellular staining for Dsg, with complete absence of staining in dysplastic areas (25 cases). In five cases negative pericellular staining in dysplastic areas was associated with juxtanuclear accumulation of the Dsg marker. A strong negative correlation between Dsg staining and degree of dysplasia was obtained. The Dsg pattern in KA is similar to normal epidermis and shows a clear difference between KA and SCC. AK has a limited loss of Dsg expression in a SCC-like pattern that is congruent with its premalignant nature. As the stain works on frozen tissue, it may be helpful for rapid differentiation in selected cases in cutaneous oncology and Mohs micrographic surgery. This antibody may also have great potential for the detection of the effects of chemopreventive agents in skin cancer.

Animals↗
PubMed1998

Comparison of a patient-controlled analgesia system with continuous infusion for administration of diamorphine for mucositis.

Mucositis remains an important problem following BMT and may delay discharge from hospital. Patient-controlled analgesia (PCA) systems have been reported to be of benefit in controlling BMT-associated mucositis. The present study comprised 65 patients (age range 16-68 years; 19 allografts, 29 peripheral blood stem cell autografts and 17 autologous bone marrow). Subjects were prospectively randomised to receive intravenous diamorphine for pain relief either by conventional continuous infusion (CI) or by PCA, using a Medex Walkman 440 delivery system. Each patient assessed his/her pain control and nausea daily by a visual analogue scale. Twenty-two patients did not require any diamorphine. Four patients required diamorphine for pain other than mucositis, and four patients failed PCA control. Of 35 assessable cases, no difference in pain control was noted between CI and PCA. However, PCA-controlled patients required significantly less diamorphine than CI controlled patients (mean, 131 +/- 23 mg for PCA vs 296 +/- 40 mg for CI; P = 0.001), and PCA required fewer days of diamorphine than CI (mean, 7.17 +/- 0.66 days for PCA, 9.00 +/- 0.65 days for CI; P = 0.03). Side-effects were minimal and equivalent in the two arms. The findings suggest that PCA and CI offer equivalent control of the pain of BMT-associated mucositis, but PCA requires less total consumption and duration of diamorphine therapy.

Adolescent↗
PubMed1998

Previous treatment predicts the efficiency of blood progenitor cell mobilisation: validation of a chemotherapy scoring system.

Following mobilising chemotherapy and myeloid growth factors, some heavily pretreated patients do not mobilise adequate numbers of peripheral blood progenitor cells (PBPC). It would be clinically useful to identify such patients in advance. A recent scoring system based on previous therapy may be useful in predicting CD34-positive cell yield. In this study we validated this scoring system on an independent group of 99 patients undergoing 103 harvesting episodes. In 61 patients mobilised with cyclophosphamide 1.5 g/m2 and G-CSF, those with treatment scores less than 21 yielded significantly more CD34-positive cells than patients with scores greater than 63 (P = 0.0012). Previous treatment with melphalan or carmustine was associated with a significantly lower yield of CD34-positive cells (P= 0.0001). No relationship was seen between the time from previous chemoradiotherapy and harvest outcome. Patients with treatment scores less than 21 required a shorter duration of G-CSF therapy (P = 0.05). Similar findings were seen in 42 further mobilisation cycles undertaken with alternative mobilisation schedules. The present data suggest that a score summarising previous treatment can be used to predict CD34 yields, and could be of clinical use to identify poor PBPC mobilisers in advance.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Autologous transplantation in chronic myeloid leukaemia using peripheral blood stem cells.

Forty-three patients with chronic myeloid leukaemia in first chronic phase were recruited to study intensive chemotherapy (idarubicin plus cytarabine; IdAC) followed by collection of peripheral blood stem cells (PBSC) in the recovery phase. PBSC autografting was performed on 32 patients. One patient died during mobilization and three died following autograft. All procedural deaths occurred in patients who received IdAc more than a year from diagnosis. Nine further patients died, eight following progression of CML. 72% of transplanted patients showed a major cytogenetic response but most cases have returned to Philadelphia-positive haemopoiesis. 62% of autografted patients remain alive (median survival from diagnosis 52 months). Four of the 11 patients who did not receive a transplant remain in chronic phase.

Adult↗
PubMed1998

The influence of target protein half-life on the effectiveness of antisense oligonucleotide analog-mediated biologic responses.

During the course of a study aimed at improving antisense oligodeoxynucleotide-mediated ex vivo bone marrow purging of patients suffering from chronic myeloid leukemia (CML), the properties of a number of antisense structures intended to reduce the expression of c-myc, mutant p53, and bcr-abl mRNAs and proteins were examined. The majority of the antisense oligodeoxynucleotides were designed to be capable of directing ribonuclease H (RNase H) cleavage of their target mRNAs. Streptolysin O (SLO) reversible permeabilization was used to deliver the oligodeoxynucleotides into the CML line KYO-1. We found that the efficiency and specificity of antisense oligonucleotide-induced reductions of target protein expression depended on target protein half-life, the oligonucleotide structure, and the specific sequence within the target mRNA. Transient reductions of c-myc mRNA and protein were achieved with a chimeric methylphosphonate-phosphodiester oligodeoxynucleotide antisense to the initiation codon, but cell proliferation was unaffected. In contrast, a chimeric oligodeoxynucleotide of similar structure targeted to an alternative site in the coding region of c-myc mRNA reduced target mRNA and protein levels for over 24 hours and halted cell proliferation. Chimeric methylphosphonate-phosphodiester oligodeoxynucleotide antisense to a point mutation in KYO-1 p53 mRNA efficiently reduced target mRNA expression, but only small, transient reductions in p53 protein expression were observed. However, a chimeric methylphosphonate-phosphorothioate oligodeoxynucleotide targeted to the same site reduced p53 protein to 30% of control levels over a 48-hour period. BCR-ABL protein expression was unaffected by chimeric oligodeoxynucleotides targeted to the breakpoint in bcr-abl mRNA, even when mRNA levels at early times were substantially reduced.

Base Sequence↗
PubMed1998

Microscopically controlled surgical excision combined with ultrapulse CO2 vaporization in the management of a patient with the nevoid basal cell carcinoma syndrome.

Nevoid basal cell carcinoma syndrome is an autosomal dominant condition characterized by multiple basal cell carcinomas, skeletal abnormalities and sometimes mental retardation. The large number of tumors, which are often disfiguring, presents extreme difficulties in the treatment of these patients. Microscopically controlled excision, compared to other modalities (radiation therapy, photodynamic therapy, intralesional interferon alpha-2b) offers the highest cure rate. However, because of the large size and involvement of wide areas of the skin, this approach is sometimes impractical. The ultrapulse CO2 laser with high energy and short pulses achieves char-free ablation of the tumors, bloodless surgical field, minimal nonspecific thermal damage, rapid healing and diminished postoperative pain. Also, a number of lesions can be removed in a single session. We present a 48-year-old man with a 6.5 x 4.5 cm large basal cell carcinoma involving the anterior abdomen and navel area. The central thick portion of the tumor was resected by microscopically controlled excision with 3 stages, and wide thinner peripheral crescentic plaque vaporized with ultrapulse CO2 laser. The laser settings were 300 mJ energy/pulse and 100 W average power, which corresponds to the fluence of 7.5 J/cm2. Computerized pattern generator (ultrascan handpiece) was adjusted to patterns of 3 (circle) and 1 (square) with sizes varying from 5 to 7, and density of 9 (60% overlapping). The tumor was vaporized with 6 passes, all the way to deep reticular dermis. A fifteen month-follow up disclosed no recurrent disease. Subsequent biopsies revealed only a scar with postinflammatory hyperpigmentation. Our experience indicates that combined treatment with microscopically controlled excision and ultrapulse CO2 laser ablation is a suitable modality for the large tumor plaques involving concave and convex areas of the skin respectively. Microscopically controlled excision of thicker, concave portions of basal cell carcinoma plaques, where CO2 laser surgery is less feasible, presents an effective addition that renders this combined modality a successful method for the treatment of nevoid basal cell carcinoma syndrome.

Abdominal Neoplasms↗
PubMed1998

Cost-effectiveness of assertive community treatment versus standard case management for persons with co-occurring severe mental illness and substance use disorders.

OBJECTIVE: To determine the cost-effectiveness of Assertive Community Treatment (ACT) in comparison to Standard Case Management (SCM) for persons with severe mental illness and substance use disorders. DATA SOURCES AND STUDY SETTING: Original data on the effectiveness and social costs of ACT and SCM that were collected between 1989 and 1995. Seven community mental health centers in New Hampshire provided both types of treatment. STUDY DESIGN: Persons with schizophrenia, schizoaffective disorder, or bipolar disorder and a concurrent substance use disorder were randomly assigned to ACT or SCM and followed for three years. The primary variables assessed were substance use, psychiatric symptoms, functioning, quality of life, and social costs. DATA COLLECTION METHODS: Effectiveness data were obtained from interviews at six-month intervals with persons enrolled in treatment and with their service providers. Social cost and service utilization data came from client reports; interviews with informal caregivers; provider information systems and Medicaid claims; law enforcement agencies; courts; and community service providers. PRINCIPAL FINDINGS: Participants in both groups showed significant reductions in substance use over time. Focusing on quality of life and substance use outcomes, ACT and SCM were not significantly different in cost-effectiveness over the entire three-year study period. Longitudinal analyses showed that SCM tended to be more efficient during the first two years but that ACT was significantly more efficient than SCM during the final year of the study. CONCLUSIONS: In an adequately funded system, ACT is not more cost-effective than SCM. However, ACT efficiency appears to improve over time.

Adolescent↗
PubMed1997

The importance of cerebellar cortex and facial nucleus in acquisition and retention of eyeblink/NM conditioning: evidence for critical unilateral regulation of the conditioned response.

Experiment 1 examined acquisition of the classically conditioned eyeblink response in rabbits (Oryctolagus cuniculus) during reversible cooling lesions of the cerebellar cortex (CX), facial nucleus (FN), or lateral parvocellular reticular formation (RF). Retention was then evaluated during periods of training during reversible cooling lesions and without cooling in rabbits that had acquired the conditioned response. We found that cooling the CX did not prevent acquisition, but did retard the acquisition rate. Cooling the FN during acquisition prevented the expression of the unconditioned and conditioned response, but did not prevent the acquisition when assessed during subsequent training without cooling. Cooling the RF had no effect on the acquisition or expression of the conditioned response. During subsequent retention testing, in well-trained animals, cooling the CX did not abolish the learned response. Cooling the FN abolished both the conditioned and the unconditioned response. The results from Experiment 1 indicate that the CX is more important for acquisition than retention of the conditioned response. The FN is not important for the acquisition of the conditioned response, but is essential for the expression of the conditioned and unconditioned response. Experiment 2 examined bilateral recordings from the cerebellum in well-trained rabbits, before and during interpositus or FN cooling. We found that cooling the interpositus abolished all learning related activity in the ipsilateral or contralateral cerebellum, but did not affect the stimulus evoked responses. Cooling the FN did not abolish stimulus evoked activity or learning related activity in the cerebellum. The results emphasize the critical importance of the ipsilateral cerebellum in classical eyeblink conditioning and suggest that the memory trace for this type of learning is mediated by unilateral circuitry.

Animals↗
PubMed1997

Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans. Results of a multiinstitutional series with an analysis of the extent of microscopic spread.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon soft-tissue tumor of the skin; its microscopic extent of invasion beyond the grossly visible tumor is frequently difficult to appreciate. Although wide local excision has been the standard treatment of DFSP, recurrence rates range from 11% to 53%. Because Mohs micrographic surgery allows the extent of excision to be tailored to the microscopic extent of tumor, we evaluated this technique for the treatment of primary and recurrent DFSP. OBJECTIVE: Our purpose was to determine the local recurrence rate and microscopic extent of spread of primary and recurrent DFSP after treatment with Mohs micrographic surgery. METHODS: The records of 58 patients with primary and recurrent DFSP treated with Mohs micrographic surgery at three institutions were reviewed and the macroscopic and microscopic extents of tumor were recorded. RESULTS: One patient with a twice-recurrent DFSP had another recurrence after Mohs micrographic surgery, for an overall local recurrence rate of 2% (zero for primary tumors and 4.8% for recurrent tumors). There were no cases of regional or distant metastases. Macroscopic tumor size ranged from 0.3 x 0.6 cm to 30 x 20 cm, whereas microscopic (postoperative) size ranged from 1.8 x 1.0 cm to 35 x 40 cm. We calculated the likelihood that a given width of excision around the macroscopic tumor would clear the entire microscopic extent of tumor. Standard wide excision with a width of 1 cm around the primary tumor would have left microscopic residual tumor in 70.7%; a width of 2 cm, 39.7%; 3 cm, 15.5%; and 5 cm, 5.2%. Even an excision width of 10 cm would not have cleared the microscopic extent of some tumors, despite taking a huge excess of normal tissue. CONCLUSION: Treatment of primary and recurrent DFSP by Mohs micrographic surgery results in a low recurrence rate because of the ability of the technique to permit the detection and excision of microscopic tumor elements in even the most asymmetric tumors. Whatever type of surgery is chosen to treat DFSP, it is necessary to assess the entire perimeter of the tumor for microscopic extension and to achieve tumor-free margins in all directions.

Adolescent↗
PubMed1997

Financing assertive community treatment.

Assertive community treatment (ACT) is a widely-used intervention for the most severely impaired persons with mental illness. Because it differs from traditional treatment approaches in its philosophy, its organization, and in the clients it serves, financing strategies that are appropriate for standard services may not be optimal for ACT. In developing new payment systems, policymakers must choose between targeted strategies that attempt to influence the treatment process directly and those that establish broad goals for effectiveness, access, and efficiency while allowing providers more latitude in the treatment process. These choices profoundly influence how and to whom ACT is available.

Community Mental Health Services↗
PubMed1997

European results of matched unrelated donor bone marrow transplantation for chronic myeloid leukemia. Impact of HLA class II matching. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

We have retrospectively analyzed the impact of prognostic factors on the outcome of serologically HLA-matched unrelated donor (UD) BMT for CML. For this purpose, we have studied a cohort of 366 patients transplanted in Europe between January 1985 and December 1994. The median age of the 211 males and 155 females was 34 years; 238 patients were transplanted in first chronic phase and 116 in advanced phases. The median interval from diagnosis to BMT was 827 days. GVHD prophylaxis consisted of CsA and MTX in 202 patients or of ex vivo or in vivo T cell depletion (TCD) in 129. Recently, DNA-based methods of HLA-class II typing have been used to improve donor selection. We obtained complete data on 300 donor/recipient (D/R) pairs. Among them, we have identified three groups of patients, according to specific HLA-DRB1 D/R compatibility. Two hundred and ten patients received marrow from donors identical for HLA-DRB1 (group 1). Thirty-one patients received BMT from a donor who was HLA-DRB1 mismatched (group 2) and 59 from a donor in whom specific HLA-DRB1 typing was not performed (group 3). The overall survival was 37 +/- 3% at 2 years and leukemia-free survival (LFS) was 31 +/- 3%. In univariate analysis, five variables had a favorable effect on LFS: transplant in first chronic phase (P = 0.0001), time interval from diagnosis to BMT shorter than the median (P = 0.01), prophylaxis of GVHD without TCD (P + 0.001), acute GVHD < grade III (P = 0.0009) and HLA-DRB1 D/R matching (P = 0.0001). Transplant-related mortality (TRM) was 49 +/- 4% in group 1, 79 +/- 8% in group 2 and 80 +/- 6% in group 3 (P = 0.0001). Multivariate analysis confirmed that HLA-DRB1 matching was the most significant factor influencing survival (P = 0.04), LFS (P = 0.013) and TRM (P = 0.0049). From these results, we have defined a 'good risk' group, ie patients transplanted in first chronic phase, from an HLA-DRB1 matched donor, without TCD as prophylaxis against GVHD. The 2 year LFS, TRM and relapse incidence for this group were 51 +/- 5%, 47 +/- 5% and 2 +/- 2%, respectively. This suggests that the long-term outcome of patients with favorable prognostic features can approach that of patients transplanted from geno-identical siblings. In contrast, the TRM for patients transplanted for advanced disease from non HLA-DRB1-identical donors was 94%. Such a high TRM clearly indicates that UD BMT is not justifiable for these individuals.

Adolescent↗
PubMed1997

Preclinical studies of streptolysin-O in enhancing antisense oligonucleotide uptake in harvests from chronic myeloid leukaemia patients.

Antisense oligodeoxyribonucleotides (ODN) have been shown to produce a sequence-specific cleavage of BCR-ABL mRNA. They may therefore have clinical potential for purging harvests from chronic myeloid leukaemia (CML) patients, prior to autografting. Whilst ODN are highly effective in cell-free systems, their uptake into intact cells is very poor. We have previously reported that reversible permeabilisation of CML cell lines with Streptolysin-O (SL-O) can dramatically increase intracytoplasmic and nuclear ODN uptake. In this study, we examined whether SL-O permeabilisation could be used to enhance ODN uptake into bone marrow (BM) and peripheral blood stem cell (PBSC) harvests from CML patients, without undue toxicity. All 19 harvests studied were from patients in stable chronic phase of CML. Samples studied were either fresh BM harvests following leucoconcentration, fresh PBSC collections, or from previously cryopreserved harvests. Cells were permeabilised by SL-O to load them with fluorescein-labelled ODN. The proportion of permeabilised and viable cells was assessed by fluorescein uptake and propidium iodide exclusion, respectively, by flow cytometry. The effect of SL-O on ODN uptake and cell toxicity was unpredictable on simple mononuclear fractions of harvests. In contrast, SL-O consistently significantly enhanced ODN uptake in samples which were first selected for CD34-positive cells, and this was achieved without either direct toxicity or inhibition of CFU-GM growth. The SL-O concentration required for optimal permeabilisation varied considerably from case to case, in line with previous data on cell lines. PBSC harvests positively selected for CD34-positive cells tended to achieve superior permeabilisation to CD34 positively selected BM harvests. SL-O can be used to safely enhance the intracellular uptake of antisense ODN. This is best achieved on harvests which are first selected for CD34-positive cells.

Adult↗
PubMed1997

Treatment of chronic myeloid leukaemia in first chronic phase with idarubicin and cytarabine: mobilization of Philadelphia-negative peripheral blood stem cells.

Peripheral blood stem cell (PBSC) mobilization using idarubicin and cytarabine was investigated in 40 patients with chronic myeloid leukaemia in first chronic phase (CML CP1). Disease contamination was evaluated in harvests from 41/44 (93%) mobilization episodes. Using cytogenetics, 22/37 (59%) showed a complete or major response; Southern blot analysis demonstrated a complete or major response in 9/17 (53%). No harvests were RT-PCR negative. In the 41 evaluable episodes, more complete or major responses were seen when PBSC mobilization occurred within 24 months [17/23 (74%) versus 6/18 (33%); P = 0.02] and within 12 months of diagnosis [10/11 (91%) versus 13/30 (43%); P = 0.018]. 20 patients underwent PBSC transplantation and 18/20 successfully engrafted. Post-transplant cytogenetic analysis was available on 15 cases, of whom five achieved a major cytogenetic response at 1-3 months, with five partial cytogenetic remissions. Two of 40 patients died during mobilization therapy (5%) and three of 20 after the transplant (15%). Overall mortality was high at five of 40 patients, and the procedural mortality was 20%. This study demonstrates that Ph-negative PBSCs can be mobilized in a significant proportion of patients with CML CP1, with the best results observed within a year of diagnosis. These cells can subsequently be used for autologous transplantation, however, the impact on long-term survival requires longer follow-up, and potential benefits may be compromised by the high mortality.

Adult↗
PubMed1997

Effect of increased maxillo-mandibular relationship on isometric strength in TMD patients with loss of vertical dimension of occlusion.

The effect on isometric strength of the shoulders and limbs while biting in habitual occlusion, on a bite-elevating appliance and on a placebo appliance was analyzed. Twenty female volunteer patients, presenting with temporomandibular pain dysfunction syndrome and obvious loss of vertical dimension, served as subjects. All were weaker to the manual application of the isometric Deltoid Press (IDP) when biting, as opposed to maintaining the mandible in an unsupported rest position. Two intraoral appliances were fabricated for each subject: a bite-elevating appliance (BEA) set by a functional criterion of peak strength to the IDP and a placebo appliance which did not interfere with occlusion but was "set" with a mock IDP procedure. Testing was carried out by the Neuromuscular Research Testing Laboratory of the Neurology Department of Tufts New England Medical Center. Testing was independent of the dentist who fabricated and set the appliances. A standard neuromuscular test with the Maximal Voluntary Isometric Contraction apparatus was used to assess strength of right and left shoulder, elbow and knee flexion and extension as is routinely performed with all neuromuscular disease patients. Twelve strength tests were carried out for each of three conditions: 1. Baseline-biting in habitual occlusion; 2. Elevated-biting on the BEA; and 3. Placebo-biting with the placebo appliance inserted. The order of conditions 2 and 3 was counterbalanced without knowledge of the subjects. Twelve repeated measures ANOVAs (each subject as their own control) were conducted for each of the 12 strength measures. All F-tests indicated a significant main effect for treatment differences (p < 0.0001). Mean strength biting on the BEA was consistantly greater (p < 0.001) than Baseline or Placebo strength. Baseline and Placebo condition were equivalent. These findings confirmed previous observations at this TMD Center: individuals with loss of vertical dimension of occlusion respond to a bite raising appliance by increased isometric-strength.

Analysis of Variance↗
PubMed1997

Molecular status of individual CFU-GM colonies derived from chemotherapy-mobilised peripheral blood stem cells in chronic myeloid leukaemia.

Following chemotherapy in chronic myeloid leukaemia (CML), some peripheral blood (PB) cells may be Philadelphia (Ph) chromosome negative. The BCR-ABL mRNA status of residual Ph+ progenitors is not known. We examined the BCR-ABL mRNA status of individual colony-forming-unit granulocyte-macrophage (CFU-GM) colonies derived from PB harvested following chemotherapy. Seven patients were treated with 200 mg/m2/day cytarabine and 20 mg/m2/day Idarubicin and followed by Lenograstim. PB collections commenced daily when the white blood cell count reached 0.6 x 10(9)/l and continued until at least 5 x 10(8)/kg nucleated cells were obtained. CD34+ cells, Ph status, and CFU-GM were estimated at each harvest. For each patient, up to 24 individual CFU-GM colonies were analysed for BCR-ABL status. Two cases were BCR-ABL negative on all colonies and completely Ph-, and another case was BCR-ABL positive in all colonies and completely Ph+. In contrast, in two patients all colonies were BCR-ABL negative, despite virtually complete Ph+ metaphases. The final assessible case had five of nine BCR-ABL negative colonies, despite 94% Ph+ metaphases. After chemotherapy priming, the PB may contain Ph+ CFU-GM that do not express BCR-ABL.

Antineoplastic Combined Chemotherapy Protocols↗